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Research We Fund

With hundreds of projects currently underway, we fund scientists through our academic grant programs and biotech partners through our strategic venture philanthropy initiative. Use the filters below to find an LLS-funded project.

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photo of Anushree Vichare

Anushree Vichare, PhD, MBBS

The George Washington University

Washington, District of Columbia
United States

Addressing Inequities in Access to Care for Patients with Hematologic Malignancy: Understanding the Impact of Telehealth Policies in Medicaid

Telehealth could improve access for Medicaid patients with a blood cancer who experience barriers to specialty care, but not all specialists offer it. Using Medicaid data, this study will provide novel information on whether blood cancer specialists are continuing to use telehealth following the COVID-19 pandemic when telehealth use increased dramatically. This study will also examine if telehealth helps address inequities in access to specialists, including for racial/ethnic minoritized groups and those living in rural areas.

Program: Equity in Access
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Basher

Fahmin Basher, MD, PhD

Duke University Medical Center

Durham, North Carolina
United States

The Role of the DNA Sensor AIM2 in B Cell Fate and Function After HCT

Altered B cell homeostasis plays a key role in the development of chronic graft-vs-host-disease (cGVHD) after hematopoietic stem cell transplantation (HCT). We hypothesize that the DNA sensor AIM2 plays a critical role in the fate of BCR-activated B cells after HCT. We will utilize novel mouse models to investigate AIM2-BCR modulation with clear translational implications in autoreactivity perpetuating cGVHD as well as functional humoral deficiency and vaccine hyporesponsiveness after HCT.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Manabu

Fujisawa Manabu, MD, PhD

BC Cancer


Canada

Spatial architecture and malignant cell characterization of nodular lymphocyte-predominant Hodgkin lymphoma

Nodular lymphocyte-predominant Hodgkin lymphoma is recognized as a disease entity in a spectrum of related diseases, including T-cell rich B-cell lymphoma. Although treatments are generally effective, a subset of patients suffers from lymphoma progression and aggressive disease transformations. Here, we propose to analyze clonal evolution of tumor cells and describe the spatial architecture of tissues with the goal to improve molecular classification and develop novel therapeutic approaches.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2026
Dr. Vick

Eric Vick, MD, PhD

University of Cincinnati

Cincinnati, Ohio
United States

Targeting Myeloid Malignancies through IRAK4 Synthetic Lethality Dependencies

Based on our preliminary data, we hypothesize that IRAK4 inhibition leads to LSPC reprogramming in MDS and AML. Aim 1 will evaluate the mechanism by which IRAK4 inhibition leads to LSPC reprogramming in cell lines, mice, and PDX samples. Aim 2 will concentrate on understanding of how IRAK4 inhibition creates synthetic lethal dependencies with the CELMoD CC-885 and how neosubstrates of CC-885 mediate the synergy upon IRAK4 inhibition in leukemic cells.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Wei

Manyi Wei, PhD

Yale

New Haven, Connecticut
United States

Harnessing METTL3 inhibition in acute megakaryoblastic leukemia driven by the t(1;22) fusion involving a member of the m6A writer complex

I want to understand how the t(1;22) translocation that involves a member of the m6A writer complex drives acute megakaryoblastic leukemia (AMKL). To identify culprit genes and pathways I will use multi-omics, including RNA, eCLIP, and TimeLapse Seq and proteomics. I will dissect the RBM15-MKL specific effects of a novel METTL3 inhibitor in primary murine and human AMKL in vitro and in vivo. My ultimate goal is to cure this rare infant leukemia by harnessing METTL3 inhibition.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2026
Dr. Young

Andrew Young, MD, PhD

Washington University in St. Louis


United States

Understanding How Hematopoietic Developmental State Determines Oncogenic KMT2A Fusion Formation and Leukemic Potential

My goal is to understand how cancer-associated gene fusions arise and cause disease. Specifically, I am studying how oncogenic fusions involving the gene KMT2A arise in different hematopoietic cell-types and how developmental context drives the development of leukemia. My long-term goals are to leverage an increased fundamental understanding of leukemogenesis provided by this research to improve treatment and lengthen lifespan for patients with KMT2A fusion-driven leukemias.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Vujovic

Ana Vujovic, PhD

University of Colorado Denver, Anschutz Medical Campus

Denver, Colorado
United States

Investigating the dependency for protein synthesis in Venetoclax/Azacitidine-resistant acute myeloid leukemia

Relapsed and/or refractory acute myeloid leukemia (AML) display resistance to Venetoclax and Azacitidine (Ven/Aza) with approximately one third of patients demonstrating upregulated protein synthesis. This proposal will investigate the mechanism(s) underlying the dependence of Ven/Aza-resistant AML on protein synthesis as well as the functional consequences of targeting this pathway. Successful completion of these studies will provide novel insights into Ven/Aza resistance mechanisms.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Kain

Bailee Kain, PhD

Cincinnati Children's Hospital

Cincinnati, Ohio
United States

Functionalizing novel PHIP variants in ancestry specific Acute Myeloid Leukemia

AML risk stratification established by previous studies do not reflect survival outcomes observed in Black patients. Exome sequencing of 100 Black AML patients revealed the novel variants previously not affiliated with AML, including PHIP. Using multiomic patient sample captures and GEMMs, we will functionalize variants in PHIP and assess if they drive leukemogenesis and/or therapy resistance. The overall goal of this work is to implement inclusive genetic assessment tools for AML diagnosis.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Biswas

Jeetayu Biswas, MD, PhD

Memorial Sloan Kettering Cancer Center

New York, New York
United States

Targeting SF3B1 splicing factor mutant myeloid malignancies through dependency on GPATCH8

Mutations in RNA splicing factors, particularly those involving the core splicing factor SF3B1 are amongst the most common mutations found in myeloid neoplasms. We recently identified a cofactor protein known as GPATCH8 which is required for the aberrant function of mutant SF3B1. We now seek to understand and target the ways in which GPATCH8 and SF3B1 interact. In so doing we hope to develop new treatments for leukemias containing mutant splicing factors.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Massoni-Badosa

Ramon Massoni-Badosa, PhD

Weill Cornell Medicine

New York, New York
United States

Uncovering MGA-driven epigenetic reprogramming in Richter's syndrome

Richter’s syndrome (RS) is a critical complication of chronic lymphocytic leukemia. RS patients are refractory to most existing therapies and show a median survival of ~12 months. I aim to dissect the function of a frequently mutated gene in RS (i.e., MGA) through cutting-edge single-cell analyses of patient samples and mouse models. The objective of these studies is to understand transformation biology, unravel novel therapeutic vulnerabilities, and provide the basis for personalized therapy.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Diefenbach

Catherine Diefenbach, MD

NYU Grossman School of Medicine

New York, New York
United States

T cell Memory in Cure of Diffuse Large B Cell Lymphoma: An Investigation of the Immune Interactome

While many patients with diffuse large B cell lymphoma (DLBCL) are cured with initial treatment, some patients relapse even after multiple therapies, and their outcomes are poor; we believe that the quality of the patient’s T cell memory plays a critical role in determining how they respond to treatment. To investigate, we will analyze the response pattern of circulating immune cells in cured and relapsed DLBCL patients, as well as the immune signals generated by the tumors, and create CAR T cells from the T cells with anti-tumor properties found in cured patients. We will evaluate the ability of these CAR T cells to fight lymphoma; if successful, our research can rapidly be translated into new immune therapies for patients with high risk or relapsed DLBCL.

Program: Translational Research Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Cerchietti

Leandro Cerchietti, MD

Weill Cornell Medicine

New York, New York
United States

Targeting the microenvironment to increase immunity and immunotherapy response in DLBCL

To survive and proliferate lymphoma cells must co-opt normal cells residing the tumor microenvironment. This process results in the suppression of the activity of immune cells that otherwise will attack cancer cells. In this project we will develop a novel oral treatment that by acting on the microenvironment will restore lymphoma immunity and increase the activity of immunotherapy.

Program: Translational Research Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Rubenstein

James Rubenstein, MD, PhD

University of California, San Francisco

San Francisco, California
United States

Towards Risk-Adapted Therapeutic Strategies in CNS Lymphoma

This project will significantly advance the treatment and prevention of CNS lymphomas in two key areas. One, we will further develop and validate candidate genomic biomarkers that identify high risk disease and that are useful in risk stratification in future clinical investigations in primary CNS lymphoma. Two, we will evaluate novel pharmacologic interventions that we hypothesize will: a) potentiate both the anti-lymphoma immune response, including agonists of the toll like receptor 7 and 8 pathway, as well as the combination of the anti-CD19 monoclonal antibody tafasitamab plus lenalidomide; and b) antagonize the NFkB pathway, via the orally-administered BTK degrader, Nx-5948, that we have demonstrated to be active in preclinical models using patient-derived CNS lymphomas.

Program: Translational Research Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Shortt

Jake Shortt, PhD

Monash University

Clayton, Victoria
Australia

Exploiting escape from Y-inactivation as a synthetic dependency in MYC-driven lymphoma

As a lymphoma develops it expresses genes that are normally silenced to convey a survival advantage. When these genes are on the X or Y (sex chromosomes) they may present a gender-specific therapeutic target. We have identified a gene (DDX3X in females or DDX3Y in males) that is reactivated in lymphomas such that the lymphomas cannot survive if this gene is removed. This project will develop new ways to inhibit DDX3X and Y as a novel treatment for poor-risk and aggressive lymphoma.

Program: Translational Research Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. DiPersio

John DiPersio, MD, PhD

Washington University in St. Louis

St. Louis, Washington
United States

KT1, a novel NK trispecific antibody for the treatment of AML and MDS

New treatments for AML and MDS are urgently needed. We have developed and performed preliminary testing of a novel, patent-protected, trispecific NK cell engager named KT1 which targets AML blasts and leukemia stem cells (LSCs) expressing CD33 and CD123 for elimination by effector cells that express CD16a/b. We plan to test the ability of KT1 to release cytokines and facilitate killing of CD33- and/or CD123-expressing targets by different types of CD16a/b-positive effector cell populations including resting natural killer (NK) cells, cytokine-induced memory-like (ML) NK cells, gamma/delta T cells, and macrophages both in vitro and in leukemic mice. We anticipate that a future treatment of AML and/or MDS with KT1 combined with a donor leukocyte transfer of allogeneic NK, ML NK, or gamma/delta T cells will have excellent therapeutic efficacy and a far better safety profile than many currently studied immunotherapies being tested in patients with AML or MDS.

Program: Translational Research Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Carter

Bing Carter, PhD

MD Anderson Cancer Center

Houston, Texas
United States

Targeting TP53-Y220C mutant AML

TP53-Y220C is a recurrent hotspot TP53 mutation observed predominantly in AML and MDS among hematological malignancies. This study aims to investigate the mechanism of action and therapeutic activity of PC14586, a compound designed to bind p53-Y220C protein and stabilize it in the wild-type conformation and to develop mechanism-based combinations that improve its efficacy in TP53-Y220C mutant AML.

Program: Translational Research Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Takahashi

Koichi Takahashi, MD

The University of Texas MD Anderson Cancer Center

Houston, Texas
United States

Targeting Leukemia Stem Cells with the Novel Antibody Drug Conjugate

To improve the cure rate of patients suffering from acute myeloid leukemia (AML), our study aims to target resistant leukemia stem cells by developing an 'antibody-drug conjugate' (ADC) against CD99, a protein expressed on these cells. Initial tests of two ADC versions have shown promise in combating AML. Our next steps involve refining the anti-CD99 antibody, identifying the optimal drug for conjugation, and testing the ADC on patient-derived leukemia models. Completing these objectives will pave the way for a phase 1 clinical trial, offering a potentially transformative treatment for AML.

Program: Translational Research Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Daley

George Daley, MD, PhD

Boston Children's Hospital

Boston, Massachusetts
United States

Pluripotent Stem Cell-derived CAR-T and CAR-NK Cells for Immunotherapy of Leukemia and Lymphoma

Cytotoxic cells of the immune system, including T and NK cells, can be targeted to seek out and destroy leukemia, lymphoma and myeloma cells by engineering them to express chimeric antigen receptors (CARs) which empower the cell to home to and kill the cancer cells. Typically, such CAR-T and CAR-NK cells are generated from a patient's own blood, but sometimes heavy pre-treatment with chemotherapy leaves inadequate supplies of T and NK cells. We propose to generate T and NK cells from Pluripotent Stem Cells, which through genetic manipulation can be rendered suitable for treating any patient with an "off-the-shelf" cell product, hence facilitating otherwise cumbersome, labor-intensive, and expensive patient-specific cell therapies.

Program: Translational Research Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Vannini

Nicola Vannini, PhD

Universite de Lausanne

Écublens
Switzerland

Mitochondrial reprogramming to restore age-driven dysfunction in T cell and boost CAR-T cell therapy

In the Cancer Immunology field, the “aging” variable has not been investigated profoundly yet, even though aging is the first factor associated to cancer. This represents a major limitation on the significance of the experimental results and their translation to the clinic. We believe that with our proposal we can shade light on important biological processes which drive immunotherapy failure. We have shown that T cell function is dependent not only on the differentiation state but also on their biological age. Thus, taking in consideration aging and the age-driven metabolic defects in T cells will help to better understand their biology and develop better strategies to boost immunotherapy.

Program: Translational Research Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Janz

Siegfried Janz, MD

Medical College of Wisconsin

Wauwatosa, Wisconsin
United States

Improving outcomes of multiple myeloma using TGF-beta resistant BCMA-targeted CAR T cells

Immunotherapy using chimeric antigen receptor (CAR) T cells, or CARTs for short, holds great promise for improving outcomes and survival of patients with relapsed and/or refractory multiple myeloma (RRMM). Next-generation “armored” CARTs that can overcome transforming growth factor beta (TGF-beta) dependent immune suppression in the tumor microenvironment may provide deeper and more durable disease control than the TGF-beta sensitive CART products currently in clinical use.

Program: Translational Research Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Croucher

Peter Croucher, PhD

Garvan Institute of Medical Research

Darlinghurst
Australia

Targeting the Osteogenic Lineage as a Therapeutic Strategy in Multiple Myeloma

Multiple myeloma causes devastating bone disease characterised by focal bone lesions and generalise bone loss, which leads to an increase in bone fractures. Current therapies only stop bones from getting worse so patients continue to suffer fractures. We discovered that inhibiting a molecule called sclerostin in mice increases bone and is much better than current treatments. In this program we will investigate whether inhibiting sclerostin is able to restore lost bone and reduce fractures in patients with myeloma.

Program: Translational Research Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Beavis

Paul Beavis, PhD

The University of Melbourne

Melbourne
Australia

Enhancing the “fitness” of anti-BCMA CAR T cells for improved efficacy in multiple myeloma

Chimeric antigen receptor (CAR) T cell therapy is a form of immune-based therapy where a patient’s own immune cells are genetically engineered to recognize and kill the tumor cells. This therapy has revolutionized the treatment of certain blood cancers and excitingly, two CAR T cell products were recently approved for the treatment of multiple myeloma.

Despite impressive initial clinical data showing responses in 73-98% of patients, most patients still relapse after CAR-T cell therapy within 3 years. Therefore, there is a significant unmet need to further enhance the effectiveness of CAR T cell therapy in this disease. In this project we will investigate whether an approach we have shown to make CAR T cells “fitter” and more effective in solid tumors is also effective in the context of multiple myeloma.

Program: Translational Research Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Khandelwal

Pooja Khandelwal, MD

Cincinnati Children’s Hospital Medical Center

Cincinnati, Ohio
United States

A randomized clinical trial of oral vitamin A to reduce chronic graft versus host disease in BMT

Vitamin A is safe, well tolerated and positively affects gut immune health. Graft versus host disease (GVHD) is a life-threatening complication of bone marrow transplant (BMT) which happens due to inflammatory changes in the gut. We harnessed the anti-inflammatory properties of vitamin A by giving it to children before bone marrow transplant (BMT) and showed reduction in acute gut and moderate/severe chronic GVHD. We will validate our findings in this currently proposed study of an independent group of adult BMT patients. We will give vitamin A or placebo before BMT to adult BMT patients and observe for reduction of chronic GVHD in vitamin A recipients compared to placebo. This study will be a step forward in adoption of vitamin A as a universal strategy to prevent GVHD which is affordable ($1.25 for entire treatment), non-toxic, and doesn’t suppress the immune system.

Program: Academic Clinical Trials Program (ACT)
Project Term: Start Date: October 1, 2024 End Date: September 30, 2027
Dr. Rouce

Rayne Rouce, MD

Baylor College of Medicine

Houston, Texas
United States

Novel CD7 CAR T-cells for refractory T-cell malignancies affecting pediatric and AYA patients

T-cell leukemias and lymphomas have devastating outcomes if they recur after or don’t respond to standard treatment, with the only hope of cure being bone marrow transplant (BMT). Unfortunately, many pediatric, adolescent and young adult (AYA) patients are unable to achieve clinical remission (and thus unable to proceed to BMT) with standard salvage therapies, which are often even more toxic than upfront therapies. Available treatment options for patients with relapsed or refractory T-cell malignancies (particularly pediatric and AYA patients) are lacking, thus 3-year survival rates are <15% for these patients. This proposal aims to study a less toxic, targeted approach using patient or donor-derived T-cells engineered to target an antigen expressed on over 90% of T-cell malignancies that affect pediatric and AYA patients (CD7 Chimeric Antigen Receptor T-cells).

Program: Academic Clinical Trials Program (ACT)
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Lee

Yoke Seng Lee, PhD

The Brigham and Women’s Hospital

Boston, Massachusetts
United States

Cotargeting oncogenic protein translation and apoptosis in acute myeloid leukemia

The focus of my research is to evaluate the efficacy of and to unravel the molecular mechanisms underpinning a novel drug combination in AML targeting oncogenic protein translation and apoptosis. We will utilize genetic perturbation and other orthogonal approaches, including in vitro and ex vivo assays, and in vivo AML PDX models. The goal of my research is to transform the clinical management of AML patients, particularly for relapsed and difficult-to-treat subgroups.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2026
Dr. Chen

Bingyi Chen, PhD

Memorial Sloan Kettering Cancer Center

New York, New York
United States

Targeting the cell surface U5 snRNP complex as a novel immunotherapy for AML

A major limitation of immunotherapy approaches for AML has been the lack of known targetable cell surface antigens specific to AML cells. This project characterizes the pathologic and biologic effects of a novel cell surface antigen complex uniquely present on AML cells but not normal hematopoietic precursors, known as the U5 snRNP complex. Furthermore, we will interrogates U5 snRNP complex components as novel AML-associated antigens and CAR T cells targets for AML treatment.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Odak

Ivan Odak, PhD

Icahn School of Medicine at Mount Sinai

New York, New York
United States

Prevention of antigen escape by modulation of off-target tumor killing in T cells

T-cell mediated therapies are all impeded by the same cause- tumoral antigen (Ag) escape: rare Ag– cells in tumors survive the initial attack and lead to relapse. We recently took an innovative approach by enhancing T cells' ability to attack the Ag- cells during the initial treatment. That process is modular by pharmaceutical intervention.

The proposed project will analyze cryopreserved excisional B-NHL biopsies to identify possible pharmaceutical targets potentiating their 'vulnerability’.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2026
Dr. Kumar

Anita Kumar, MD

Memorial Sloan Kettering Cancer Center

New York, New York
United States

Novel Immunotherapy Combinations in Relapsed, Refractory Mantle Cell Lymphoma

We are evaluating two parallel clinical trials with synergistic immunotherapies in mantle cell lymphoma (MCL), including 1) tafasitamab and lenalidomide and 2) glofitamab and lenalidomide. We will investigate how these treatments impact the MCL immune microenvironment and mediate anti-tumor immune responses, and will correlate these changes with outcome.

Our goal is to develop safe, effective, and "off-the-shelf" immunotherapies to improve outcomes for patients with relapsed, refractory MCL.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2029
Dr. Cruz-Rodriguez

Nataly Cruz-Rodriguez, PhD

Versiti Blood Center of Wisconsin

Milwaukee, Wisconsin
United States

Understanding the role of Metabolic Regulator SIRT5 in Acute Lymphoblastic Leukemia

SIRT5 is a master regulator of central energy metabolism. The survival and growth of Acute Myeloid Leukemia (AML) cells depend on SIRT5. I will employ genetic SIRT5 disruption and small molecule inhibitors to target SIRT5 in Acute Lymphoblastic Leukemia (ALL) cells and primary samples. This study aims to 1) determine the effects of SIRT5 inhibition on ALL in vitro and in vivo, and 2) identify SIRT5-regulated pathways and mechanisms underlying SIRT5 dependency in T-ALL.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2026
Dr. Takeda

Reina Takeda, MD, PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Mechanisms of oncogenic transcription in NPM1-mutant myeloid leukemia

NPM1-mutated leukemia is the most common AML in adult and characterized by upregulations of HOXA/B genes and MEIS1. Given the importance of oncogenic transcriptional program, I will determine regulatory molecules that cooperate with mutant NPM1 on chromatin by combining CRISPR/Cas9 screening approach in an innovative model system of endogenous transcription reporters with proteomics approach. This will facilitate identification of novel therapeutic targets specific for NPM1-mutated AML.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2026
Dr. Sundaravel

Sriram Sundaravel, PhD

Albert Einstein College of Medicine

Bronx, New York
United States

Glycotyping as a novel approach to study leukemia stem cell heterogeneity and function

Leukemia stem cells (LSCs) are highly heterogeneous populations and key contributors to AML progression. Here, I aim to employ heparan sulfate (HS) glycotyping to resolve LSC heterogeneity. Using complementary genetic and antibody-based approaches, I will delineate the functional roles of HS pathway during AML progression. The newer insights provided by these studies could potentially uncover novel LSC therapies and facilitate diverse training for me to become an independent leukemia researcher.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2026
Dr. Goyal

Gaurav Goyal, MD

The University of Alabama at Birmingham

Birmingham, Alabama
United States

Patient-Reported Outcomes and Survivorship in Histiocytic Neoplasms

Advances in the treatment of Langerhans cell histiocytosis and Erdheim-Chester disease have led to a growing survivor population; however, there is a lack of information regarding the long-term outcomes, healthcare needs, and health-related quality of life in the era of targeted therapies. We propose the creation of a large national cohort of survivors with histiocytosis to address unanswered questions, eventually leading to targeted survivorship programs for this vulnerable population.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2029
Dr. Cieri

Nicoletta Cieri, MD, PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

TCR-like CARs targeting GvL mHAgs for the treatment of post-transplant AML relapse

AML recurrence is a devastating event after allo-HCT. I hypothesize that it could be counteracted through targeting of leukemia-restricted mHAgs via TCR-like CARs. I will identify scFVs recognizing mHAg:HLA complexes using a cell-free nanobody screening platform, and test the anti-leukemia activity and safety of CAR-Ts bearing such scFVs in vitro and in vivo. Through this approach, I will build a library of CAR constructs able to provide population-scale coverage for at-risk allo-HCT patients.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2026
Dr. Laurent

Anouchka Laurent, PhD

Columbia University Irving Medical Center

New York, New York
United States

Role of ID2 in mature T-cell lymphoma

Overexpression of ID2 is a recurrent event in mature T-cell lymphoma (TCL), and its significance is yet to be established. We will use a multidisciplinary approach combining epigenetic, transcriptomic, and proteomic analysis in human and murine models to identify the mechanisms leading to ID2 overexpression and their effect on T-cell transformation. Our goal is to define the role of ID2 in lymphomagenesis and determine its potential as a novel therapeutic target in TCL.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2026
Dr. Mailankody

Sham Mailankody, MBBS

Memorial Sloan Kettering Cancer Center

New York, New York
United States

Improving outcomes with immune therapies for multiple myeloma

The primary focus of research is to better understand mechanisms of resistance to immunotherapies and design treatment approaches to improve outcomes. I hope to accomplish this by conducting clinical trials that concurrently target both BCMA and GPRC5D in patients with advanced multiple myeloma and by studying antigen expression, tumor genetics, and T cell characteristics to better understand mechanisms of resistance. The goal is to develop more effective immune treatments for myeloma.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2029
Dr. Reagan

Michaela Reagan, PhD

Maine Medical Center

Scarborough, Maine
United States

Multiple Myeloma Support from the Microenvironment: Bone Marrow Adipocytes and the Fatty Acid Binding Proteins

Our project’s goal is to change how multiple myeloma is understood and treated by interrogating a novel part of the cellular “soil” (the bone marrow adipocyte), in which myeloma cells, or “seeds”, land and grow. We will discover new forms of cancer drug resistance that are driven by adipocyte-derived factors and the fatty acid binding proteins. This work will expose new ways to overcome drug resistance to improve survival and quality of life for myeloma and other hematological cancer patients.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2029
Dr. Li

Sheng Li, PhD

University of Southern California

Los Angeles, California
United States

Epigenetic heterogeneity in age-related clonal hematopoiesis and acute myeloid leukemia

Our focus is to unravel how clonal hematopoiesis (CH) progresses to leukemia. We will investigate how epigenetic heterogeneity affects Tet2-mutant hematopoietic stem cells (HSCs) during aging. We plan to simultaneously trace HSC clonal identity and clonal history by genetic barcode and single-cell multi-omics and determine their epigenetic configurations adaptive in the aged, inflammatory bone marrow. The long-term goal is to create innovative therapeutics to mitigate CH and prolong health span.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2029
Lev Kats

Lev Kats, PhD

The University of Melbourne

Parkville, Victoria
Australia

Novel targeted therapies for acute myeloid leukaemia and multiple myeloma

Outcomes for acute myeloid leukemia (AML) and multiple myeloma (MM) patients remain inadequate and new treatment options to combat resistance against existing agents are urgently needed. My research aims to identify and target selective vulnerabilities of AML and MM cells. I am particularly interested in epigenetic and metabolic pathways that control self-renewal and differentiation of hematopoietic cells and that can be leveraged to modulate cell fate for therapeutic benefit.

Program: Career Development Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2029
Dr. Zhan

Fenghuang Zhan, MD, PhD

University of Arkansas for Medical Sciences

Little Rock, Arkansas
United States

Toward improvement of BCMA/CST6-CAR-T therapy to target both myeloma cells and bone resorption

We have observed that non-glycosylated CST6 proteins suppress osteoclast differentiation and function without causing immunosuppression. We aim to determine whether BCMA-CAR-T cells which are engineered to secret CST6 proteins kill myeloma cells and suppress bone lytic lesions without immune suppressive effects in myeloma. Our ultimate goal is to develop a CAR-T-cell based immune therapy to prevent bone loss and disease progression in myeloma patients.

Program: Translational Research Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Alfred Garfall

Alfred Garfall, MD

Perelman School of Medicine at the University of Pennsylvania

Philadelphia, Pennsylvania
United States

Limited-duration bispecific antibody therapy for multiple myeloma

Bispecific antibodies are a new, highly effective immunotherapy for multiple myeloma. Most bispecific antibody therapies have been tested as continuous therapies in which patients continue receiving the treatment until the myeloma starts growing again. Preliminary results suggest that patients with good responses may be able to stop therapy and enjoy a period of time off-therapy with close observation, which may limit long term toxicities caused by continuous therapy. We propose a clinical trial to test this limited-duration approach with recently approved bispecific antibodies for multiple myeloma.

Program: Academic Clinical Trials Program (ACT)
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Park

Steven Park, MD

Atrium Health Foundation

Charlotte, North Carolina
United States

Next-Generation Targeted Therapy in Mantle Cell Lymphoma and Transformed Follicular Lymphoma

Program: Translational Research Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Murakami

Mark Murakami, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Exploiting tumor-immune dynamics to inform curative combination therapy for follicular lymphoma

Follicular lymphoma is a common form of blood cancer, affecting 15,000 new patients annually in the United States, but it remains incurable with conventional treatments. Bispecific antibodies represent a new class of therapies that engage the immune system to attack lymphoma cells and have shown promising effectiveness in inducing remissions in patients with this disease, but even they are unlikely to be curative. Researchers from the Dana-Farber Cancer Institute here propose to analyze lymphoma cells from patients undergoing treatment with bispecific antibodies on several complementary clinical trials to determine how these cells evade the immune system and develop resistance. It is believed that such mechanisms of resistance may reveal vulnerabilities within the lymphoma cells that novel treatments can overcome in combination with bispecific antibodies to cure patients with follicular lymphoma.

Program: Translational Research Program
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Dr. Armand

Philippe Armand, PhD, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Bispecific antibody-based frontline therapy for follicular lymphoma

We are conducting a clinical trial testing a novel form of immunotherapy, called a bispecific antibody, as part of initial treatment for patients with follicular lymphoma. The goal of the trial is two-fold: 1) to establish a highly effective, chemotherapy-free treatment option for patients with follicular lymphoma, and 2) to establish predictors of response and toxicity that can guide treatment decisions for future patients with follicular lymphoma.

Program: Academic Clinical Trials Program (ACT)
Project Term: Start Date: July 1, 2024 End Date: June 30, 2027
Ryvu

Ryvu Therapeutics, SA

TAP Partner

Krakow
Poland

A phase 2 study of RVU120, a novel CDK8 inhibitor, in combination with venetoclax in patients with AML

In August 2017, LLS TAP partnered with Ryvu Therapeutics (formerly known as Selvita) to support "A Phase Ib Study of SEL120 in Patients With Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome."

Ryvu Therapeutics is a clinical-stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology using a proprietary discovery engine platform.

RVU120 (SEL120) is a highly selective first-in-class CDK8/CDK19 small molecule inhibitor. Ryvu is currently enrolling several Phase 2 clinical trials, RVU120 as monotherapy in genetically defined cohorts of patients with relapsed/refractory AML and high-risk myelodysplastic syndromes (RIVER-52, NCT06268574), and RVU120 in combination with venetoclax for patients with relapsed/ refractory AML (RIVER-81, NCT06191263).

Program: Therapy Acceleration Program
Project Term: Start Date: August 7, 2017 End Date: July 24, 2024
George Vassiliou

George Vassiliou, MBBS, PhD

University of Cambridge

Cambridge
United Kingdom

Development of a clinical program for myeloid cancer prevention

The majority of myeloid cancers remain incurable. We previously showed that individuals at risk can be identified years in advance, indicating that prevention may be a viable alternative to treatment. Here, we propose a program of work to establish a clinical platform for myeloid cancer prevention. This includes development of a screening strategy, improved understanding of myeloid cancer evolution, identification of treatment targets and establishment of a specialized clinic to deliver therapy.

Program: Specialized Center of Research Program
Project Term: Start Date: February 1, 2024 End Date: January 31, 2029
Kymera

Kymera Therapeutics, INC

TAP Partner

Watertown, Massachusetts
United States

A phase 1 study of KT-253, a MDM2 protein degrader, in patients with AML

In March 2020, LLS made an equity investment in Kymera Therapeutics to "Support Studies with Protein Degraders for Development in Hematological Patients."

Kymera Therapeutics is a clinical-stage biopharmaceutical company founded with the mission to discover, develop, and commercialize transformative therapies while leading the evolution of targeted protein degradation, a transformative new approach to address previously intractable disease targets. Whereas most targeted therapies inhibit or inactivate the proteins or genes that drive the cancer, targeted protein degradation harnesses the body’s natural system of ridding itself of unwanted, “old” or “broken” components of cells.

KT-253 is a MDM2 protein degrader and is enrolling AML patients in a Phase 1 clinical trial (NCT05775406).

Program: Therapy Acceleration Program
Project Term: Start Date: March 11, 2020 End Date: July 24, 2024
Dr. Butterworth

Sam Butterworth, PhD

University of Manchester

Manchester
United Kingdom

Development of peptide-drug conjugates for the treatment of Chronic Myelomonocytic Leukaemia (CMML)

We are aiming to bring a new treatment option to patients with chronic myelomonocytic leukemia (CMML) by utilising CCL2-drug conjugates that specifically target and eliminate cancerous cells. Our leading conjugate shows potent and selective efficacy in killing CMML cells. The proposed work will help us understand how this drug works, which patients are most likely to benefit and how it can be combined with current treatments to achieve the greatest patient benefit.

Program: CMML Initiative
Project Term: Start Date: November 1, 2023 End Date: October 31, 2026
Ravindra Majeti

Ravindra Majeti, PhD, MD

Stanford

Palo Alto, California
United States

Targeting the inflammatory GM-CSF pathway in high risk CMML

Chronic myelomonocytic leukemia (CMML) is a rare but poorly understood blood cancer often presenting with crippling inflammatory symptoms that frequently evolves into acute leukemia. In an ongoing clinical trial, we have compelling molecular and clinical data that this disease responds effectively to blockade of GM-CSF with lenzulimab, a well-tolerated and safe antibody, in combination with azacitidine. Here, we propose an integrated research program to investigate targeting of the GM-CSF pathway in high risk CMML using our carefully matched patient samples, proprietary GM-CSF tools, and humanized in vivo CMML models.

Program: CMML Initiative
Project Term: Start Date: November 1, 2023 End Date: October 31, 2028
Dr. Stieglitz

Elliot Stieglitz, MD

University of California, San Francisco

San Francisco, California
United States

CLL-1 CAR-T cells and trametinib for the treatment of Ras-mutated CMML and JMML

We hypothesize that demonstrating activity of CLL-1 CAR-T (CLL1CART) cell therapy with or without trametinib in pre-clinical models of chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) is the most efficient method to bring cellular therapy to patients with these orphan diseases. In Aim 1, we will determine the in vitro and vivo efficacy of CAR-T cells redirected against CLL-1 using patient-derived xenograft (PDX) models of CMML and JMML. In Aim 2, we will evaluate the role of combining trametinib with CLL1CART cells. Based on our preliminary data, we hypothesize that trametinib will have direct antileukemia activity and will increase the efficacy of CLL1CART by decreasing T-cell exhaustion and augmenting T-cell fitness.

Program: CMML Initiative
Project Term: Start Date: November 1, 2023 End Date: October 31, 2026
Dr. Padron

Eric Padron, MD

Moffitt Cancer Center

Tampa, Florida
United States

Advancing the therapeutic landscape for Chronic Myelomonocytic Leukemia (CMML)

CMML is a universally lethal blood cancer characterized by increased monocytes (a type of white blood cell) in the peripheral blood and abnormal appearing cells within the bone marrow. Most CMML patients are clinically asymptomatic and remain so for weeks to months following diagnosis, with disease progression remaining inevitable. Despite therapeutic advances in similar blood cancers, no specific molecularly targeted therapies currently exist to treat CMML. Our team aims to identify new therapies and repurpose existing therapies to address the emergent unmet need for new treatments that meaningfully improve, and extend, the lives of patients with CMML.

Program: CMML Initiative
Project Term: Start Date: November 1, 2023 End Date: October 31, 2027
Dr. Salman

Huda Salman, MD

Indiana University

Indianapolis, Indiana
United States

Development of cellular therapy for CMML and the Immune landscape of response and resistance

We will test the efficacy of CAR T cell therapy for CMML. We will modify the tumor microenvironment to enhance their efficacy. and we will upscale CAR T cells to the next level in terms of their genetic structure.

Program: CMML Initiative
Project Term: Start Date: November 1, 2023 End Date: October 31, 2028
Dr. Verma

Amit Verma, MBBS

Albert Einstein College of Medicine

Bronx, New York
United States

Targeting the inflammasome in CMML

Overactivation of the inflammasome is seen in CMML and leads to worsening of this condition. We will explore the potential of a new inflammasome inhibitor drug, HT-6184, in CMML patient samples and in animal models. Our preliminary results show that this drug can decrease inflammation and improve red cell development in CMML models. The new drug is approved for clinical trial use and our work will potentially lead to its use in clinical investigations in CMML.

  

Program: CMML Initiative
Project Term: Start Date: November 1, 2023 End Date: October 31, 2026
Jennifer Lewis

Jennifer Lewis

Memorial Sloan Kettering Cancer Center

New York, New York
United States

Development of Immunotherapy Targeting U5 snRNP200 for the Treatment of Hematologic Malignancies

The therapeutic landscape of acute myeloid leukemia (AML) has witnessed considerable expansion following recent U.S. FDA endorsements of novel therapies; however, the 5-year survival rate for most adult patients remains below 10%. The absence of immunotherapeutic options for AML can be attributed, in part, to the dearth of identified antigens that selectively discriminate between AML cells and normal hematopoietic precursor cells. Through extensive investigative efforts, our laboratory has made a significant discovery of a membrane antigen, U5 snRNP200, which exhibits promising potential for Fc-engineered anti-U5 snRNP200 therapy. The overarching objective of this endeavor is to engender a novel cellular immunotherapeutic modality with the potential for broad therapeutic impact across a diverse spectrum of myeloid and lymphoid hematologic malignancies.

Program: Underrepresented Minority Medical Student Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2024
Dr. Hunter

Zachary Hunter, PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Characterization of Isoform Usage, Novel Isoforms, and Tumor Evolution in Waldenström's Macroglobulinemia

The goals of this project can best be summarized with the following specific aims:

  1. To identify and functionally characterize novel isoforms and isoform dysregulation in Waldenstrom’s Macroglobulinemia;
  2. To investigate the mechanisms that underlie a novel form of post-transcriptional gene regulation in healthy donor B-cells that is absent in patients with Waldenstrom’s Macroglobulinemia;
  3. To conduct a multi-omic analysis of tumor evolution in Waldenstrom’s Macroglobulinemia by disease subtype
Program: Special Grants
Project Term: Start Date: July 1, 2023 End Date: June 30, 2024
Vittoria

Vittoria Biotherapeutics, INC

TAP Partner

Philadelphia, Pennsylvania
United States

A phase 1 study of VIPER-101, a CD5-edited dual population chimeric antigen receptor cell therapy, to enhance immunotherapy against T-cell non-Hodgkin lymphoma

In October 2023, LLS made an equity investment in Vittoria to "Support Clinical Development of VIPER-101, a CAR-T Cell Therapy for T-cell lymphomas."

Vittoria Biotherapeutics is developing novel CAR-T cell therapies that transcend the limitations of current cell therapies. Based on technology exclusively licensed from the University of Pennsylvania, Vittoria's proprietary Senza5 platform unlocks the antitumor potential of engineered T cells and utilizes a five-day manufacturing process to maximize stemness, durability, and target cell cytotoxicity. By acting on the fundamental biology of T cells, Senza5 can be used to improve the efficacy of engineered T cell therapies with pipeline applications in oncology and autoimmune diseases.

Vittoria aims to conduct a Phase 1 dose escalation clinical trial for its lead program VIPER-101, an autologous, dual population CD5-knockout CAR-T cell therapy for T-cell Lymphoma featuring the novel Senza5 platform technology. The Phase 1 dose escalation clinical trial is expected to begin soon. Several other products are in earlier preclinical development.

Program: Therapy Acceleration Program
Project Term: Start Date: October 31, 2023 End Date: July 24, 2024
Dr. Goldfinger

Mendel Goldfinger, MD

Montefiore Medical Center

Bronx, New York
United States

Metabolically Optimized, Non-cytotoxic Low Dose Weekly Decitabine/Venetoclax in MDS and AML

Dr. Mendel Goldfinger and collaborators of Einstein have shown in a preliminary trial that weekly low dose decitabine plus one a week venetoclax is highly effective in newly diagnosed patients with MDS or AML. The regimen has reduced toxicity compared to the current dose and schedule of azacitidine plus venetoclax. The proposed new work is attempting to demonstrate in a prospective trial at 3 sites that this data can be replicated and expanded.

Program: Special Grants
Project Term: Start Date: October 1, 2023 End Date: September 30, 2024
Dr. Cohen

Jonathon Cohen, MD

Emory University

Atlanta, Georgia
United States

Making an IMPACT on hematology care in Georgia: The Georgia Blood Cancer Trials Network (BCTN)

Winship Cancer Institute is the only NCI-Designated Comprehensive Cancer Center in Georgia, the largest state by land area east of the Mississippi River, and 8th largest state by population. The Winship IMPACT program will leverage existing relationships throughout the state to bring hematology trials to patients in their communities. The goals are to strengthen our relationship with community sites and to increase opportunities for patients to access cutting edge trials throughout our state.

Program: IMPACT
Project Term: Start Date: October 1, 2023 End Date: September 30, 2028
dr. Fehniger

Todd Fehniger, MD PhD

Washington University in St. Louis

St. Louis, Washington
United States

Developing Novel Immunotherapies for Challenging Lymphomas

This team science program from Washington University will develop new immunotherapy treatments for patients with hard to treat or incurable lymphomas. The team includes physicians and scientists who have developed new ideas in the laboratory for immune-based treatment, and will translate these to clinical trial testing. These include engineered natural kill cells, healthy donors T cell engineered to attack a T cell lymphoma, and lymphoma-patient specific mutations as vaccine targets.

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2023 End Date: September 30, 2028
Dr. Jordan

Craig Jordan, PhD

University of Colorado Denver, Anschutz Medical Campus

Aurora, Colorado
United States

Therapeutic targeting of AML stem cells 2023

The goal of this SCOR project is to identify and eradicate the root cause of acute myeloid leukemia, the so-called leukemia stem cell (LSC). In the previous cycle of this SCOR grant, we developed two unique strategies, each of which efficiently eradicates LSCs in the laboratory. Going forward, we will expand our scientific efforts to further improve these approaches and also conduct clinical trials to determine whether our approaches to killing LSCs will benefit AML patients.

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2023 End Date: September 30, 2028
Dr. Ito

Keisuke Ito, PhD, MD

Albert Einstein College of Medicine

Bronx, New York
United States

Dissecting the mitochondrial alterations by aberrant NPM1 to the pathogenesis of myelodysplastic syndrome

Survival rates for those afflicted with MDS have not improved despite extensive effort to identify the key genetic events in its pathogenesis. This project elucidates the contributions of aberrant NPM1 to hematological disorders, with a focus on mitochondrial fitness and inflammasome activation. The resulting insights into the metabolic, genetic and proteomic requirements of homeostasis that are critical to preventing aging will have a major impact on the treatment of hematological malignancies.

Program: Discovery
Project Term: Start Date: October 1, 2023 End Date: September 30, 2026
Dr. Hormoz

Sahand Hormoz, PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Predicting progression in myeloproliferative neoplasm patients by reconstructing the history of disease in each patient

Blood cancers called myeloproliferative neoplasms occur when one of the blood stem cells picks up a mutation. Some patients stay in the chronic phase of the disease for years whereas others rapidly progress with poor outcome. We recently measured when the cancer mutation first occurs and the rate of expansion of the cancer cells in individual patients. We will develop a method that uses the history of disease in each patient to identify those that are at risk of progression.

Program: Discovery
Project Term: Start Date: October 1, 2023 End Date: September 30, 2026
Dr. Dalla-Favera

Riccardo Dalla-Favera, MD

Columbia University Medical Center

New York, New York
United States

Genomics of Diffuse Large B Cell Lymphoma: pervasive role of super-enhancer hypermutation in dysregulating oncogene expression

We recently identified a pervasive, pathogenically relevant mutational mechanism that targets super-enhancers (SE) in DLBCL, leading to target gene deregulation. Here we will dissect the mechanistic role of 3 highly recurrent hotspots in the BCL6, BTG2 and CXCR4 SEs in driving lymphomagenesis and tumor dependency in vitro and in vivo using novel mouse models. These studies will significantly transform our understanding of DLBCL and identify novel therapeutic targets.

Program: Discovery
Project Term: Start Date: October 1, 2023 End Date: September 30, 2026
Dr. Konopleva

Marina Konopleva, MD, PhD

Albert Einstein College of Medicine

Bronx, New York
United States

Targeting metabolic reprogramming in MDS and AML stem/progenitor cells

Myelodysplastic neoplasms are malignant disorders driven by expansion of diseased hematopoietic stem cells and progression to leukemia. Our investigations have identified the important role of the transporter of amino acid glutamine SLC38A1 in sustaining metabolic demands of rapidly growing malignant stem cells. The goal of this project is to genetically target this transporter to understand its role on tumorigenesis and progression; and to develop SLC38A1 inhibitors as novel therapeutic tools.

Program: Discovery
Project Term: Start Date: October 1, 2023 End Date: September 30, 2026
Dr. Boise

Lawrence Boise, PhD

Emory University

Atlanta, Georgia
United States

Functional dissection of heterogeneity of responses to CAR T cells using Spatiotemporal Image-guided Genomic and Cellular Analysis (SaGA) in myeloma

Despite remarkable progress in the last 20 years, multiple myeloma remains an incurable disease. In recent years, 2 CAR T cell products that target BCMA on the myeloma cell have been approved. These products result in remarkable initial responses however the duration of these responses has been disappointing. In this proposal, we will take a novel approach to isolate and characterize myeloma cells that interact with CAR T cells but are not killed by them as a potential resistance mechanism.

Program: Discovery
Project Term: Start Date: October 1, 2023 End Date: September 30, 2026
Dr. Tao

Jianguo Tao, MD PhD

University of Virginia

Charlottesville, Virginia
United States

Understanding Resistance Mechanism to Enhance CAR-T Immunotherapy for MCL

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by resistance to standard treatments and short survival. For the 2023 LLS MCLII Synergistic Team Award, we have assembled a team of leaders in basic, translational, and clinical research in MCL to tackle the current significant obstacles in understanding and treating MCL. In the last decade, we investigated the therapy resistance mechanism of MCL, and pioneered clinical trials for targeted therapies (ibrutinib, lenalidomide) and chimeric antigen receptor T-cell (CAR-T) therapy. However, despite these dramatic advancements, resistance to these newer therapies, including targeted therapy and CAR-T cells, is seen in over 50% of patients. Thus, it remains an unmet need to better define the mechanisms of resistance and then develop rationally designed strategies to overcome resistance. The overall goal of this Synergistic Team Award is to develop improved curative therapies for patients with MCL at relapse. The goals will be addressed in three highly focused, independent but highly integrated projects that utilize state-of-the-art genomic technologies, patient-derived xenograft models, clinical data and primary MCL samples. With the joint effort of our laboratories, highly interactive and accomplished scientists, and physician researchers from multiple institutions with expertise in MCL and therapy, we are uniquely poised to develop improved next-generation of combination therapy for relapsed MCL patients.

Program: Mantle Cell Lymphoma Research Initiative
Project Term: Start Date: July 1, 2023 End Date: June 30, 2027
Madhav Dhodapkar

Madhav Dhodapkar, MBBS

Emory University

Atlanta, Georgia
United States

Pilot trial of microbial targeting to prevent myeloma

Our recent studies have identified specific bacteria that can potentially promote the growth of human myeloma tumor cells. We are now testing if eradicating these bacteria in MGUS patients will be effective for prevention of myeloma.

Program: Academic Clinical Trials Program (ACT)
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Dreyling

Martin Dreyling, MD

Ludwig Maximilian University of Munich

Munich
Germany

MULTIlayer Predictive models for relapsed MCL after ibrutinib as first line therapY (MULTIPLY)

The MULTIPLY is a large multi-institutional project aimed at characterization of a variety of clinical predictors, both baseline and at relapse through three interconnected Work Packages (WP) with the following objectives: I) Identification of clinical factors affecting prognosis and characterization of relapses; II) Identification of lymph node biomarkers III) characterization of liquid tissue associated biomarkers. All parameters will be integrated through biostatistical and artificial intelligence tools to establish a comprehensive model of relapse prediction and optimal salvage treatment. The proposal is conducted by the Eu-MCL-Network which is the largest group conducting clinical and translational research worldwide in MCL including the largest phase III trials ever conducted. MULTIPLY will exploit the extensive dataset and tissue bank of the TRIANGLE trial that will be presented as abstract #1 at the ASH plenary session. This study will establish a novel standard by the addition of ibrutinib to first-line treatment, but will also raise relevant issues for prediction and management of disease relapse in first-line BTK-era. The expected results will be the generation of comprehensive integrated models for relapse prediction MCL and development of an effective platform to develop rational chemotherapy-free strategies based on genetic alterations of the malignant cell and innovative biomarker-driven strategies.

Program: Mantle Cell Lymphoma Research Initiative
Project Term: Start Date: July 1, 2023 End Date: June 30, 2027
Dr. Mondello

Patrizia Mondello, MD PhD

Mayo Clinic

Rochester, Minnesota
United States

Identifying the oncogenic cooperation between IRF4 and MYD88l265p and their impact on the Tumor Microenvironment of Waldenstrom Macroglobulinemia

Although many patients with IgM MGUS remain asymptomatic, some of them progress to Waldenstrom Macroglobulinemia (WM) requiring treatment. Recently, we have found that the hereditable alteration of IRF4 gene increases the risk to develop WM, however little is known on the molecular mechanisms responsible for this feature. In this project, we aim to elucidate the role of the germline alteration of IRF4 in promoting WM through oncogenic cooperation with MYD88 and dysregulated immune microenvironment, ultimately paving the way for novel precision therapies for this patient population.

Program: Special Grants
Project Term: Start Date: August 21, 2023 End Date: August 20, 2025
Kimberly Stegmaier

Kimberly Stegmaier, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

New Targeted Therapies for Pediatric Acute Myeloid Leukemia

Our research focuses on the preclinical evaluation of new targeted therapies for high-risk subtypes of childhood AML. We are deploying screening approaches to delete each gene, one-by-one, to identify genes whose deletion leads to death of the leukemia cells. We will evaluate drugs developed against these targets in state-of-the-art models of pediatric AML. Our goal is to translate the most promising findings to clinical trials for children with these very poor outcome subsets of AML.

Program: Dare to Dream
Project Term: Start Date: July 1, 2023 End Date: June 30, 2025
Dr. Epstein-Peterson

Zachary Epstein-Peterson, MD

Memorial Sloan Kettering Cancer Center

New York, New York
United States

Targeting mutant IDH2 in angioimmunoblastic T-cell lymphoma

Angioimmunoblastic T-cell lymphoma is a rare, aggressive form of T-cell lymphoma associated with poor clinical outcomes in response to current therapeutic approaches. Recurrent oncogenic mutations in isocitrate dehydrogenase 2 (IDH2) have been identified in patients with angioimmunoblastic T-cell lymphoma and this represents a targetable lesion in other malignancies. However, comprehensive investigations of mutant IDH2 inhibition in angioimmunoblastic T-cell lymphoma are lacking, and this may represent a new therapeutic avenue for a patient population in need of newer treatments

Program: Academic Clinical Trials Program (ACT)
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Goyal

Gaurav Goyal, MD

The University of Alabama at Birmingham

Birmingham, Alabama
United States

A Multi-Center, Multi-National Investigation of Survivorship and Patient-Reported Symptoms in Erdheim-Chester Disease

Advances in the treatment of Erdheim-Chester Disease (ECD) have led to a growing survivor population; however, there is a lack of information on the burden of chronic health problems, symptomatology, psychological dysfunction, and mortality experienced by this group of individuals. We propose a multi-institutional international study in collaboration with the ECD Global Alliance to answer these critical questions. Results from our study will help in counseling patients in the clinic about what to expect in the future and develop interventions to reduce the risk of health issues and disease or treatment-related symptoms.

Program: Special Grants
Project Term: Start Date: July 1, 2023 End Date: June 30, 2025
Dr. Crispino

John Crispino, PhD

St. Jude Children's Research Hospital

Memphis, Tennessee
United States

Aberrant Megakaryopoiesis in the MPNs

A key feature of the MPNs is aberrant megakaryopoiesis, including increased numbers of platelet-producing megakaryocytes in essential thrombocythemia and atypical megakaryocytes that drive fibrosis in myelofibrosis (MF). Recent studies have found that increased activity of the chromosome 21 kinase DYRK1A, which is a feature of the MPNs, enhances megakaryocyte growth while its loss suppresses their expansion. This effect appears to be mediated, at least in part, by DYRK1A’s control of NFAT2 phosphorylation and subcellular localization. The goals of this research are to determine whether DYRK1A is a therapeutic target in chronic phase MPNs and to define the contributions of NFAT2 phosphorylation to the disease.

Program: Special Grants
Project Term: Start Date: February 1, 2023 End Date: January 31, 2024
Robert Orlowski

Robert Orlowski, PhD, MD

The University of Texas MD Anderson Cancer Center

Houston, Texas
United States

Targeting HSP70 to Immune Effector Cells to Overcome the Immune Suppressive Myeloma Microenvironment

Development of a strong anti-cancer immune response requires coordinated action of the innate and adaptive parts of the immune system, but cancer cells alter their environment to suppress virtually every step in this process, which promotes cancer progression and treatment resistance. One promising strategy could be to target Heat shock protein 70 (HSP70), which plays an important role in both innate and adaptive immunity, and we therefore developed a series of novel antibodies to HSP70, one of which cured mice of multiple myeloma. Based on strong preliminary data, we propose additional studies to better understand how this antibody activates various types of immune cells, how it works against both cancer cells and modifies the immune environment in mouse models, and how it could work even better in combination with other agents against myeloma. Since this antibody is already being developed into a drug for phase I clinical trials, these studies will directly inform its use in the clinic against multiple myeloma, and possibly against other blood-related cancers such as B-cell lymphomas.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Enterome

Enterome, SA

TAP Partner

Paris
France

A phase 2 trial of EO2463, a novel microbial-derived peptide therapeutic vaccine, as monotherapy, and in combination with lenalidomide and rituximab, for treatment of patients with indolent NHL

In October 2023, LLS made an equity investment in Enterome to "support the ongoing Phase 2 SIDNEY study of EO2463 in indolent non-Hodgkin B-cell lymphoma."

Enterome is a clinical-stage biopharmaceutical company developing breakthrough immunomodulatory drugs for the treatment of cancer and immune diseases. Enterome’s pioneering approach to drug discovery is based on its unique and powerful bacterial Mimicry drug discovery platform, allowing it to analyze and uncover new biological insights from the millions of gut bacterial proteins in constant cross-talk with the human body. Its first-in-class small protein and peptide drug candidates modulate the immune system by closely mimicking the structure, effect or actions of specific antigens, hormones, or cytokines. 

EO2463 is a clinical-stage off-the-shelf OncoMimics™ peptide-based immunotherapy. It combines four microbial-derived OncoMimics™ peptides that closely mimic specific cytotoxic T cell (CD8+ T cell) epitopes in B cell Tumor-Associated Antigens CD20, CD22, CD37, and CD268 (BAFF receptor), as well as a helper CD4 peptide, UCP2. The SIDNEY trial is a multicenter, Phase 2 trial investigating EO2463 in monotherapy and in combination with standard of care - rituximab and rituximab in combination with lenalidomide – for treatment of patients with indolent NHL (NCT04669171).

Program: Therapy Acceleration Program
Project Term: Start Date: October 24, 2023 End Date: July 24, 2024
Dr. Walter

Roland Walter, MD PhD

Fred Hutchinson Cancer Center

Seattle, Washington
United States

211Astatine-CD123 Radioimmunotherapy for Cancer (Stem) Cell-Directed Treatment of Acute Leukemia

Because acute leukemias are very sensitive to radiation, radioisotopes are ideal payloads to arm antibodies against these difficult-to-cure, aggressive blood cancers. Here, we will develop fully human anti-CD123 antibodies carrying the highly potent alpha-emitter astatine-211 (211At) as a new therapy for acute leukemia. CD123 is broadly displayed on acute leukemia cells in most patients and overexpressed on leukemic stem cells but is only found on a small subset of normal blood cells, enabling the use of 211At-CD123 radioimmunotherapy in the transplant and non-transplant setting with limited toxicities to normal tissues.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Matsui

William Matsui, MD

The University of Texas at Austin

Austin, Texas
United States

Stem cell features and Notch signaling in p53 deleted multiple myeloma

We have investigated the consequences of p53 loss on stem cell properties, namely clonogenic growth, self-renewal, and drug resistance in multiple myeloma. We have found that both the level of Notch signaling and BCMA impact these properties, and we will explore novel strategies to improve outcomes in p53 mutant multiple myeloma.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Bahlis

Nizar Bahlis, MD

University of Calgary

Calgary
Canada

Development of a novel BCL2L1 armored CAR T-cell and a tumor-immune interactome in multiple myeloma

Novel immune approaches have revolutionized the treatment paradigms in multiple myeloma (MM) with deep responses seen in heavily pretreated patients. However responses are largely not durable with significant gaps remaining in our understanding of the mechanisms mediating the immune escape to to CAR T cells and T cell engagers. Harnessing the power of single cell immunogenomics and building on the knowledge we amassed to date, we plan to address these therapeutics and mechanistic challenges firstly through the informed design and clinical development of a BCL2L1 armoured BCMA-targeting CAR T cell, and secondly by establishing a dictionary of the MM-TME interactome through serial interrogation of primary MM cells and their immunome generating a dynamic risk prediction model to better guide the delivery of immuno-therapeutics.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
dr. Fehniger

Todd Fehniger, MD PhD

Washington University in St. Louis

St. Louis, Washington
United States

NK cell immunotherapy to reduce relapse after haploidentical transplant for high-risk pediatric AML

Leukemia recurrence remains the most common type of treatment failure after allogeneic hematopoietic cell transplant for children and young adults with high-risk acute myelogenous leukemia (AML), occurring in 40-50% of patients. Novel treatment strategies are needed to attain durable remissions and provide long-term cure. We have developed a novel memory-like (ML) NK cell immunotherapy that has demonstrated potent activity against AML in preclinical and early clinical studies. We propose a new clinical trial combining donor-derived ML NK cells adoptive cellular therapy with modified αβT cell-depleted haploidentical HCT to enhance graft-versus-leukemia and reduce relapse in pediatric and young adult patients with high-risk AML.

Program: Academic Clinical Trials Program (ACT)
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Stock

Wendy Stock, MD

University of Chicago

Chicago, Illinois
United States

A phase 1b/2 study targeting apoptotic and signaling pathways in T-acute lymphoblastic leukemia

T-acute lymphoblastic leukemia (T-ALL) is an aggressive leukemia with limited treatment options after first-line chemotherapy. Our preclinical work in animal models of T-ALL demonstrated the activity of a novel-novel combination treatment strategy, which includes LP-118 (activator of suicide pathways within leukemic cells) and tyrosine kinase inhibitors (inhibiting growth-promoting LCK and ACK1 signaling pathways). Leveraging the mechanistic insights gained from our laboratory work, we propose a phase Ib/II study investigating the feasibility and efficacy of the combined LP-118, ponatinib, and salvage chemotherapy in patients with relapsed T-ALL. This precision medicine approach addresses an unmet need in a fatal disease which lacks effective therapies.

Program: Academic Clinical Trials Program (ACT)
Project Term: Start Date: July 1, 2023 End Date: April 30, 2027
Venkata Lokesh Battula

Venkata Lokesh Battula, PhD

The University of Texas MD Anderson Cancer Center

Houston, Texas
United States

Arming NK Cells to Target B7-H3+ AML Cells

In order to develop a novel immunotherapy approach to treating AML, we propose targeting B7-H3 (CD276), a promising immune checkpoint that has been reported to inhibit NK cell activation. We have generated a novel anti–B7-H3 monoclonal antibody (T-1A5) to block B7-H3 function, showing the best in vitro and in vivo activity against AML cells. We will test the hypothesis that combination strategies such as targeting B7-H3 along with BCL2 inhibition (venetoclax) or IL-15r agonist (NKTR-255) result in synergistic inhibition of AML growth.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 1, 2026
Dr. Wang

Jenny Wang, PhD

The University of Sydney

Sydney
Australia

Strategic combinations to overcome therapeutic resistance and relapse in acute myeloid leukemia

Acute myeloid leukemia (AML) is the most fatal type of leukemia and has a high rate of relapse following current therapies. We have recently uncovered that RSPO3-LGR4 pathway is a key regulator of leukemia-initiating cell activity and is exclusively activated in relapsed and refractory AML. Our project aims to investigate the mechanistic link between the pathway activation and therapy resistance, and design combination therapies that would overcome resistance and improve the treatment of relapsed leukemia.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Dawson

Mark Dawson, PhD

The University of Melbourne

Melbourne
Australia

Understanding molecular determinants of immune evasion to CAR-T cells at single clone resolution

Cellular immunotherapies such CAR-T cells are now firmly established as major pillars of anti-cancer therapy particularly in B-cell malignancies. However, despite their remarkable success in mediating an objective clinical response in up to 90% of patients, long-term durable remissions remain confined to only a minority of patients. It is now increasingly apparent that genetic evolution through the acquisition of new mutations cannot solely explain the molecular basis for therapeutic resistance. Therefore, to meet our ambition of precision medicine we need a better understanding of both the genetic and non-genetic mechanisms of malignant clonal dominance and therapeutic adaptation. To address this important challenge, we have developed new ex vivo and in vivo (mouse models) of resistance to CAR-T therapy. These will be coupled to a synthetic clone tracing strategy termed SPLINTR (Single-cell Profiling and LINeage Tracing) using expressed barcodes. In this proposal we will use SPLINTR in our models to uncover the clone intrinsic properties of cancer cells that enable them to evade these pioneering cellular immunotherapies. This research will deliver a blueprint around which future clinical trial strategies could be enabled to improve outcomes with these ground-breaking therapies.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Li

Shirong Li, PhD

Columbia University Medical Center

New York, New York
United States

Targeting GCK as a novel and selective therapeutic strategy against RAS mutated Multiple Myeloma

RAS/MAPK mutations are the key drivers in MM, which occurs in 50% of newly diagnosed and higher in relapsed MM patients. However, RAS remains undruggable in MM. We found that RAS mutation MM growth is highly dependent on germinal center kinase(GCK). The goal of this project is to develop small molecule inhibitors against GCK with the expected outcome to provide novel treatments for relapsed/refractory and especially multi-drug resistant MM with RAS mutation, as well as other B-cell malignancies.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Jennifer Woyach

Jennifer Woyach, MD

The Ohio State University

Columbus, Ohio
United States

Inhibition of PKCβ as a strategy for BTK inhibitor refractory CLL

Patients with CLL that have progressed on BTK inhibitors have high risk disease with few clinical options. Here we propose a novel, selective inhibitor of PKCβ, MS-553, as a strategy for these patients. Our project will evaluate this drug alone and in combination with venetoclax preclinically and will perform correlative studies from an ongoing phase 1/2 trial of this drug alone and in combination with venetoclax.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Gottschalk

Stephen Gottschalk, MD

St. Jude Children's Research Hospital

Memphis, Tennessee
United States

CD70-directed CAR T-cell therapy for the treatment of relapsed/refractory pediatric AML

In this project, we will test an innovative therapy called CAR T-cell therapy for children with a type of cancer called AML. In the laboratory, we have identified and developed a powerful CAR T-cell therapy that targets a protein called CD70 on AML cells. We propose to now develop a clinical trial in which we will study the effects of this CD70.CAR T-cell therapy in children with AML.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Wendy Béguelin

Wendy Béguelin, PhD

Weill Cornell Medicine

New York, New York
United States

Discovery and therapeutic targeting of novel mechanisms driving Double Hit Lymphomas

Double-hit lymphoma (DHL) is an aggressive form of diffuse large B-cell lymphoma (DLBCL) defined by co-occuring MYC and BCL2 rearrangements. DHL has been linked to very poor outcomes when treated with R-CHOP chemotherapy. Effective treatments to prevent treatment failure remain a critical unmet need. This proposal will develop novel, mechanism-based therapeutic regimens for DHL that overcome chemotherapy resistance and defective immune surveillance to improve outcomes.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Zhou

Yubin Zhou, PhD, MBBS

Texas A&M Institute of Biosciences and Technology

College Station, Texas
United States

Development of mutant GTPase-specific degraders for peripheral T cell lymphoma treatment

This project aims to develop targeted therapies against peripheral T cell lymphoma (PTCL), a diverse group of aggressive blood cancers with poor clinical outcomes. This project is tightly relevant to cancer control and treatment, promising to advance our understanding on how blood cancers initiate and progress, and lead to new therapeutics for the treatment of peripheral T cell lymphoma (PTCL). We will develop targeted therapeutics to engage an oncogenic RHOA GTPase mutant to treat PTCL and other types of tumors with similar genetic backgrounds.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Yi

Qing Yi, MD PhD

Houston Methodist Research Institute

Houston, Texas
United States

Developing Novel CAR-T Cell Therapy For Hematologic Malignancies

We observed that patients with many hematologic cancers expressed high levels of DKK1 and generated novel human DKK1-A2 CAR-T cells that can kill cancer cells from HLA-A2+ patients with myeloma, lymphoma, or leukemia. We also found that Th9-polarized T cells have enhanced antitumor effects in vivo. In this proposal, we will determine 1) whether and how Th9-polarized DKK1-A2 CAR-T cells are promising effector T cells for immunotherapy of human patients, and 2) whether Th9-polarized DKK1-A2 CAR-T cells are associated with reduced on- and off-target toxicities. Completing these studies are critical for developing new and effective CAR-T therapy for patients with hematologic malignancies who are still dying from the disease.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Yang

Jing Yang, PhD

Houston Methodist Research Institute

Houston, Texas
United States

Targeting acetyl-CoA synthetase 2 to remodel obesity-evoked inflammatory microenvironment in myeloma

Our proposal aims to develop a novel strategy to improve therapeutic efficacy for patients with multiple myeloma by remodeling obesity-induced inflammatory microenvironment. We hypothesize that acetyl-CoA synthetase 2, which is stimulated by obesity, enhances inflammatory cytokine production from myeloma cells, leading to an inflammatory niche where anti-tumor function of CD8+ T cells is dampened, and tumor growth is promoted. Our study will be the first to explore a novel insight for how obesity impacts the interaction between myeloma cells and microenvironment. In preparation of using the inhibitor of acetyl-CoA synthetase 2 in the clinical setting, we will establish its potential as a single agent or in combination of other chemo- or immuno- drugs to treat myeloma.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Carrasco

Ruben Carrasco, MD PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Developing selective inhibitors of the b-catenin/BCL9 transcriptional complex for myeloma therapy

The b-catenin/BCL9 transcriptional complex, is a novel dependency in multiple myeloma (MM). Disruption of this complex inhibits MM cell growth in culture and in MM xenograft models. Development of potent selective b-catenin/BCL9 inhibitors will provide valuable tools to further investigate their mechanism of MM inhibition. We have established a chemistry, structural biology, and molecular pathology platform to facilitate novel inhibitor development, and explore its translational potential in MM.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Stahl

Maximilian Stahl, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Memory-like natural killer cells and venetoclax to eradicate measurable residual disease in AML

This proposal is to conduct a phase I (early phase) clinical trial to test whether the combination of the approved targeted therapy venetoclax with memory-like Natural Killer (NK) cells is safe and active in patients with acute myeloid leukemia (AML). Based on laboratory research at Dana-Farber Cancer Institute, we believe that the addition of memory-like NK cells obtained from an haploidentical (‘half matched’) donor will be able to eradicate residual leukemia cells left over after prior venetoclax treatment and hence prevent a future relapse of the disease. A total of 10 patients will be treated with two different doses of NK cells and a constant dose of venetoclax. We also plan scientific studies on patient samples to learn more about the function of NK cells when combined with venetoclax, evaluate for clearance of residual leukemia cells with this combination therapy and explore potential resistance mechanisms.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Arber

Caroline Arber, MD

Centre Hospitalier Universitaire Vaudois

Lausanne
Switzerland

Designed biosensor to enhance CAR T cell therapy for multiple myeloma

We will develop a novel T cell therapy strategy for multiple myeloma (MM) that will combine existing chimeric antigen receptors (CARs) with a novel designed biosensor responding to soluble factors abundantly present in the MM bone marrow environment in patients. The biosensor will be expressed as novel type of chimeric receptor in T cells concomitantly with the CAR and signal the T cells to persist longer and keep eliminating cancer cells from the body. We will deeply characterize the effects of our novel biosensor in CAR T cells to precisely understand how the treatment works. If successful, we expect that CAR T cell therapy for MM can be made more efficient, and the same strategy could potentially also be applied to other cancer types.

Program: Translational Research Program
Project Term: Start Date: September 1, 2023 End Date: August 31, 2026
Dr. Odejide

Oreofe Odejide, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Health Insurance and End-of-Life Care for People with Hematologic Malignancies

Patients with blood cancers from racial and ethnic minority groups are more likely to experience suboptimal end-of-life (EOL) care. These disparities may be partially driven by health insurance differences but there is limited research examining insurance access as a potential contributor to EOL care disparities for this population. We will leverage complementary local and national datasets to assess the relationship between insurance status and type with EOL quality measures. We will also develop a Blood Cancer Health Insurance Initiative to translate our research findings to policy initiatives to dismantle disparities in access to high-quality EOL care for patients with blood cancers. We will translate our research findings to policy initiatives to dismantle disparities in access to high-quality EOL care for patients with blood cancers.

Program: Equity in Access
Project Term: Start Date: June 1, 2023 End Date: May 31, 2026
Dr. Doshi

Jalpa Doshi, PhD

Perelman School of Medicine at the University of Pennsylvania

Philadelphia, Pennsylvania
United States

Impact of Insurance Type and Cost Sharing on Equity in Access to Oral Anticancer Medications for Blood Cancers

This project will evaluate the association of insurance type with insurer rejection and patient abandonment of new OAM prescriptions for blood cancers, overall and by sociodemographic factors. It will also evaluate the association of cost sharing with patient abandonment of OAM prescriptions for blood cancers and conduct simulations under alternative cost sharing scenarios to inform policy reform proposals among commercially insured enrollees. Finally, the study will evaluate the effect of cost-sharing reductions under the Inflation Reduction Act on patient abandonment of new OAM prescriptions for blood cancers among Medicare Part D enrollees, overall and by sociodemographic factors.

Program: Equity in Access
Project Term: Start Date: June 1, 2023 End Date: May 31, 2026
Dr. Li

Meng Li, PhD

MD Anderson Cancer Center

Houston, Texas
United States

Investigating the Impact of Insurance Coverage on Access to Care and Outcomes among Lymphoma Patients

In this proposal we will investigate the association between insurance coverage and access to care, survival, and financial hardship among patients across Non-Hodgkin lymphoma (NHL) subtypes and to what extent insurance coverage explains and modifies racial disparity in access to care and outcomes. To this end, we will use the Optum Clinformatics DataMart database, the Texas Cancer Registry, the Harris Health System Cancer Database and Data from the Lymphoma Epidemiology of Outcomes (LEO) Cohort Study. These four databases will provide a sample that covers a diverse patient population in terms of insurance coverage, race and ethnicity, and geographic regions. The LEO Cohort Study also provides information on self-reported financial toxicity that is not available in cancer registries, administrative claims data, or surveys. This study will reveal whether insurance coverage, neighborhood socioeconomic factors and healthcare resources are associated with access to care and outcomes of NHL patients.

Program: Equity in Access
Project Term: Start Date: June 1, 2023 End Date: May 31, 2026
Dr. Muffly

Lori Muffly, MD

Stanford University

Palo Alto, California
United States

Towards Equity in Specialized Cancer Care for Adolescents and Young Adults with Newly Diagnosed Acute Lymphoblastic Leukemia

Our study is designed to directly inform the pathways through which health insurance influences access to care at an SCC for individuals with AYA ALL using a combination of cancer registry, survey, and cost-benefit analyses. This research will contribute to knowledge of the implications of health insurance coverage on ALL cancer care in young adults and inform policy-relevant solutions, including determining whether patients are bypassing an SCC for treatment at a more distant facility, calculating estimates of insurance acceptance and access challenges at ALL treating facilities and identifying the financial implications of shifting care to SCCs with demonstrated survival improvements for this population.

Program: Equity in Access
Project Term: Start Date: June 1, 2023 End Date: May 31, 2026
Dr. Parsons

Helen Parsons, Phd

University of Minnesota

Minneapolis, Minnesota
United States

The Impossible Choice: The Role of Insurance Design on Financial Toxicity and Access to Care for Individuals with Blood Cancer

The overall goal of this project is to understand the role of insurance design on financial toxicity and access to care among individuals with blood cancer. To understand this interplay, we will use a unique and innovative linkage of the 2012-2019 Colorado Cancer Registry (CCR) to the 2013-2021 Colorado All-Payer Claims Database and the LexisNexis and TranUnion financial and life event databases. Our specific aims are to 1) Estimate the number of individuals with blood cancer who are potentially underinsured over time relative to individuals with solid tumors or no history of cancer; 2) Examine the relationship between being underinsured and experiencing financial toxicity after diagnosis in individuals diagnosed with blood cancer relative to those with solid tumors or no history of cancer; and 3) Examine differences in access to cancer care including time to treatment, treatment intensity and survival in underinsured individuals with blood cancer versus those with more generous insurance coverage.

Program: Equity in Access
Project Term: Start Date: June 1, 2023 End Date: May 31, 2026
Constantine Mitsiades

Constantine Mitsiades, PhD, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Pharmacological strategies to enhance T- and NK-cell-based therapies in blood cancers

Although they represent a major therapeutic progress for blood cancers, CAR-T cells and other T-cell based therapies are subject to eventual development of resistance to many patients. Natural killer (NK) cell-based therapies are highly active against many types of blood cancer cells which are resistant to T cells, but in our CRISPR studies death receptor signaling defects emerge as a common downstream mechanism of resistance to both T- and NK-cell therapies. Building on extensive pharmacological and genomic screens, this project will specifically examine the role of SMAC mimetics and JAK/STAT inhibitors in enhancing the response of blood cancer cells (e.g., multiple myeloma, leukemias) to CAR-T or NK cell therapies. We will place emphasis of studies with patient-derived samples in vitro (Integrated Functional Immune Profiling Platform) and in vivo, including humanized bone marrow-like scaffolds, to provide a translationally-relevant simulation of the potential of these compounds to enhance the clinical activity of cell-based immunotherapies in blood cancers.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Treon

Steven Treon, MD PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Targeting mutated MYD88 pro-survival signaling in B-cell malignancies

Our laboratory and those of others discovered highly recurring mutations in the gene MYD88 which are found in patients with various B-cell cancers including Waldenstrom’s Macroglobulinemia (95-97%), ABC Subtype of Diffuse B-cell Lymphoma (30-40%), Primary Central Nervous Lymphoma (80%), Marginal Zone Lymphoma (10%) and Chronic Lymphocytic Leukemia (5-10%). Our laboratory and those of others showed that mutated MYD88 triggers BTK, which is the target of BTK-inhibitors like ibrutinib, acalabrutinib and zanubrutinib though complete remissions are rare with these agents largely in part because other pro-survival molecules are activated by mutated MYD88 such as HCK and IRAK1. In these studies, we will develop potent and selective inhibitors to HCK and IRAK1, including PROTACs which inhibit and degrade these molecules, using lead molecules and scaffolds whose target selectivity and activity we previously validated. We will also investigate the mechanisms underlying the inactivation of the Inhibitor of BTK (IBTK) as a potential new target for development of inhibitors for use in MYD88 mutated lymphomas.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Rashidi

Armin Rashidi, MD PhD

Fred Hutchinson Cancer Center

Seattle, Washington
United States

Fecal microbiota transplantation to prevent acute GVHD after allogeneic stem cell transplantation

In up to half of patients with hematologic malignancies undergoing allogeneic stem cell transplantation, the trajectory of a smooth recovery toward cure is disrupted by acute graft-versus-host disease (aGVHD). Inspired by the role of intestinal microbial communities in aGVHD pathogenesis, we recently completed the largest fecal microbiota transplantation (FMT) trial to date in transplant recipients. We established the safety of standardized third-party FMT and characterized FMT effects on the microbiota, leading to the proposed randomized, placebo-controlled phase 2 trial of FMT to prevent aGVHD.

Program: Academic Clinical Trials Program (ACT)
Project Term: Start Date: July 1, 2023 End Date: October 31, 2026
Dr. Frank

Matthew Frank, MD PhD

Stanford University

Palo Alto, California
United States

Autologous CD22 CAR T cell Therapy for the Treatment of non-Hodgkin Lymphoma

CD19 targeting chimeric antigen receptor (CAR) T cell therapies (CAR19) are effective treatments for patients with non-Hodgkin Lymphoma (NHL), however, the majority of these patients will relapse. We have now evaluated a CD22 targeting CAR T cell therapy (CAR22) in patients who have large B cell lymphoma who have relapsed after CAR19 therapy and found that this therapy is both safe and effective resulting in a high rate of durable complete responses. We will now test this promising CAR22 for the first time in patients with other non-Hodgkin Lymphoma subtypes including mantle cell lymphoma, follicular lymphoma, and other CD22-expressing lymphomas.

Program: Academic Clinical Trials Program (ACT)
Project Term: Start Date: July 1, 2023 End Date: March 14, 2027
Margaret Shipp

Margaret Shipp, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Analysis and Targeting of Tumor-Associated Monocytes/Macrophages that Inhibit PD-1 Blockade

Inhibition of a tumor-triggered immune exhaustion pathway, termed PD-1 blockade, enables immune effector cells to attack cancers. In classic Hodgkin Lymphoma (cHL), PD-1 blockade is now a standard treatment for relapsed disease and a component of experimental frontline therapy. We have identified a major population of monocyte/macrophages in patients with cHL that inhibit tumor cell killing and limit the efficacy of PD-1 blockade. Our goal is to fully characterize these tumor-specific monocytes/macrophages and target their immunosuppressive and tumorigenic program for therapeutic benefit in patients with cHL and other lymphoid malignancies.

Program: Translational Research Program
Project Term: Start Date: June 30, 2023 End Date: June 30, 2026
Dr. Genovese

Pietro Genovese, PhD

Boston Children's Hospital

Boston, Massachusetts
United States

Towards clinical testing of epitope editing to enable novel adoptive immunotherapies

Innovations in gene engineering have made it possible to reprogram immune cells to attack specific targets on cancer cells, allowing the first adoptive cellular immunotherapies, known as CAR T cells, to be approved by the FDA for the treatment B lymphoblastic leukemia. A similar approach is currently under development for AML, but in contrast to B-ALL, there is no leukemia-specific target which would be amenable to targeting by immune cells without incurring severe adverse effects. Here, we aim to modify normal bone marrow stem cells used for allogeneic transplantation to make them resistant to CAR-T cells, thus enabling targeting proteins essential for tumor survival without the risk of severe toxicity on the healthy tissue counterpart.

Program: Translational Research Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Yonezawa

Taishi Yonezawa, PhD

Baylor College of Medicine

Houston, Texas
United States

Uncovering mechanisms of DNMT3A stability in hematologic malignancies

DNMT3A is a critical tumor suppressor in hematologic malignancies; DNMT3A protein levels affect both tumor latency and type. DNMT3A is regulated in part by protein stability, but the mechanisms remain incompletely understood. Here, I will dissect the mechanisms that regulate DNMT3A protein turnover using CRISPR screening and genetically engineered mouse leukemia models. This work will reveal whether its stabilization could contribute to a new therapeutic approach for hematologic malignancies.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Stewart

Jessica Stewart, PhD

UNC Lineberger Comprehensive Cancer Center

Chapel Hill, North Carolina
United States

Elucidating the role of FAM72A in EBV-driven B cell lymphomagenesis

This work focuses on characterizing the role of FAM72A in EBV-driven B cell tumorigenesis. This protein is upregulated by EBV during the transformation of B cells and overexpressed in many hematologic cancers. Using a combination of in vitro and in vivo EBV transformation models, high-throughput drug screens, and structural analysis we aim to find small molecules inhibitors that target FAM72A and determine if these drugs can prevent or hinder EBV-associated B cell malignancies.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Parsons

Tyler Parsons, PhD

Washington University in St. Louis

St. Louis, Missouri
United States

Mechanisms of Clonal Evolution in the Transformation of MPN to sAML

This research will investigate blood stem cell mutations associated with progression of myeloproliferative neoplasm (MPN) to secondary acute myeloid leukemia (sAML). Our preliminary data suggest that pre-leukemic cells with particular mutations may have a selective advantage in a background of certain MPN subtypes. We will confirm this by utilizing mouse models and both MPN and sAML primary patient samples. Ultimately, we will examine and test inhibition of mechanisms which drive MPN to sAML.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Paczkowska

Julia Paczkowska, PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Characterization and Targeting of Tumor-Associated Monocytes/ Macrophages that Limit the Efficacy of PD-1 Blockade in Lymphoma

Inhibition of the PD-1 exhaustion pathway enables the immune system to attack cancers. PD-1 blockade is now a standard treatment for relapsed classic Hodgkin Lymphoma (cHL) and a component of experimental frontline therapy. In patients with cHL, a newly identified population of monocytes/macrophages limits the efficacy of PD-1 blockade. We will characterize and target these tumor-programmed monocytes/macrophages for therapeutic benefit in patients with cHL and other lymphoid malignancies.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Nagler

Adi Nagler, PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

The microbiome-induced immune response role in bronchiolitis obliterans syndrome following allogeneic hematopoietic cell transplantation

The microbiome is increasingly recognized as contributing to chronic graft-versus-host disease (cGVHD). I hypothesize that microbial antigens drive the devastating complication of bronchiolitis obliterans syndrome (BOS). To determine if such antigen targets are at the heart of BOS pathology, I will integrate spatial transcriptomic approaches, immunopeptidome analysis, and direct antigen specificity testing of TCRs from biospecimens collected from preclinical models and patient biospecimens.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Mistry

Jayna Mistry, PhD

The Jackson Laboratory

Bar Harbor, Maine
United States

Bone Marrow Stromal Cell Senescence Induced by Dnmt3a-Mutant Hematopoiesis Drives Clonal Hematopoiesis and Transformation to Myeloid Malignancy

This project focuses on how age-associated clonal hematopoiesis (CH) alters the bone marrow (BM) microenvironment, and whether this promotes transformation of CH to acute myeloid leukemia (AML). I will utilize single cell RNA-seq data, genetic knockout models, and targeted inhibitors to perturb the non-hematopoietic and hematopoietic compartments of a mouse model of CH. The goal is to determine if manipulation of the BM microenvironment can attenuate CH and prevent AML transformation.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Marinaccio

Christian Marinaccio, PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Identification and characterization of genetic factors affecting MLL/KMT2A fusion proteins stability in MLL/KMT2A rearranged leukemias

MLL1/KMT2A rearranged leukemias are the most common blood cancer occurring in children characterized by dismal prognosis. Given the importance of fusion proteins in driving the disease, I will determine factors affecting the fusion protein stability through a CRISPR/Cas9 screening approach in an innovative model system where the MLL fusions are endogenously tagged with a fluorescent protein. This will facilitate development of molecular glue degraders specifically targeting the MLL fusions.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Hall

Trent Hall, PhD

St. Jude Children's Research Hospital

Memphis, Tennessee
United States

Identifying novel regulators of leukemic progression in GATA2-deficiency syndrome

GATA2 deficiency is an inherited pediatric syndrome with a high rate of progression to myeloid malignancy, the mechanisms of which remain largely undefined. Here, we will use our recently generated mouse model, Gata2R396Q, to determine the effects of GATA2 deficiency on hematopoietic function and identify novel drivers of myeloid malignancy via focused CRISPR screens. Our work will provide further insight into the mechanisms driving leukemic progression of this syndrome.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Sugio

Takeshi Sugio, MD, PhD

Stanford University

Palo Alto, California
United States

An integrated liquid biopsy framework for surveillance of residual disease and host immune status of T-cell lymphomas

I aim to develop an accurate disease monitoring system and identify immunologic determinants of development and progression in T-cell lymphoma (TCL). I will integrate noninvasive liquid biopsy methods by high-throughput sequencing. I will study blood samples at various milestones, including pre-diagnostic, diagnostic/baseline, and post-treatment specimens during the natural history of TCL. Using these novel tools and unique specimens, my goal is the development of effective therapies for TCL.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2025
Dr. Montefiori

Lindsey Montefiori, PhD

St. Jude Children's Research Hospital

Memphis, Tennessee
United States

Molecular basis and new therapeutic strategies in lineage ambiguous leukemia

Lineage-ambiguous leukemias are high-risk blood cancers with unclear biologic basis and suboptimal treatment options. Here, I will identify the cell of origin of lineage ambiguous leukemia and investigate new therapeutic strategies through in vitro and in vivo experimental modeling approaches and preclinical drug studies in patient-derived xenografts. These studies will clarify the cellular and molecular alterations driving lineage ambiguity and advance a new, rational therapeutic approach.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2025
Dr. Zhang

Christine Zhang, PhD

Washington University in St. Louis

St. Louis, Washington
United States

Deciphering the role of p53 signaling in NPM1-mutant AML

NPM1c and TP53 mutations are exclusive in acute myeloid leukemia (AML) despite both being commonly present in patients, suggesting a fitness disadvantage for cells with co-occurring mutations. However, the mechanisms underlying this exclusivity have not been explored. This project will utilize novel models to dissect the importance of TP53 signaling in NPM1c+ (pre)-leukemic stem cells. Generated results may highlight therapeutic opportunities for improved risk management of NPM1c+ AML patients.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2025
Dr. Liu

Yiman Liu, PhD

Perelman School of Medicine at the University of Pennsylvania

Philadelphia, Pennsylvania
United States

Investigating the impact of hotspot mutations in a chromatin reader on leukemogenesis

The goal of this proposal is to investigate the consequence of the chromatin reader eleven-nineteen-leukemia (ENL) gain-of-function mutations in the pathogenesis of leukemia. Our studies leverage the expertise in the molecular and chromatin biology of chromatin reader in leukemia utilizing mouse model, high resolution image, epigenomic and transcriptomic approaches. Our goal is to understand how chromatin reader contributes to cancer development, progression, and therapeutic outcome.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2025
Dr. Isshiki

Yusuke Isshiki, MD PhD

Weill Cornell Medicine

New York, New York
United States

Exploring the roles of EZH2 mutation for the development of double hit lymphoma and acquisition of chemotherapy resistance

We aim to clarify the role of EZH2 mutations in the development of double hit lymphoma (DHL) and acquisition of chemo-resistance. We confirmed that Ezh2 mutation is essential to develop aggressive murine GCB lymphoma and deplete T cells from tumor in combination with BCL2 and MYC. The mice showed resistance to chemotherapy and the combination with EZH2 inhibitors improve the outcome in vivo. Our goal is to show the synergy and propose a new mechanism-based therapeutic approach for DHL.

Program:
Project Term: Start Date: July 1, 2023 End Date: June 30, 2025
Dr. Collins

Cailin Collins, MD PhD

Stanford University

Palo Alto, California
United States

Investigating the role of preleukemia duration and clonal burden in progression to AML

The development of acute myeloid leukemia (AML) is preceded by a “preleukemic” phase in which mutated hematopoietic stem cells expand due to a fitness advantage. Our work uses prospective models and analysis of patient samples to study how the duration of preleukemia and how the preleukemic clonal burden affect progression to AML. Results of our studies will shed new light on AML pathogenesis and help guide clinical management of preleukemic conditions such as clonal hematopoiesis.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Wang

Michael Wang, MD

MD Anderson Cancer Center

Houston, Texas
United States

Development of novel BTK-MALT1 dual inhibitors to treat MCL

Most patients respond well to drugs that inhibit an important MCL target named BTK. However, almost all of them will eventually relapse and then do very poorly. Inhibition of MALT1, a target which is biochemically downstream of BTK, may rescue many of these patients, and inhibiting both BTK and MALT1 may be better still. Developing a drug that inhibits both targets at the same time, from the beginning of treatment, will avoid some complications and likely be best of all; we will find out.

Program: Mantle Cell Lymphoma Research Initiative
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Dr. Will

Britta Will, PhD

Albert Einstein College of Medicine

Bronx, New York
United States

Therapeutically actionable molecular safeguards in leukemic stem cells

Our research program’s goal is to identify therapeutically actionable pathways in pre-leukemic and leukemic stem cells in myeloid malignancies. We specifically dissect molecular circuits governing stem cell self-renewal and differentiation, how these change during aging, and contribute to leukemic stem cell evolution and maintenance. Accomplishing this work will enable the rational design of curative intervention and perhaps even prevention strategies for patients with myeloid malignancies.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2028
Dr. Wan

Liling Wan, PhD

Perelman School of Medicine at the University of Pennsylvania

Philadelphia, Pennsylvania
United States

Epigenetic Mechanisms in Acute Myeloid Leukemia

The goal of this project is to investigate the role of the epigenetic regulator Eleven-Nineteen-Leukemia (ENL) and its cancer mutations in acute myeloid leukemia (AML). Our studies leverage the expertise in chromatin biology, functional genomics, and AML modeling, as well as unique chemical compounds and mouse models. Results from this project will provide novel biological insights into our understanding of AML pathogenesis and facilitate the development of novel epigenetic therapies.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2028
Dr. Pietras

Eric Pietras, PhD

University of Colorado Denver, Anschutz Medical Campus

Denver, Colorado
United States

Targeting the pathogenic 'fire triangle' of inflammation, metabolism and mutations in myeloid leukemogenesis

My lab is focused on understanding the pathogenic interplay between oncogenic mutations, chronic inflammation and aberrant metabolism as a driver of the evolutionary processes that culminate in lethal myeloid malignancies. We leverage mouse models and human patient samples to establish modalities for targeting this interplay throughout disease pathogenesis. My long-term goal is to improve patient outcomes by establishing therapies that prevent and/or delay evolution to acute leukemia.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2028
Dr. Doulatov

Sergei Doulatov, PhD

University of Washington

Seattle, Washington
United States

Modeling and targeting leukemic transformation of human hematopoietic stem cells

Our research seeks to understand how ordered acquisition of oncogenic mutations transforms human hematopoietic stem cells into myeloid malignancies. We leverage patient-derived induced pluripotent stem cells and primary normal and malignant stem cells to study how mutation cooperation drives leukemic progression in vitro and in vivo. Our long-term goal is to identify disease mechanisms and develop targeted therapies to eradicate malignant stem cells.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2028
Dr. de Smith

Adam de Smith, PhD

University of Southern California

Los Angeles, California
United States

Leveraging Susceptible Populations and Unique Resources in a Pathway to Prevention of Childhood Acute Lymphoblastic Leukemia

The focus of my research is to understand the causes and early-life origins of acute lymphoblastic leukemia (ALL). We use a two-pronged approach: 1) conducting epidemiological studies of ALL in susceptible populations to understand genetic predisposition, and 2) investigating the in utero origins of ALL across subtypes. Our goals are to identify children at the highest risk of developing ALL through genetic screening and to lay the groundwork for precision prevention strategies.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2028
Dr. Maude

Shannon Maude, MD PhD

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania
United States

Improving CAR T-cell Therapy Efficacy in Acute Lymphoblastic Leukemia by Optimizing Design and Placement

Pediatric acute lymphoblastic leukemia (ALL) that is resistant to standard therapy is a challenge that has been partially overcome by T-cell therapy, yet relapse still occurs in up to 50%. We are conducting two clinical trials that test a next-generation T-cell therapy and the first incorporation of T-cell therapy into initial therapy. These trials will inform future development and the optimal place for this therapy with the goal of improving cure rates for children with very high risk ALL.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2028
Dr. Kahn

Justine Kahn, MD

Columbia University Medical Center

New York, New York
United States

Leveraging cancer registries, clinical trials, and community partnerships to address disparities in pediatric, adolescent, and young adult lymphoma

I aim to identify drivers of pediatric and adolescent/young adult lymphoma disparities so that targeted health equity interventions can be developed. Integration of large datasets, systematic collection of social determinants data in clinical trials, and collaboration with patient advocates will: a) create new population-based resources to study lymphoma outcomes; b) establish a novel framework for equity research in lymphoma clinical trials; and c) identify real-world targets for intervention.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2028
Dr. Ahn

Inhye Ahn, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Clinical and molecular determinants of CLL eradication with targeted combination therapy

The genomic architecture of residual CLL and molecular determinants of disease progression after targeted combination therapy are unknown. In a phase 2 study of zanubrutinib and venetoclax in CLL, I will investigate the depth of response and genomic changes using cellular and circulating tumor DNA. Data generated from this proposal will provide foundational evidence to develop genomic markers for non-invasive monitoring of treatment response and precise prediction of outcome.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2028
Dr. Bjelosevic

Stefan Bjelosevic, PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Metabolic Regulation of Leukemic Cell Fate

Cell-intrinsic metabolic processes are dysregulated in acute myeloid leukemia (AML) and can act to sustain an oncogenic state of differentiation arrest. Using AML cell lines and patient-derived material grown in sophisticated liquid culture medium that mimics human plasma, we will perform metabolically focused in vitro and in vivo CRISPR-Cas9 screens to reveal metabolic regulators of AML cell fate that can be exploited via dietary or pharmacologic intervention as a novel therapeutic strategy.

Program: Career Development Program
Project Term: Start Date: July 1, 2023 End Date: June 30, 2026
Rgenta

Rgenta Therapeutics, INC

TAP Partner

Cambridge, Massachusetts
United States

Supporting development of RNA-targeting molecules for blood cancers

In June 2023, LLS made an equity investment in Rgenta Therapeutics to "Support development of RNA-targeting molecules for blood cancers." 

Rgenta Therapeutics is developing a pipeline of oral, small-molecule RNA-targeting medicines with an initial focus on oncology and neurological disorders. Rgenta has a proprietary platform to mine the massive genomics data to identify targetable RNA processing events and to design small-molecule glues to modulate the interactions among the spliceosome, regulatory proteins, and RNAs. 

Rgenta is working closely with LLS TAP to further develop RNA-targeting molecules by supporting preclinical studies with the goal of moving towards clinical development in hematological malignancies. 

Program: Therapy Acceleration Program
Project Term: Start Date: June 30, 2023 End Date: July 24, 2024
Dimericon

Dimericon Therapeutics, AG

TAP Partner

Zurich
Switzerland

Supporting development of dimericons (crosslinked helix dimers) for blood cancers

In May 2023, LLS made an equity investment in Dimericon to "Support development of dimericons (crosslinked helix dimers) for blood cancers." 

Dimericon is a private biotech company focused on exploring crosslinked helix dimers (Dimericons) as therapeutics and templates for small molecule development. Dimericon’s technology targets hard-to-drug intracellular protein-protein interactions using rationally designed mimetics of helix dimers. The Seed round of financing will support preclinical studies to further develop the current lead compound to be an IND ready clinical candidate in hematological malignancies.

Program: Therapy Acceleration Program
Project Term: Start Date: May 24, 2023 End Date: July 24, 2024
BioInvent

BioInvent International, AB

TAP Partner

Lund
Sweden

A phase 1/2 study of BI-1206, a monoclonal antibody to CD32b (FcyRIIB), in combination with rituximab in patients with indolent NHL that has relapsed or is refractory to rituximab

In January 2023, LLS made an equity investment in BioInvent to "Support Clinical Development of BI-1206 for NHL Indications and BI-1808 for T-Cell Lymphoma Indications Including CTCL."

BioInvent International AB is a clinical-stage biotech company that discovers and develops novel and first-in-class immuno-modulatory antibodies for cancer therapy, with currently four drug candidates in five ongoing clinical programs in Phase 1/2 trials for the treatment of hematological cancer and solid tumors, respectively. The Company's validated, proprietary F.I.R.S.T™ technology platform identifies both targets and the antibodies that bind to them, generating many promising new drug candidates to fuel the Company's own clinical development pipeline and providing licensing and partnering opportunities.

BI-1206 is a novel anti-FcyRIIB antibody currently being studied in two Phase 1/2 trials, in combination with rituximab in NHL (NCT03571568) and in combination with pembrolizumab in solid tumors (NCT04219254).

Program: Therapy Acceleration Program
Project Term: Start Date: January 17, 2023 End Date: July 24, 2024
BioInvent

BioInvent International, AB

TAP Partner

Lund
Sweden

A phase 2 study of BI-1808, a monoclonal antibody to TNFR2, as a single agent and in combination with pembrolizumab in patients with solid tumors and CTCL

In January 2023, LLS made an equity investment in BioInvent to "Support Clinical Development of BI-1206 for NHL Indications and BI-1808 for T-Cell Lymphoma Indications Including CTCL."

BioInvent International AB is a clinical-stage biotech company that discovers and develops novel and first-in-class immuno-modulatory antibodies for cancer therapy, with currently four drug candidates in five ongoing clinical programs in Phase 1/2 trials for the treatment of hematological cancer and solid tumors, respectively. The Company's validated, proprietary F.I.R.S.T™ technology platform identifies both targets and the antibodies that bind to them, generating many promising new drug candidates to fuel the Company's own clinical development pipeline and providing licensing and partnering opportunities.

BI-1808 is an anti-TNFR2 antibody being evaluated in a Phase 2 trial, as a single agent and in combination with the anti-PD-1 therapy Keytruda® (pembrolizumab) in patients with ovarian cancer, non-small cell lung cancer and cutaneous T-cell lymphoma (NCT04752826).

Program: Therapy Acceleration Program
Project Term: Start Date: January 17, 2023 End Date: July 24, 2024
Dren logo

Dren Bio, INC

TAP Partner

Foster City, California
United States

A phase 1 study of DR-01, an anti-CD94 monoclonal antibody, in patients with large granular lymphocytic leukemia or cytotoxic lymphomas

In November 2022, LLS made an equity investment in Dren Bio to "Support Clinical Development of the DR-01 Program for Rare Leukemia & Lymphoma Indications Including Large Granular Lymphocyte Leukemia (LGLL) and Cytotoxic Lymphomas."

Dren Bio is a clinical-stage biopharmaceutical company focused on developing therapeutic antibodies for the treatment of cancer, autoimmune and other serious diseases. Dren Bio’s pipeline encompasses two distinct programs, the first focusing on the engineering of antibodies with enhanced antibody-dependent cellular cytotoxicity (ADCC) capabilities and the second revolving around its proprietary Targeted Myeloid Engager and Phagocytosis Platform.

DR-01 is a novel antibody targeting CD94 which is known to be upregulated on LGLL cells. DR-01 functions through depletion of target cells via ADCC by means of fratricide, a method in which the same cell type induces ADCC on each other. A Phase 1 trial has been initiated to assess the safety and efficacy of DR-01 in previously treated LGLL patients (NCT05475925).

Program: Therapy Acceleration Program
Project Term: Start Date: November 21, 2022 End Date: July 24, 2024
Dr. Mak

Tak Mak, PhD

Princess Margaret Cancer Centre, University Health Network

Toronto, Ontario
Canada

The Immune Niche in the Development of Hematological Malignancies and Implications for Novel Therapy

Our SCOR Program, composed of four complementary Projects supported by three shared Cores, is designed to determine how the immune niche and factors in its composition and regulation affect the initiation and progression of hematopoietic malignancies. Using genetically engineered mouse models, cell cultures and patient samples, the power of multi-omics analyses will be brought to bear to identify common drivers and expose underlying mechanisms. Findings from this work should reveal multiple candidate therapeutic targets whose exploitation may lead to the development of broadly applicable therapeutics for leukemias/lymphomas. Partnerships with pre-clinical and clinical trials experts at our home institutions and beyond will facilitate the translation of our findings to the bedside and potentially provide new hope to patients suffering from these devastating cancers.

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2022 End Date: September 30, 2027
Dr. Soiffer

Robert Soiffer, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Understanding and Overcoming Mechanisms of Immune Evasion after Allogeneic Transplant

Outcomes for patients with acute myelogenous leukemia who relapse after transplantation are dismal. This SCOR brings together an international group of collaborators with deep expertise in genomics, epigenetics, antigen presentation, and immune-regulation. They will focus on mechanisms of immune evasion by leukemia cells, identifying effective T cell responses to those evasive processes, and providing critical insights into the optimal approaches to model new and promising targets for immunotherapy with a goal of eliminating leukemia recurrence.

 

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2022 End Date: September 30, 2027
Dr. Crews

Leslie Crews, PhD

University of California, San Diego

San Diego, California
United States

Inflammation-responsive mechanisms of malignant stem cell generation and eradication in multiple myeloma

The focus of my research is to elucidate the core molecular regulators of malignant stem cell generation in multiple myeloma. My approach addresses the tumor cell-intrinsic versus niche-dependent mechanisms of myeloma regeneration by exploring transcription factor expression and stemness profiles within single cells from primary samples and patient-derived models. The central goal of my research is to uncover novel therapeutic strategies and translate these into new myeloma treatments.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2027
Dr. Flowers

Christopher Flowers, MD

The University of Texas MD Anderson Cancer Center

Houston, Texas
United States

Research Infrastructure to Promote Enrollment of Underserved Patients on Clinical Trials

The goal of the Clinical Trial Network of South Texas is to expand access to high quality clinical trials for under-represented minority (African American and Hispanic) patients with lymphoid cancers who receives care at the UT San Antonio Mays Cancer Center (MCC) and community oncology centers in South Texas. To achieve this goal, we will leverage the existing partnership between MD Anderson Cancer Center (MDACC) and its robust clinical trial infrastructure to identify and deploy suitable clinical trials. We also will strengthen the research infrastructure at MCC and community sites, including providing equipment, clinical trial navigation support, and oversight to successfully deploy trials. By establishing MDACC/MCC as a hub for clinical trials, developing the necessary research infrastructure at community oncology centers, and allowing patients to participate in clinical trials at their local oncology centers, this IMPACT program has the potential to improve clinical outcomes.

Program: IMPACT
Project Term: Start Date: October 1, 2022 End Date: September 30, 2027
Ari Melnick

Ari Melnick, MD

Weill Cornell Medicine

New York, New York
United States

Molecular Pathogenesis and Therapeutic Targets for Transformed Marginal Zone and BN2 Lymphomas

This project is the first to explore the origin of a newly discovered type of lymphoma called “BN2-DLBCL”. Mutations in a gene called “SPEN” are a defining feature of these tumors. Strikingly, SPEN mutations are more common in females and cause more deadly disease. Our proposal will reveal for the first time how these tumors originate from the immune system, how they are intimately linked to autoimmune disorders such as Lupus, why they occur preferentially in women, and how to cure them.

 

Program: Discovery
Project Term: Start Date: October 1, 2022 End Date: September 1, 2025
Eirini Papapetrou

Eirini Papapetrou, PhD, MD

Icahn School of Medicine at Mount Sinai

New York, New York
United States

GNAS as a new therapeutic target for MDS

Myelodysplastic syndrome (MDS) is a blood disease with poor prognosis and frequent progression to acute myeloid leukemia (AML). There are currently no effective treatments. This proposal is based on a recent discovery by my group and proposes to investigate a protein called G⍺s (alpha subunit of the stimulatory G protein), as a novel therapeutic target for MDS. If successful, this work can lead to novel therapies that can transform the treatment of MDS, AML and possibly other cancers.

Program: Discovery
Project Term: Start Date: October 1, 2022 End Date: September 30, 2025
Dr. Godley

Lucy Godley, MD PhD

Northwestern University

Evanston, Illinois
United States

CHEK2 as a predisposition gene for clonal hematopoiesis and hematopoietic malignancies

This proposal explores how inherited mutations in the DNA repair gene CHEK2 lead to blood cancers. Our work employs two unique resources: patient-derived cell lines and mice engineered with an inherited Chek2 variant that accurately models how bone marrow stem cells acquire DNA changes over time leading to bone marrow cancers. Our results may lead to new approaches that slow or prevent blood cancers in people with high risk.

Program: Discovery
Project Term: Start Date: October 1, 2022 End Date: September 30, 2025
Michael Kharas

Michael Kharas, PhD

Memorial Sloan Kettering Cancer Center

New York, New York
United States

Discovering the function and targeting dysregulated nuclear condensates in myeloid leukemia

Although molecular targeted therapy has dramatically changed how we treat cancer, the treatment for acute myeloid leukemia (AML) remains focused on the use of cytotoxic drugs with many patients eventually relapsing with their disease. Our studies have a uncovered a new nuclear structure that is dysregulated in myeloid leukemia. This proposal studies the identity and function of this nuclear body in human AML and strives to identify novel therapeutic strategies and targets in leukemia.

Program: Discovery
Project Term: Start Date: October 1, 2022 End Date: September 30, 2025
Dr. Jaiswal

Siddhartha Jaiswal , MD PhD

Stanford University

Stanford, California
United States

Uncovering the role of TCL1A as a driver of clonal hematopoiesis and hematological malignancies

Mutations in a diverse set of genes can lead to pre-cancerous expansion of blood stem cells, but the factors that mediate the growth of these mutant clones are unknown. We recently discovered that many of these mutations lead to abnormal activation of a gene called TCL1A. Consequently, TCL1A may be an attractive target for treating or preventing blood cancers, but little is known about its function. Here, we will uncover how TCL1A influences the biology of pre-cancerous blood stem cells.

Program: Discovery
Project Term: Start Date: October 1, 2022 End Date: September 30, 2025
Dr. Siddiqi

Tanya Siddiqi, MD

City of Hope National Medical Center

Duarte, California
United States

Establishing Hematology Clinical Trial Hubs within the City of Hope Community and Affiliate Network

City of Hope (COH) has embarked on a strategic initiative to optimize our clinical network and increase research capacity at our Community and Affiliate Network (CAN) sites in Southern California. I would like to spearhead this endeavor for the Hematology program at our new Irvine campus in Orange county, which is set to open in August 2022. We are employing a hub-and-spokes model, in which the Duarte main campus is the main research center, with 3-5 multi-disciplinary CAN sites ultimately designated as research hubs. These CAN sites (hubs) will serve geographically proximal practice sites (spokes), which will refer patients for treatment on clinical trials at either the CAN site itself or at the main Duarte campus. Following a 6-month pilot for optimizing staffing, investigational pharmacy setup, specimen and data collection in Irvine, an additional CAN site will be initiated each year over a 5-year period to allow a wider area of Southern California residents to have access to high quality and impactful clinical trials in Hematology. Our ultimate goal is to accrue 20-50 patients per year from the community, depending on the number of sites activated each year.

Program: IMPACT
Project Term: Start Date: October 1, 2022 End Date: September 30, 2027
Dr. Gill

Saar Gill, MD PhD

Perelman School of Medicine at the University of Pennsylvania

Philadelphia, Pennsylvania
United States

Role of the AML "Immunome" in response and failure of chimeric antigen receptor T cell therapy

Most patients with acute myeloid leukemia (AML) are not cured with chemotherapy alone, and most long-term survivors of AML have undergone an allogeneic stem cell transplant (also known as bone marrow transplant). The outlook is quite grim for patients whose AML relapses after transplant. We have developed a new type of treatment for AML called chimeric antigen receptor (CAR) T cells for these patients. The goal of this project is to investigate how to improve CAR T cells for AML.

Program: Discovery
Project Term: Start Date: October 1, 2022 End Date: September 30, 2025
Dr. Jones

Courtney Jones, PhD

Cincinnati Children’s Hospital Medical Center

Cincinnati, Ohio
United States

Interrogation of glutathione biology in relapsed acute myeloid leukemia stem cells

Acute myeloid leukemia (AML) is a devastating blood cancer. Most AML patients will initially respond to standard therapy; however, for many patients the disease recurs resulting in patient death. Consequently, there is an urgent need to develop new therapeutic strategies for relapsed AML patients. The objective of our proposal is to understand and target properties specific to relapsed AML cells with the overall goal of improving relapsed AML patient outcomes.

Program: Discovery
Project Term: Start Date: October 1, 2022 End Date: September 30, 2025
Dr. Qi

Jun Qi, PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Dissect the function of histone demethylase KDM5 on overcoming drug resistance toward immunotherapy in multiple myeloma

We identified that KDM5 can regulate important transcription factors in multiple myeloma (MM) and regulate the bone marrow (BM) microenvironment in providing protection toward MM, which also reduces anti-MM immunity. Thus, our study will utilize our novel potent and selective KDM5 inhibitor to fully dissect the interactions between MM cells, the BM microenvironment and the immune system in cellular and animal models to establish important mechanistic insights into MM.

Program: Discovery
Project Term: Start Date: October 1, 2022 End Date: September 30, 2025
Dr. Ji

Xu Ji, PhD

Emory University

Atlanta, Georgia
United States

Impact of Health Insurance on Mortality for Children and AYAs Newly Diagnosed with a Blood Cancer: A Population-Based Multistate Evaluation

Lacking continuous insurance is a key barrier to access to timely care. This study will provide the first evidence of whether insurance continuity provides a survival benefit, and how Medicaid expansion under the Affordable Care Act affects insurance continuity and the associated downstream changes in survival for children, adolescents, and young adults with blood cancers. This study will inform policy interventions toward increasing access and reducing disparities in blood cancer outcomes.

Program: Equity in Access
Project Term: Start Date: June 1, 2022 End Date: May 31, 2024
Dr. Wong

F. Lennie Wong, PhD

Beckman Research Institute of the City of Hope

Duarte, California
United States

Role of Health Insurance and Medicaid Expansion in Racial Inequity in Patterns of Care and Outcomes in Multiple Myeloma

Multiple myeloma is the most common blood cancer in African Americans. Thanks to advances in treatment, over 50% of patients now survive 5 years compared to 35% in 2000. However, African American patients may not be enjoying the same health gain as White patients, possibly due to poorer access to healthcare. This study will examine the role of health insurance and living in states with expanded eligibility for Medicaid on treatment patterns and survival in African Americans compared to White patients with multiple myeloma.

Program: Equity in Access
Project Term: Start Date: June 1, 2022 End Date: May 31, 2024
Dr. Dusetzina

Stacie Dusetzina, PhD

Vanderbilt University Medical Center

Nashville, Tennessee
United States

Making the Right Choice: Medicare Plan Selection and Access to Cancer Care

Selecting a Medicare plan is a time-sensitive and complex decision with substantial financial implications, particularly for individuals with cancer. The proposed project evaluates the financial and health outcomes for individuals selecting different Medicare coverage options and how these outcomes vary by the presence and timing of a cancer diagnosis. The goal of this work is to identify opportunities to improve plan selection and reduce inequities in cancer care and outcomes.

Program: Equity in Access
Project Term: Start Date: June 1, 2022 End Date: May 31, 2024
Jonathan Licht

Jonathan Licht, MD

University of Florida

Gainesville, Florida
United States

Adenylate Kinase 2-A Novel Therapeutic Target in Multiple Myeloma

We identified the adenine nucleotide regulator AK2 as a selective dependency in multiple myeloma (MM) that is more essential for survival of MM cells overexpressing the histone methyltransferase NSD2. Here, we propose a series of experiments to understand the role of AK2 in MM cell fitness and response to existing therapies and elucidate the molecular basis of the increased dependence on AK2 driven by NSD2 overexpression. This study will elucidate the effects of AK2 inhibition in MM and will credential the enzyme as a therapeutic target.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Steidl

Christian Steidl, MD PhD

BC Cancer, The University of British Columbia

Vancouver, British Columbia
Canada

Targeting aberrant non-canonical NF-κB pathway activation in B-cell lymphomas

The impact of biological heterogeneity on treatment outcomes is evidenced by a large proportion of lymphoma patients who experience relapsed/refractory disease. To address this knowledge gap, we sequenced primary lymphoma samples and found recurrent mutations in the non-canonical NF-kB pathway (NC NF-kB) and uncovered the NIK kinase as a targetable candidate. Our next steps focus on using advanced genetic modelling approaches to provide preclinical rationale for targeting NC NF-kB in lymphomas.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Kathleen Sakamoto

Kathleen Sakamoto, PhD, MD

Stanford University

Palo Alto, California
United States

Niclosamide for the Treatment of Relapsed/Refractory Pediatric Acute Myeloid Leukemia

Niclosamide is an FDA approved anti-parasitic drug that is well tolerated and acts synergistically with chemotherapy to kill AML cells. We will conduct a Phase I clinical trial with niclosamide in combination with cytarabine for children with relapsed/refractory pediatric AML. ShRNA/CRISPR screens demonstrated that Bcl-2 is upregulated in niclosamide resistant cells. We will study the effects of the Bcl-2 inhibitor venetoclax in combination with niclosamide in pediatric AML.

Program: Translational Research Program
Project Term: Start Date: June 30, 2022 End Date: June 30, 2025
Dr. Paul

Suman Paul, MBBS PhD

The Johns Hopkins University School of Medicine

Baltimore
United States

TCR directed immunotoxins and antibody drug conjugates for the treatment of T cell malignancies

Few treatment options are available for T cell leukemias and lymphomas, collectively called T cell cancers that affect ~100,000 patients worldwide each year. The current proposal will generate new antibodies attached to drugs and toxins that kill the T cell cancers. Importantly, the antibodies will preserve enough healthy T cells to maintain a functioning immune system. These modified antibodies may improve patient outcome and limit side effects associated with traditional chemotherapies.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Hamilton

Mark Hamilton, MD PhD

Stanford University

Stanford, California
United States

Cell-free DNA analysis of persistent CAR T-cell populations in humans

The focus of this research project is to understand how therapeutic chimeric antigen receptor (CAR) T-cells mediate long-term remission of diffuse large B-cell lymphomas. I will use cell free DNA collected from patient plasma to understand if there is an association of CAR T-cell persistence and long-term tumor remission. The goal of this research is to define how CAR T-cells suppress tumors over time to develop better CAR T-cells in the future.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: July 24, 2024
Dr. Nassar

Nicolas Nassar, PhD

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio
United States

Overcoming RAS-driven Mechanisms of Resistance in Leukemia

The mitogen-activated protein kinase (MAPK) pathway is activated in high-risk leukemia and is a hallmark of resistance to therapies. This project uses patient-derived xenograft models of relapsed pediatric ALL and AML with activated RAS/MAPK to test whether clinically relevant MAPK mutations activate the VAV3/RAC pathway and if pharmacological inhibition of that pathway by a small molecule we developed synergizes with a MAPK-inhibitor to provide a new treatment strategy for RAS-driven leukemia.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Markus Muschen

Markus Muschen, PhD, MD

Yale University

New Haven, Connecticut
United States

Targeting SYK:ZAP70 coexpression in refractory B-cell malignancies

The B-cell kinase SYK and its T-cell homolog ZAP70 have almost identical functions but are strictly segregated to B- and T-cells. We recently discovered that B-cell malignancies frequently coexpress ZAP70 and that only SYK but not ZAP70 can trigger negative B-cell selection and cell death. Here we test the hypothesis that ZAP70 enables malignant B-cell transformation, test pharmacological SYK-hyperactivation and validate ZAP70 as biomarker of patients who benefit from this approach.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Strati

Paolo Strati, MD

The University of Texas MD Anderson Cancer Center

Houston, Texas
United States

A Phase I/II Study of the Combination of ALX148, Rituximab and Lenalidomide in Patients with Indolent and Aggressive B-cell Non-Hodgkin Lymphoma

SIRPα+ macrophages mediate resistance to lenalidomide in B-cell lymphoma, limiting the activity of immunotherapy for these patients. Therefore, we propose a phase I/II study, investigating the safety and efficacy of ALX148, a novel fusion protein of the SIRPα binding domain, in combination with rituximab and lenalidomide in patients with B-cell lymphoma. We hypothesize that this combination will be safe and effective, providing a chemotherapy-free option for these patients.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2027
Dr. Wen

Hong Wen, PhD

Van Andel Research Institute

Grand Rapids, Michigan
United States

Investigating and targeting the histone acetylation reader protein ENL in acute leukemias

Leukemia often results from aberrant gene expression caused by epigenetic alterations. Previously we discovered a novel histone acetylation reader domain in the ENL protein and demonstrated that this domain is essential for the survival of a wide range of acute leukemias, making it an attractive therapeutic target. We will develop specific inhibitors of ENL activity in acute leukemias and will use mouse models to define the role of ENL mutations identified in patients in leukemogenesis.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2027
Dr. Herranz

Daniel Herranz, PharmD, PhD

Rutgers University

New Brunswick, New Jersey
United States

Therapeutic exploitation of novel mouse models and metabolic interventions in leukemia

Our research program aims to gain a deeper understanding of the pathobiology of T-ALL and HSTL.

To this end, we will use novel mouse models, cutting-edge techniques and comprehensive genetic, pharmacological and metabolic interventions. In addition, we will perform unbiased experiments to identify novel therapeutic targets.

Our goal is to uncover new tools and targets for the treatment of T-ALL and HSTL, which could be used for the benefit of patients in the short/mid-term.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2027
Dr. McNerney

Megan McNerney, MD PhD

The University of Chicago

Chicago, Illinois
United States

Genomic interrogation of high-risk myeloid neoplasms to identify new therapies

The long-term goal of my research program is to improve the outcomes for patients with high-risk myeloid blood cancers, particularly those with loss of chromosome 7 or CUX1. We are tackling this question using an arsenal of innovative methods and tools, including mouse models, human cells and patient samples, and state-of-the-art technologies to examine the cancer cell genome. Accomplishing this work will reveal new treatments and strategies for preventing blood cancers from arising.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2027
Dr. Yang

Yibin Yang, PhD

Fox Chase Cancer Center

Philadelphia, Pennsylvania
United States

Analysis and therapeutic targeting of the immune regulatory and ubiquitination pathways in Anaplastic Large Cell Lymphoma and Hodgkin Lymphoma

My lab is focused on the immune regulatory mechanisms and ubiquitin-dependent machinery in lymphoma. We have established multiple high-throughput screening technologies and animal models to rapidly and accurately identify critical pathways that are suitable for targeted therapy and immunotherapy. Gaining insight into the pathological roles of these pathways can lead to improved understandings of the molecular circuitry that drives lymphoma pathogenesis and provide novel therapeutic strategies.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2027
Dr. Maxson

Julia Maxson, PhD

Oregon Health & Science University

Portland, Oregon
United States

Targeting the interplay between signaling and transcriptional dysfunction in myeloid leukemias

Our research program is focused on understanding the intersection between signaling and transcriptional dysfunction in myeloid leukemias. We leverage murine models, cell lines and human samples to uncover how biological context shapes the manifestation of oncogenic programs at the molecular level. Our long-term goal is to harness this knowledge to identify multipronged therapeutic strategies that improve outcomes for patients with myeloid malignancies.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2027
Dr. Lindsley

Coleman Lindsley, MD PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Genetic pathways of myeloid transformation and treatment response

Our central goal is to improve clinical outcomes in patients with myeloid malignancies through developing an enhanced mechanistic understanding of disease. We use multiomic analyses of primary patient samples combined with complementary laboratory models using mice and cell lines to generate and test our hypotheses. The results of our studies will help improve patient outcomes by identifying strategies to mitigate risk of disease progression/relapse and treatment toxicity.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2027
Dr. Busino

Luca Busino, PhD

Perelman School of Medicine at the University of Pennsylvania

Philadelphia, Pennsylvania
United States

Relevance of ubiquitin dependent proteolysis in Diffuse Large B-cell lymphoma

The goal of this proposal is to investigate the significance of genes of the ubiquitin proteasome system (UPS) that are mutated in Diffuse Large B-cell Lymphoma (DLBCL). Our studies leverage the expertise in the molecular modeling of the UPS in the pathogenesis of DLBCL utilizing mouse models, patient derived xenotransplant (PDX) and cell lines. Our goal is the understanding of how genetic mutations contribute to disease development, progression and therapeutic outcome.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2027
Dr. Takahashi

Koichi Takahashi, MD

The University of Texas MD Anderson Cancer Center

Houston, Texas
United States

Understanding the clonal origin, evolution, and progression of myeloid malignancies

The overarching focus of my research is to understand the clonal origin, evolution, and progression of myeloid malignancies and biological and clinical factors that influence the process. We tackle this question by analyzing patient samples with integrated approach combining single-cell omics, evolutionary genetics, and computational analytics. The ultimate goal of our research is to develop clinical strategies for early detection, prevention, and treatments of myeloid malignancies.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2027
Dr. LeBlanc

Thomas LeBlanc, MD, MA, MHS, FAAHPM

Duke University

Durham, North Carolina
United States

Patient Experience Research and Palliative Care Integration in Malignant Hematology

My research aims to improve the patient and caregiver experience of blood cancer care. To achieve this, I conduct trials of integrated palliative care interventions. Palliative care improves patient and caregiver outcomes for those with solid tumors, but less is known about its role in hematology. My research aims to design and implement integrated palliative care interventions in blood cancer settings, to improve the patient and caregiver experience of illness, regardless of treatment outcome.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2027
Dr. Philips

Tycel Phillips, MD

Beckman Research Institute of the City of Hope

Duarte, California
United States

Stratified treatment of newly diagnosed MCL based on the presence or absence of high risk features utilizing non-cytotoxic agents.

We believe that regimens without chemotherapy can induce significant and durable remissions in patients with Mantle cell lymphoma (MCL). We will confirm this hypothesis by conducting two clinical trials stratified by the presence or absence of high risk features. We will utilize BH3 profiling and MRD testing to assist with predicting treatment response and remission. Our goal is to verify the efficacy of our regimen and prove the utility of BH3 profiling and MRD testing in outcome prediction.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: September 30, 2027
Dr. Mehta-Shah

Neha Mehta-Shah, MD

Washington University School of Medicine in St. Louis


United States

Predictors of response to therapy in A051902, a US Intergroup study of duvelisib+CHO(E)P vs CC-486+CHO(E)P vs CHO(E)P in peripheral T-cell lymphoma

We are evaluating if adding duvelisib or azacitidine to standard chemotherapy increases the complete remission rate compared to chemotherapy alone in peripheral T-cell lymphoma. We believe that adding novel agents to chemotherapy will most benefit lymphomas with a T-follicular helper phenotype. We will also study if tests for lymphoma cells in the blood can predict outcomes. We hope these novel therapies will cure more patients and we can identify who is most likely to benefit from them.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2027
Dr. Shah

Nirav Shah, MD, MSHP

Medical College of Wisconsin

Milwaukee, Wisconsin
United States

Improving Bispecific CD20/CD19 CAR T-cell Therapy to Overcome Resistance Mechanisms in B-cell Malignancies

The objective of this proposal is to improve bispecific anti-CD20/anti-CD19 CAR T-cell activity and persistence by understanding impact of cell manufacturing parameters on final engineered CAR-T product and determining resistance mechanisms in relapsing patients. We will analyze patient apheresis, final CAR-T product, and peripheral blood samples from subjects enrolled on an ongoing clinical trial (NCT04186520). Data from these studies will advance CAR T-cell therapies for lymphoma patients.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2027
Dr. Jain

Nitin Jain, MD

The University of Texas MD Anderson Cancer Center

Houston, Texas
United States

Combination Targeted Therapy in Chronic Lymphocytic Leukemia

Targeted therapies have replaced chemoimmunotherapy in chronic lymphocytic leukemia (CLL). We previously reported that combined BTK inhibitor (ibrutinib) and BCL2 antagonist (venetoclax) is highly synergistic. In this proposal, we will conduct a phase II trial of combined non-covalent BTK inhibitor (pirtobrutinib) with venetoclax and obinutuzumab in patients with untreated CLL with primary endpoint of marrow MRD. We will perform BH3 profiling and scRNAseq and correlate with clinical outcomes.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2027
Dr. Kristinsson

Sigurður Kristinsson, MD PhD

University of Iceland

Reykjavík
Iceland

Early Detection and Intervention in Smoldering Multiple Myeloma: population-based screening and treatment; Edit-SMM

We build on the success from the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study, where over 80,000 consented to a nationwide screening for MM precursors. A unique cohort of patients with SMM diagnosed in iStopMM will be followed by clinical evaluation, linking to central health data registries, using novel biomarkers, and in-depth genetics. With precision early treatment we aim to induce a paradigm shift leading to improved quality of life and potentially a cure for MM.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2027
Dr. Saygin

Caner Saygin, MD

The University of Chicago

Chicago, Illinois
United States

Deciphering the interplay between apoptotic and signaling pathways to target T-lineage acute lymphoblastic leukemia

T-ALL is an aggressive leukemia with limited treatment options. T-ALL cells resist to dying by suppressing their suicide pathways. BH3 mimetics reactivate the suicide mechanisms to induce cell death. We showed that these drugs are effective in T-ALL, but acquired resistance is due to the activation of growth-promoting signaling pathways. The proposed experiments will decipher the relationship between growth and death pathways, identifying unique combination therapies to improve disease outcomes.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Morelli

Eugenio Morelli, MD

Candiolo Cancer Institute

Turin
Italy

Defining the Biologic and Therapeutic Significance of the Novel Long Noncoding RNA MYND in Multiple Myeloma

Long non-protein coding RNAs (lncRNAs) are fundamental for proper cell function, but their purpose is poorly understood in multiple myeloma. To systematically identify myeloma-promoting lncRNAs, we integrated gene expression profiling of myeloma patients with high-throughput loss-of-function studies in cell lines. Moreover, we optimized strategies to antagonize myeloma-promoting lncRNAs, thus paving the way to developing lncRNA inhibitors as the next generation of therapy.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2024
Dr. Baeten

Jeremy Baeten, PhD

Washington University in St. Louis

St. Louis, Washington
United States

Combined targeting of ATR and replicative stress in TP53-mutated AML

This research will test a promising new drug combination in acute myeloid leukemia (AML) carrying TP53 gene mutations, which is resistant to chemotherapy and has a median survival of less than 5 months. Our preliminary data show that TP53-mutated AML is selectively sensitive to the combination of an ATR inhibitor and decitabine. We will confirm activity of this novel drug combination using mouse models of leukemia and human AML samples and explore mechanisms of responsiveness.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2024
Dr. Booth

Christopher Booth, PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Mechanisms of Pathogenesis by MYB Fusions in Blastic Plasmacytoid Dendritic Cell Neoplasm

The transcription factor MYB has long been associated with leukemia, but how it contributes to disease is poorly understood. Fusions of MYB to other proteins, causing MYB activation, are found in patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN), but rare in other leukemias. I am using recently developed techniques to gain insight into how MYB fusions cause BPDCN. This will enable both new treatments for BPDCN and better understanding of the role of MYB in other leukemias.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2024
Dr. Luo

Qingyu Luo, MD PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Defining PIK3R5-related PI3K gamma dependency as a novel therapeutic target in blood cancers including BPDCN

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive blood cancer without adequate treatment. In a genome-wide CRISPR interference screen, BPDCN was highly dependent on the PI3Kγ pathway and specifically the PIK3R5 adaptor subunit. A subset of leukemias may share this vulnerability. We will interrogate the mechanism of this unique dependency and integrate PIK3R5/PI3Kγ targeting with leukemia therapy. Our goal is to provide novel treatments for PIK3R5-dependent malignancies.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Kramer

Frederike Kramer, PhD

Brigham and Women’s Hospital

Boston, Massachusetts
United States

Investigating the Role of ASXL1 Mutations in CALR-mutated Myeloproliferative Neoplasms

My research focuses on myeloproliferative neoplasms (MPN) and the mutations that drive the progression of these blood cancers. Currently, I am investigating mutations in the gene ASXL1, which are associated with a poor prognosis. I am using mouse models and patient-derived cells to determine how ASXL1 mutations mediate epigenetic changes in MPN. My goal is to identify ways of targeting the pathological mechanisms caused by ASXL1 mutation, resulting in new treatment strategies for patients.

Program: Career Development Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Kipps

Thomas Kipps, MD PhD

University of California, San Diego

San Diego, California
United States

Targeting Oncoembryonic Antigens ROR1 and ROR2 For Therapy Of Patients With Hairy Cell Leukemia

We will study the function of ROR1 and ROR2 on HCL cells that we have collected from 120 patients, examining whether they influence expression of genes that can promote the growth/survival of HCL cells. We have made antibodies that are highly specific for ROR1 or ROR2 that react with HCL cells, but not normal blood cells or tissues. We will determine if these antibodies can be used as naked antibodies, antibody-drug conjugates, or in chimeric receptors on T cells to specifically kill HCL cells.

Program: HCL2025
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Grant Challen

Grant Challen, PhD

Washington University in St. Louis

St. Louis, Missouri
United States

Precision Medicine For DNMT3A-Mutant T-cell ALL

T-cell ALL is an aggressive blood cancer with poor overall survival, high relapse rates, and significant treatment-related side effects. Using primary T-ALL patient samples, this project will study the importance of JAK/STAT signaling and the gene BIRC5 in the pathology of T-ALL driven by DNMT3A mutations using genetic and pharmacological tools. The goal of this proposal is to develop precision medicine approaches for DNMT3A-mutant adult T-ALL patients, a group with poor clinical outcomes

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Ferrari De Andrade

Lucas Ferrari De Andrade, PhD

Icahn School of Medicine at Mount Sinai

New York, New York
United States

Optimizing MICA/B antibody for AML by selective binding to Fc activating receptors

Acute myeloid leukemia (AML) is a blood cancer characterized by poor clinical outcomes. We developed an antibody that inhibits AML in models by triggering anti-leukemia immunity. Now we developed a new version of this antibody with higher affinity to the leukocyte receptors that mediate anti-leukemia immunity. We will establish the ability of this optimized antibody to elicit greater inhibition of AML. The studies will generate important information about how to induce anti-leukemia immunity.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Ruella

Marco Ruella, MD

Perelman School of Medicine at the University of Pennsylvania

Philadelphia, Pennsylvania
United States

Precision Targeting of Hairy Cell Leukemia using Chimeric Antigen Receptor T cells

Though effective treatments in hairy cell leukemia and variant (HCLv) exist, they are associated with profound immunosuppression; thus, more targeted, non-toxic therapies are warranted. In order to specifically target leukemic cells while sparing most normal B cells, we will develop a novel chimeric antigen receptor T cell immunotherapy against the IGHV-4-34 B-cell receptor that is found in a significant subset of HCL and associates with poor prognosis.

Program: HCL2025
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Klein

Peter Klein, MD PhD

Perelman School of Medicine at the University of Pennsylvania

Philadelphia, Pennsylvania
United States

Targeting splicing factor mutant myelodysplastic syndromes through GSK-3

Myelodysplasia (MDS) is a lethal stem cell disorder characterized by defective blood formation and progression to leukemia. MDS is frequently caused by mutations in splicing factors, but these mutations also create an Achille’s heel that can be targeted to kill MDS cells while sparing normal blood cells. We identified a group of clinically safe drugs that target this weakness and selectively kill MDS cells in vitro. We will test whether these drugs are effective in mouse models of MDS.

Program: Discovery
Project Term: Start Date: October 1, 2022 End Date: September 30, 2025
Dr. Rowan

Alieen Rowan, PhD

Imperial College, University of London

London
United Kingdom

Detection and treatment of Adult T cell leukemia/lymphoma in the premalignant stage.

Clonally expanded T cells carrying somatic mutations circulate in the premalignant phase of Adult T cell leukemia/lymphoma (ATL). We will develop capture-sequencing of recurrent ATL-driver mutations for use as a diagnostic tool for the detection/characterization of ATL-like clones in individuals with high risk of ATL, and, in an aligned clinical study, we will test whether a novel monoclonal antibody (targeting C-C chemokine receptor 4) can eradicate these high-risk cells.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Alfred Garfall

Alfred Garfall, MD

Perelman School of Medicine at the University of Pennsylvania

Philadelphia, Pennsylvania
United States

Anti-Sox2 immunotherapy to prevent multiple myeloma relapse

Advances in multiple myeloma (MM) therapy have improved survival, but serial cycles of response and relapse still lead to treatment-refractory and fatal disease in nearly all patients. To specifically target mechanisms of MM relapse, we propose to develop an immunotherapy targeting Sox2, a stem-cell transcription factor implicated in clonogenic MM growth that enables relapse.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Ruella

Marco Ruella, MD

Perelman School of Medicine at the University of Pennsylvania

Philadelphia, Pennsylvania
United States

A First-in-human Clinical Trial of CD5 knocked-out Chimeric Antigen T Cells for T-cell Lymphomas

This proposal seeks to develop for the first time in humans a novel CD5 knocked out (KO) anti-CD5 chimeric antigen receptor T cell (CART) product for patients with relapsed or refractory T-cell lymphomas. In Aim#1, we will generate and test a clinical-grade CD5 KO CART5 product, and in Aim#2, we will perform a phase I clinical trial. This project is highly relevant to those parts of the LLS's mission that pertain to the development of personalized and novel therapies for cancer treatment.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Schultz

Kirk Schultz, MD

University of British Columbia

Vancouver
Canada

A Polyomic Approach to Chronic Graft-versus-Host Disease (cGvHD) Biomarkers in Adults

Our team is the first to develop a polyomic pediatric cGvHD biomarker test for assessing the risk of developing cGvHD. A cooperative adult phase III clinical trial, CTTC1901, between Canada and Australia, focused on decreasing cGvHD (N=350 patients), offers an ideal opportunity to validate adult cGvHD biomarkers. This proposal will utilize the pediatric polyomic approach to validate a cGvHD risk assignment and diagnostic algorithm in adult hematopoietic stem cell transplant (HSCT).

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Lock

Richard Lock, PhD

The University of New South Wales

Randwick
Australia

Therapeutic targeting of T-cell acute lymphoblastic leukemia using an AKR1C3-activated prodrug

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy that is exceptionally difficult to cure after relapse. We have previously shown that T-ALL expresses high levels of the enzyme AKR1C3, leading to clinical trials of AKR1C3-activated prodrugs. This project will focus on identifying the determinants of responses to AKR1C3-activated prodrugs in T-ALL and optimizing the use of a second generation AKR1C3-activated prodrug, SN36008, in T-ALL patient-derived xenografts.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Ricky Johnstone

Ricky Johnstone, PhD

The University of Melbourne

Parkville, Victoria
Australia

Dissecting the biology and exploiting the dependency of myeloma cells on P300/CBP

In recent work of our collaborating labs, the protein acetyltransferases P300 and CBP emerged as potent and preferential dependencies for multiple myeloma (MM) based on genetic depletion, catalytic inhibition or chemical degradation studies. Our current project will define distinct vs. redundant molecular and biological functions of P300/CBP in MM, identify the mechanisms of resistance to their inhibition/degradation and exploit these findings to develop new therapeutic modalities to treat MM.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Oliaro

Jane Oliaro, PhD

The University of Melbourne

Melbourne
Australia

Improving CAR-T cell therapy outcomes for patients with for aggressive lymphoma and multiple myeloma

Despite the promise of CAR-T cell immunotherapy for patients with lymphoma and multiple myeloma, a significant proportion of patients fail to respond or relapse following treatment. This project will focus on the clinical translation of a new treatment designed to improve durable response rates by combining CAR-T cell therapy with a new class of anticancer drugs called SMAC-mimetics. The results will provide the evidence base to drive a first-in-human clinical trial of this combination strategy.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Davis

Randall Davis, MD

The University of Alabama at Birmingham

Birmingham, Alabama
United States

Immunotherapeutic Targeting of FCRL1 in CLL

Evolving insights into the B cell-restricted FCRL1 surface protein reveal that it integrates with critical signaling pathways and is a promising immunotherapeutic target in CLL. Based on preclinical evaluation of novel FCRL1 monoclonal antibodies, we propose developing chimeric antigen receptor (CAR) T cells for targeting in unique mouse models and patient-derived cells. The results will form the basis for strategic drug development and clinical testing in CLL and related B cell malignancies.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Bhatia

Ravi Bhatia, MD

The University of Alabama at Birmingham

Birmingham, Alabama
United States

Prediction and prevention of therapy-related myeloid neoplasms following autologous transplantation

The proposed studies will identify alterations in hematopoietic regulation that predict for risk for therapy-related myeloid neoplasm (TMN) and improve understanding of disease evolution to guide strategies to prevent TMN in patients receiving autologous hematopoietic cell transplantation (aHCT) for lymphoma. They will investigate alterations in hematopoietic function in peripheral blood stem cell used for aHCT, and serial evolution of hematopoietic defects leading to development of TMN.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Thomas

Daniel Thomas, MD PhD

The University of Adelaide

Adelaide
Australia

Identification and Molecular Analysis of Pre-Myelofibrotic Stem Cells

Myelofibrosis is a severe myeloproliferative neoplasm with no known cure.We have obtained unique insights into the underlying mechanisms responsible for the emergence of myelofibrosis and designed new approaches to selectively control it. By combining our mutation-specific isolation methods with single cell sequencing, we will identify myelofibrosis-initiating stem cell populations, demonstrate efficacy of stem cell targeting and enumerate residual normal stem cells to inform a Phase I/II trial.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Lentzsch

Suzanne Lentzsch, MD PhD

Columbia University Medical Center

New York, New York
United States

Targeting the MMP-13/PD-1H signaling axis for multiple myeloma bone disease and immunosuppression

Multiple myeloma is an incurable blood cancer complicated by bone diseases and compromised immune system. Our work indicated that checkpoint inhibitor PD-1H(VISTA) functions as the MMP-13 receptor, and the MMP-13/PD-1H signaling axis plays a critical role in multiple myeloma induced bone disease and immunosuppression. Therefore, immunotherapy targeting the novel MMP-13/PD-1H interaction module represents a novel approach to cure this devastating cancer.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Yahalom

Joachim Yahalom, MD

Memorial Sloan Kettering Cancer Center

New York, New York
United States

Impact of sublethal radiation dose on tumor response, microenvironment and the immune system

Extremely low dose radiation can improve blood cancer outcomes. But the mechanisms of how sublethal radiation (SRT) affects tumors, the microenvironment and immune system remain unclear. We envision a broad, nuanced role for SRT with benefits across diverse clinical situations and propose 3 clinical trials with deep translational components. Each can be paradigm-changing, but are thematically unified to improve mechanistic understanding of how such exceptionally small doses might offer so much.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Jolanta Grembecka

Jolanta Grembecka, PhD

Regents of the University of Michigan

Ann Arbor, Michigan
United States

Targeted combination therapies for leukemia with NUP98 translocations

Leukemia patients with chromosomal translocations of the Nucleoporin (NUP98) gene suffer from very poor prognosis. In this project we will identify new treatment for these patients by combining menin inhibitor with FDA approved drugs. We will evaluate effectiveness, mechanism of action and biomarkers of treatment response to these combinations in advanced pre-clinical models of NUP98 leukemia. We expect these studies will lead to future clinical trials in AML patients with NUP98 translocations.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Puig Morón

Noemí Puig Morón, MD PhD

Institute of Biomedical Research from Salamanca

Salamanca
Spain

Peripheral blood-based disease monitoring by mass spectrometry in patients with multiple myeloma

The present project will investigate the ability of quantitative immune precipitation mass spectrometry (QIP-MS) to anticipate relapsed or progressive disease in peripheral blood samples from patients with multiple myeloma. In the context of the GEM2014MAIN trial (lenalidomide and dexamethasone plus or minus ixazomib as maintenance), we will assess the presence of disease by QIP-MS in parallel with conventional methods in serum and next generation flow in bone marrow samples.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Shanmugam

Mala Shanmugam, PhD

Emory University

Atlanta, Georgia
United States

Investigating anti-neoplastic effects of beta blockers in multiple myeloma

Multiple myeloma (MM) relies on the bone marrow (BM) niche to progress to refractory disease. We found that beta blockers alter BM niche elements fostering MM growth and also reduce MM cell survival. Our objective is to elucidate the cellular and metabolic basis of how beta adrenergic signals impact the BM niche and MM progression. Knowledge of the prophylactic and therapeutic utility of beta blockers in MM will unravel new means to target neural niche remodeling fueling this fatal malignancy.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Porter

Christopher Porter, MD

Emory University

Atlanta, Georgia
United States

Targeting Siglec15 to promote immune response to malignant B cells

The goal of this project is to explore a novel immunologic therapeutic target for hematologic malignancies, SIGLEC15 (Sig15). The central hypothesis is that Sig15 is aberrantly expressed in malignant B cells, is released to attenuate immune responses and can be targeted therapeutically to promote immune responses to malignant hematopoietic cells. This work will accelerate therapeutic exploitation of the immune system for the treatment of leukemia and lymphoma by targeting Sig15.

Program: Translational Research Program
Project Term: Start Date: July 1, 2022 End Date: June 30, 2025
Dr. Verma

Amit Verma, MBBS

Albert Einstein College of Medicine

Bronx, New York
United States

Studies on clonal hematopoiesis in the 911 WTC first responders

The terrorist attacks on the World Trade Center (WTC) created an unprecedented environmental exposure to WTC aerosolized dust and gases that contained known and suspected carcinogens including polycyclic aromatic hydrocarbons, polychlorinated biphenyls, polychlorinated furans, dioxins and asbestos. Studies from Dr. Verma's group and others have reported an excess of cancer cases in the WTC-exposed Fire Department of the City of New York (FDNY) firefighters, including a trend towards higher incidence of multiple myeloma and leukemias. He now will be deep sequencing a large group of WTC-exposed firefighters to look for clonal hematopoiesis (CH) which is an acquisition of leukemia associated mutations associated with increases in the risk of hematologic cancer.

Program: Special Grants
Project Term: Start Date: June 1, 2022 End Date: July 24, 2024
Dr. Logan Spector

Logan Spector, PhD

University of Minnesota

Minneapolis, Minnesota
United States

Genomics of childhood leukemia: Analysis of diverse, worldwide populations

Common genetic variation explains a large share of childhood leukemia in children of European ancestry and may explain the differing incidence in children of other ancestries. The Childhood Cancer and Leukemia International Consortium seeks to better understand the genomic architecture of childhood leukemia risk using its collective genomic datasets comprising >20,000 diverse children with leukemia. The results will inform risk prediction for and possibly prevention of childhood leukemia.

Program: Dare to Dream
Project Term: Start Date: March 1, 2022 End Date: February 28, 2025
Faron logo

Faron Pharmaceuticals, OY

TAP Partner

Turku
Finland

A phase 2 study of Bexmarilimab, an anti-Clever1 monoclonal antibody, in combination with azacitidine in patients with high-risk MDS

In June 2022, LLS made an equity investment in Faron Pharmaceuticals to "Support Clinical Development of the Bexmarilimab Program for Leukemia Indications."

Faron is a clinical stage biopharmaceutical company developing novel treatments for medical conditions with significant unmet needs caused by dysfunction of our immune system. The Company currently has a pipeline based on the receptors involved in regulation of immune response in oncology, organ damage and bone marrow regeneration. 

Bexmarilimab, a novel anti-Clever-1 humanized antibody, is its investigative precision immunotherapy with the potential to provide permanent immune stimulation for difficult-to-treat cancers through targeting myeloid function. A Phase 2 study (BEXMAB) of bexmarilimab in combination with azacitidine is currently enrolling high-risk MDS patients in the US and Finland (NCT05428969).

Program: Therapy Acceleration Program
Project Term: Start Date: June 30, 2022 End Date: July 24, 2024
ImCheck

ImCheck Therapeutics, SAS

TAP Partner

Marseille
France

A phase 2 expansion study of ICT01, an anti-BTN3A monoclonal antibody, in combination with azacitidine and venetoclax in patients with AML

In June 2022, LLS made an equity investment in ImCheck Therapeutics to "Support Clinical Development of the ICT01 Program for Blood Cancer Indications."

ImCheck Therapeutics is designing and developing a new generation of immunotherapeutic antibodies targeting butyrophilins, a novel super-family of immunomodulators.

ICT01 is a humanized, anti-BTN3A (also known as CD277) monoclonal antibody that selectively activates γ9δ2 T cells, which are part of the innate immune system that is responsible for immunosurveillance of malignancy and infections. The EVICTION study is currently enrolling a Phase 2 cohort expansion of ICT01 in combination with azacitidine and venetoclax in patients with newly diagnosed acute myeloid leukemia (NCT04243499).

Program: Therapy Acceleration Program
Project Term: Start Date: June 13, 2022 End Date: July 24, 2024
Maria Figueroa

Maria "Ken" Figueroa, MD

University of Miami

Coral Gables, Florida
United States

The role of KLF6 in aged hematopoiesis

Coming soon.

Program: Special Grants
Project Term: Start Date: April 1, 2022 End Date: November 30, 2022
Dr. Olszewski

Adam Olszewski, MD

Rhode Island Hospital

Providence, Rhode Island
United States

Mosunetuzumab with lenalidomide augmentation as first-line therapy for patients with follicular and marginal zone lymphoma

Dr. Olszewski’s trial will examine mosunetuzumab as a first-line treatment for follicular and marginal zone lymphomas—slow-growing types of B-cell lymphoma which remain incurable using current therapies. Mosunetuzumab is a “bispecific antibody” that can trigger an immune attack of patients’ own cancer-killing T-cells against the lymphoma. Dr. Olszewski team will look for characteristics that predict complete responses when this novel immunotherapy is applied as first-line treatment.

Program: Career Development Program
Project Term: Start Date: April 1, 2022 End Date: March 31, 2027
Dr. Catherine Smith

Catherine Smith, MD

University of California San Francisco

San Francisco, California
United States

SHP2 and BCL2 Inhibition in Acute Myeloid Leukemia

The goal of our work is to use a “bench to bedside and back” approach to develop new treatments for patients with relapsed/refractory AML. Through genetic analysis of patients who relapse or do not respond to standard and investigational treatments, we discover potential resistance mechanisms. In the lab, we test novel drugs and identify new drug targets that may address these resistance mechanisms when used in combination with other therapies. The overall goal of our research program is to improve treatment options and survival of patients with refractory AML.

Program: Career Development Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2026
Dr. Ann-Kathrin Eisfeld

Ann-Kathrin Eisfeld, MD

The Ohio State University

Columbus, Ohio
United States

Improving the outcomes of young Black adults diagnosed with acute myeloid leukemia

Young Black patients diagnosed with acute myeloid leukemia (AML) have significantly shorter survival compared to White patients. To comprehensively assess genetic, genomic and biologic contributors to the race-associated survival disparity, we propose a complementary approach that addresses major knowledge gaps in our current understanding of AML biology in Black patients, including the overdue characterization of the Black AML genome and subsequent delineation of biologic response to treatment.

Program: Translational Research Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2024
Dr. Timothy Graubert

Timothy Graubert, MD

Massachusetts General Hospital

Boston, Massachusetts
United States

Exploiting Vulnerabilities in RNA Splicing to Treat Hematologic Malignancies

RNA splicing is a central metabolic pathway that is frequently perturbed in hematopoietic malignancies (HMs) that harbor mutations in spliceosome components (most commonly affecting SRSF2, SF3B1, U2AF1, or ZRSR2). These mutations are particularly prevalent in myeloid malignancies (e.g., MDS, MDS/MPN, sAML), but recent pan-cancer studies have implicated aberrant splicing in >30 tumor types. The Project Leaders have probed the molecular consequences of aberrant splicing and identified critical pathways that are amenable to targeted inhibition, including the DNA damage response (Graubert/Walter), the nonsense-mediated RNA decay (NMD) pathway (You/Walter), the spliceosome itself (Abdel-Wahab/Walter/Graubert), and others. To date, effective therapies for HMs have not capitalized on these unique vulnerabilities. The goal of this SCOR is to generate testable clinical hypotheses based on careful mechanistic studies in pre-clinical models and to rapidly move these ideas into the clinic in the near term.

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2026
Dr. Thorsten Zenz

Thorsten Zenz, MD

Universitätsspital Zürich - Klinik für Medizinische Onkologie und Hämatologie USZ

Zurich
Switzerland

Charting the surfaceome to eliminate hairy cell leukemia (HCL)

To optimize treatment of HCL, we dissect the tumors` surface proteome to understand a) surface mediated signals and b) the dependence on BRAFV600E activity, to c) eradicate remaining cell populations after BRAF inhibitor treatment. We use chemoproteomics, which enable mass-spectrometric-based surfaceome discovery to quantitatively investigate HCL. We expect to identify HCL specific and BRAF-dependent surfaceomes and identify new and critical targets for treatment.

Program: HCL2025
Project Term: Start Date: October 1, 2021 End Date: September 30, 2023
Dr. Parameswaran

Reshmi Parameswaran, PhD

Case Western Reserve University School of Medicine

Cleveland, Ohio
United States

A novel BAFF CAR-T for treatment of HCL

Despite the success of Chimeric antigen receptor T cell (CAR-T) immunotherapies, disease relapse occurs in a majority of patients. We have developed a novel ligand based BAFF-CAR, that utilizes B cell activating factor (BAFF) as a ligand, which can bind to all three receptors of BAFF, which are expressed by malignant B cells including Hairy Cell Leukemia (HCL). We hypothesize BAFF CAR-T will be an effective therapeutic strategy for HCL.

Program: HCL2025
Project Term: Start Date: October 1, 2021 End Date: September 30, 2023
Kymera

Kymera Therapeutics, INC

TAP Partner

Watertown, Massachusetts
United States

A phase 1 study of KT-333, a STAT3 protein degrader, in patients with NHL

In March 2020, LLS made an equity investment in Kymera Therapeutics to "Support Studies with Protein Degraders for Development in Hematological Patients."

Kymera Therapeutics is a clinical-stage biopharmaceutical company founded with the mission to discover, develop, and commercialize transformative therapies while leading the evolution of targeted protein degradation, a transformative new approach to address previously intractable disease targets. Whereas most targeted therapies inhibit or inactivate the proteins or genes that drive the cancer, targeted protein degradation harnesses the body’s natural system of ridding itself of unwanted, “old” or “broken” components of cells.

KT-333 is STAT3 protein degrader and is enrolling NHL patients including T-cell lymphoma (PTCL, CTCL) and LGLL in a Phase 1 clinical trial (NCT05225584).

Program: Therapy Acceleration Program
Project Term: Start Date: March 11, 2020 End Date: July 24, 2024
Andrew Lane

Andrew Lane, PhD, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Blastic plasmacytoid dendritic cell neoplasm (BPDCN): understanding disease biology to improve therapy

We focus on blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive blood cancer with limited treatment options and poor outcomes. We want to understand what causes the disease, develop laboratory tools, and identify new treatments and ways to overcome therapy resistance. We have translated our discoveries to clinical trials. Our goal is to continue this bench to beside approach to develop the next generation of BPDCN therapies that improve survival and minimize treatment toxicity.

Program: Career Development Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2026
Simona Colla

Simona Colla, PhD

The University of Texas MD Anderson Cancer Center

Houston, Texas
United States

Validation of Critical 1q21 Vulnerabilities in multiple myeloma

In previous studies of recurrently amplified 1q21 genes in myeloma, we identified ILF2 as a modulator of the DNA repair pathway, which promotes adaptive responses to genotoxic stress. Thus, ILF2 may have clinical utility as a biomarker of aggressive myeloma and blocking the ILF2-mediated repair signaling may enhance the effectiveness of current DNA-damaging agent-based therapies. We are seeking to determine the feasibility of therapeutically targeting ILF2 with antisense nucleotides and identify DNA repair effectors whose loss of function induces synthetic lethality in ILF2-depleted myeloma.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Caribou

Caribou Biosciences, INC

TAP Partner

Berkeley, California
United States

A phase 1 study of CB-012, a CRISPR-edited allogeneic CAR-T targeting CLL1, in patients with acute myeloid leukemia

In February 2021, LLS made an equity investment in Caribou Biosciences to "Support allogeneic CD371 (CLL-1) CAR development for acute myeloid leukemia."

Caribou is a clinical-stage biotechnology company, co-founded by CRISPR pioneer and Nobel Prize winner Jennifer Doudna, Ph.D., using next-generation CRISPR genome-editing technology to develop “off-the-shelf” (allogeneic) CAR therapies for hard-to-treat blood cancers.

CB-012, an allogeneic CLL1 CAR-T cell therapy engineered with five genome edits, is the first allogeneic CAR-T cell therapy with both checkpoint disruption through a PD-1 knockout, and immune cloaking. The AMpLify Phase 1 clinical trial, which is evaluating CB-012 in patients with relapsed or refractory acute myeloid leukemia (r/r AML), is currently enrolling (NCT06128044).

Program: Therapy Acceleration Program
Project Term: Start Date: February 28, 2021 End Date: July 24, 2024
Caribou

Caribou Biosciences, INC

TAP Partner

Berkeley, California
United States

A phase 1 study of CB-011, a CRISPR-edited allogeneic CAR-T targeting BCMA, in patients with multiple myeloma

In February 2021, LLS made an equity investment in Caribou Biosciences to support "A Phase 1, Multicenter, Open-Label Study of CB-011, a CRISPR-Edited Allogeneic Anti-BCMA CAR-T Cell Therapy in Patients With Relapsed/Refractory Multiple Myeloma." 

Caribou is a leading clinical-stage biotechnology company, co-founded by CRISPR pioneer and Nobel Prize winner Jennifer Doudna, Ph.D., using next-generation CRISPR genome-editing technology to develop “off-the-shelf” (allogeneic) CAR therapies for hard-to-treat blood cancers.

CB-011, Caribou’s second allogeneic CAR-T cell therapy, targets BCMA for the treatment of relapsed/refractory multiple myeloma and is immunologically cloaked for enhanced persistence. The CaMMouflage Phase 1 clinical trial, a multicenter, open-label study to evaluate the safety and efficacy of a single dose of CB-011 in adult patients with relapsed or refractory multiple myeloma (r/r MM), is currently enrolling (NCT05722418).

Program: Therapy Acceleration Program
Project Term: Start Date: February 28, 2021 End Date: July 24, 2024
Jaroslaw Maciejewski

Jaroslaw Maciejewski, MD, PhD

Cleveland Clinic Foundation

Cleveland, Ohio
United States

HLA Mutations, GvH Resistance and Relapse Following Allogeneic Hematopoietic Stem Cell Transplant

This project investigates immunogenetic determinants of relapse following allogeneic stem cell transplant for myeloid neoplasia. Herein we will determine molecular modes of inactivation of HLA immunodominant peptide-presentation including HLA mutations, deletion and down modulation as a means of immunoescape. We will also study immunogenetic predictors of the strength of graft vs. leukemia according to the HLA divergence in the context of relapse, TCR repertoire diversity and HLA mutations.

Program: Translational Research Program
Project Term: Start Date: November 1, 2021 End Date: October 31, 2024
Dr. Horwitz

Steven Horwitz, MD

Memorial Sloan Kettering Cancer Center

New York, New York
United States

Translational Discovery in Peripheral T-Cell Lymphomas

Peripheral T-cell lymphomas (PTCLs) are poorly understood and patients with PTCL are underserved by current therapies. The most common subtypes (among >20) are PTCL-not otherwise specific (NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large cell lymphoma (ALK- ALCL). Rational treatment strategies for these lymphomas are lacking, largely due to the insufficient characterization of PTCL pathobiology and historic paucity of faithful models. Over the past 4 years, our groups and others have identified recurrent alterations in PTCL subsets, developed targeted agents against PTCL and established an unprecedented repository of PTCL models for in vitro and in vivo interrogation. A clinical trial led by director Dr. Horwitz established a new standard-of-care for upfront treatment of CD30+ PTCLs. Additional trials developed through this SCOR have advanced therapeutics targeting PI3 kinase (duvelisib), JAK1/2 (ruxolitinib) and IDH2 (enasidenib) for relapsed/refractory PTCL. The central goal for the next 5 years of support is to establish informed combination strategies that eradicate resistant populations and thereby extend the duration of meaningful responses.

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2026
Kura

Kura Oncology, INC

TAP Partner

San Diego, California
United States

A phase 2 registration-directed clinical study of ziftomenib (KO-539), a menin inhibitor, in patients with NPM1-mutant relapsed or refractory AML

Starting in July 2010, LLS TAP supported a promising University of Michigan research project led by Jolanta Grembecka, PhD, to develop new treatments for patients with a rare and lethal subtype of leukemia. Through TAP, LLS engaged chemists to improve the properties that produced lead compounds that exhibited potent anti-leukemic activity. In 2014, LLS introduced Kura Oncology to the project that ultimately led to Kura Oncology completing a licensing agreement with the University of Michigan to continue to develop these molecules.

Kura Oncology is a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer with a pipeline that consists of small molecule drug candidates that target cancer signaling pathways.

Ziftomenib (KO-539) is selective small molecule inhibitor of menin. Ziftomenib is currently in a Phase 2 registration-directed clinical trial in patients with NPM1-mutant relapsed or refractory AML (NCT04067336). 

Program: Therapy Acceleration Program
Project Term: Start Date: December 22, 2014 End Date: July 24, 2024
Immune-Onc

Immune-Onc Therapeutics, INC

TAP Partner

Palo Alto, California
United States

A phase 1 expansion study of IO-202, an antibody targeting LILRB4, in combination with azacitidine in patients with monocytic differentiation AML and CMML

In March 2021, LLS made an equity investment in Immune-Onc Therapeutics to support the "Phase 1 Clinical Development of IO-202, An Antibody Targeting LILRB4, for the Treatment of AML with Monocytic Differentiation and CMML."

Immune-Onc is a private, clinical-stage cancer immunotherapy company dedicated to the discovery and development of novel myeloid checkpoint inhibitors for cancer patients. The company aims to translate unique scientific insights in myeloid cell biology and immune inhibitory receptors to discover and develop first-in-class biotherapeutics that reverse immune suppression in the tumor microenvironment. Immune-Onc has a differentiated pipeline with a current focus on targeting the Leukocyte Immunoglobulin-Like Receptor subfamily B (LILRB) of myeloid checkpoints. The company’s work builds on early research by Chengcheng (Alec) Zhang, Ph.D. at the University of Texas Southwestern Medical Center that was also funded by LLS grants.

IO-202 is a first-in-class antibody targeting the LILRB4 and has entered a phase 1 cohort expansion clinical trial (NCT0437243) for the treatment of AML (IO-202 in combination with azacitidine) and CMML (IO-202 in combination with azacitidine). 

Program: Therapy Acceleration Program
Project Term: Start Date: March 5, 2021 End Date: July 24, 2024
Ryvu

Ryvu Therapeutics, SA

TAP Partner

Krakow
Poland

A phase 2 study of RVU120, a novel CDK8 inhibitor, in genetically defined cohorts of patients with AML and high-risk MDS

In August 2017, LLS TAP partnered with Ryvu Therapeutics (formerly known as Selvita) to support "A Phase Ib Study of SEL120 in Patients With Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome."

Ryvu Therapeutics is a clinical-stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology using a proprietary discovery engine platform.

RVU120 (SEL120) is a highly selective first-in-class CDK8/CDK19 small molecule inhibitor. Ryvu is currently enrolling several Phase 2 clinical trials, RVU120 as monotherapy in genetically defined cohorts of patients with relapsed/refractory AML and high-risk myelodysplastic syndromes (RIVER-52, NCT06268574), and RVU120 in combination with venetoclax for patients with relapsed/ refractory AML (RIVER-81, NCT06191263).

Program: Therapy Acceleration Program
Project Term: Start Date: August 7, 2017 End Date: July 24, 2024
Constellation

Constellation Pharmaceuticals, INC

TAP Partner

Cambridge, Massachusetts
United States

Development of BET protein bromodomain inhibitors for the treatment of patients with hematologic malignancies

In July 2012, LLS began its partnership with Constellation to support three first-in-human Phase 1 clinical trials for blood cancer patients and the partnership led to the ongoing trial "A Phase 3, Randomized, Double-blind, Active-Control Study of CPI-0610 and Ruxolitinib vs. Placebo and Ruxolitinib in JAKi Treatment Naive MF Patients."

Constellation Pharmaceuticals was a clinical-stage biopharmaceutical company developing novel therapeutics that selectively modulate gene expression to address serious unmet medical needs in patients with cancer. MorphoSys acquired Constellation in July 2021 and continues to enroll patients with myeloproliferative neoplasms in multiple clinical studies.

Pelabresib (CPI-0610) is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins. Pelabresib in combination with ruxolitinib is in a Phase 3 clinical trial (NCT04603495) for myelofibrosis patients that have not been previously treated with Janus kinase inhibitors.

Program: Therapy Acceleration Program
Project Term: Start Date: July 31, 2012 End Date: July 24, 2024
Immunitas

Immunitas Therapeutics, INC

TAP Partner

Waltham, Massachusetts
United States

A phase 1/2 study of IMT-009, an antibody targeting CD161, in patients with advanced solid tumors or lymphomas

In August 2021, LLS made an equity investment in Immunitas Therapeutics to support the "Phase 1 Clinical Development of IMT-009, an Antibody Targeting CD161, in Patients With Advanced Solid Tumors or Lymphomas."

Immunitas is committed to discovering and developing novel, differentiated therapeutics for patients with cancer. Their discovery engine combines deep expertise in single-cell genomics with customized machine learning approaches to elucidate immune cell populations that are key actors in immuno-oncology. Immunitas complements this process with bespoke in-house therapeutic discovery rooted in antibody display and immunization. The company was founded by Longwood Fund with leading scientists from Dana-Farber, MGH, the Broad, and MIT.

IMT-009, a first-in-class NK and T cell modulator targeting CD161, is being developed for the treatment of solid tumors and lymphomas and is in a Phase 1 clinical trial (NCT05565417). 

Program: Therapy Acceleration Program
Project Term: Start Date: August 10, 2021 End Date: July 24, 2024
Affimed

Affimed, NV

TAP Partner

Heidelberg
Germany

A phase 2 study of AFM13, a bispecific cell engager targeting CD30 and CD16A, in combination with AB-101 (allogeneic natural killer cells) in patients with classical HL and CD30-positive PTCL

In August 2013, LLS began its first European partnership with Affimed that supported two clinical trials for Hodgkin lymphoma (HL) patients. Expanding upon the initial work supported by LLS TAP, Affimed is currently enrolling "A Phase 2 Study of Innate Cell Engager AFM13 in Combination With Allogeneic Natural Killer Cells (AB-101) in Subjects With Recurrent or Refractory Hodgkin Lymphoma and CD30 Positive Peripheral T-Cell Lymphoma."

Affimed is a clinical-stage immuno-oncology company committed to giving patients back their innate ability to fight cancer by actualizing the untapped potential of the innate immune system using the proprietary ROCK® platform to enable a tumor-targeted approach to recognize and kill a range of hematologic and solid tumors.

AFM13 is bispecific tetravalent engager targeting CD30 on tumor cells and CD16A on NK cells and macrophages. AFM13 in combination with AB-101 (allogeneic natural killer cells) is currently in a Phase 2 clinical trial in relapsed or refractory Hodgkin lymphoma or CD30-positive PTCL (NCT05883449).

Program: Therapy Acceleration Program
Project Term: Start Date: August 26, 2013 End Date: July 24, 2024
Abintus

Abintus Bio, INC

Abintus Bio

San Diego, California
United States

Supporting in vivo CAR development for blood cancers

In November 2020, LLS made an equity investment in Abintus Bio to "Support in vivo CAR Development for Blood Cancers."

Abintus Bio is developing cutting-edge in vivo CAR therapies that allow for powerful CAR T cells to be generated directly in a patient’s body, eliminating the need for time-consuming and costly collection, engineering and re-infusion of patient T cells. Abintus plans to develop a portfolio of first-in-class product candidates that reprogram immune cells in vivo to eliminate tumors utilizing proprietary vectors and vector-engineering technologies.

This technology is currently in preclinical testing and could, if successful, support immediate patient dosing, a substantial benefit for patients facing advanced forms of cancer with a poor prognosis. Abintus’ platform is versatile and scalable, so they have the potential to meet the needs of a much larger patient population.

Program: Therapy Acceleration Program
Project Term: Start Date: November 3, 2020 End Date: July 24, 2024
Caribou

Caribou Biosciences, INC

TAP Partner

Berkeley, California
United States

A phase 1 study of CB-010, a CRISPR-edited allogeneic CAR-T targeting CD19, in patients with B-cell NHL

In February 2021, LLS made an equity investment in Caribou Biosciences to support "A Phase 1, Multicenter, Open-Label Study of CB-010, a CRISPR-Edited Allogeneic Anti-CD19 CAR-T Cell Therapy in Patients With Relapsed/Refractory B Cell Non-Hodgkin Lymphoma."

Caribou is a leading clinical-stage biotechnology company, co-founded by CRISPR pioneer and Nobel Prize winner Jennifer Doudna, Ph.D., using next-generation CRISPR genome-editing technology to develop “off-the-shelf” (allogeneic) CAR therapies for hard-to-treat blood cancers.

CB-010, Caribou’s lead allogeneic CAR-T cell program, targets CD19 and is being evaluated in a Phase 1 clinical trial expansion cohort for second-line patients with large B cell lymphoma (LBCL). (NCT04637763). It is the first clinical-stage allogeneic CAR-T cell therapy in which PD-1 was genetically disrupted in the CAR-T genome, leading to more durable anti-tumor activity in pre-clinical studies.

Program: Therapy Acceleration Program
Project Term: Start Date: February 28, 2021 End Date: July 24, 2024
John Leonard

John Leonard, MD

Weill Cornell Medicine

New York, New York
United States

BRIDGE (Blood cancer Research Initiative Developing Greater Engagement) with community patients

The Weill Cornell Medicine (WCM) Meyer Cancer Center (MCC) has an internationally recognized, clinical/translational blood cancer research program focused at its Manhattan campus. Elsewhere in New York City, the borough of Queens has 2.3 million and the borough of Brooklyn has 2.5 million residents. Both are among the most ethnically diverse urban areas in the world, and each separately ranks just behind Los Angeles and Chicago in population. Over 50% of patients diagnosed with blood cancers in New York City live in Brooklyn or Queens, and half of those are non-white. Involvement of academic cancer centers with a hematologic malignancy clinical trials program physically located in Brooklyn or Queens has previously been limited. New York Presbyterian Hospital and WCM have now integrated with New York Presbyterian-Queens (NYP-Q) and New York Presbyterian-Brooklyn Methodist Hospital (NYP-BMH) to provide access to outstanding cancer care and research for these populations. The community outreach and engagement core of the MCC (led by Dr. Erica Phillips) partners with a robust network of affiliated ambulatory care practices in Brooklyn and Queens. The core has hosted roundtables with over 120 stakeholders (cancer advocacy groups, community physicians, social service organizations) around barriers to diagnosis and treatment in solid tumors, and we will capitalize on this program to expand to blood cancer trials. Other workshops will be targeted directly to diverse groups of patients. Additionally, WCM-MCC cross-campus Hematologic Malignancy Disease Management teams are led locally by Dr. Perry Cook (NYP-BMH) and Dr. Gina Villani (NYP-Q). Clinical trials infrastructure and staffing, a joint IRB, training and oversight are being implemented. This foundation is ideal to synergize with this proposal (BRIDGE) to accelerate access and support for clinical trial participation of blood cancer patients in Brooklyn and Queens who have been previously underserved.

Program: IMPACT
Project Term: Start Date: April 1, 2021 End Date: March 31, 2026
Yan Liu

Yan Liu, PhD

Indiana University

Indianapolis, Indiana
United States

Development of therapeutic strategy for the treatment of MDS

TP53 mutations are present in 10% of MDS cases and are associated with reduced survival and poor prognosis. However, the effect(s) of TP53 mutations on MDS pathogenesis is unknown. We discovered that MDS cells with TP53 mutations display significant alterations in pre-mRNA splicing due to increased EZH2 activity. We will investigate the mechanisms by which TP53 mutations drive MDS pathogenesis and determine the impact of inhibition of EZH2 and the spliceosome on MDS cells with TP53 mutations.

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Frederick Locke

Frederick Locke, MD

H. Lee Moffitt Cancer Center & Research Institute

Tampa, Florida
United States

Clinical investigation to improve efficacy of CAR-T Cell Therapy for Large B Cell Lymphoma

We are investigating new interventions that could improve the effectiveness of CAR T-cell therapy for lymphoma. A clinical trial will test radiation immediately followed by CAR-T. Larger lymphoma tumors are less likely to respond to CAR-T and we expect that radiation could reduce the amount of tumor, leading to improvement in responses. We will also conduct a series of trials to determine the effectiveness of vaccinations before and after CAR T cell therapy, and if anti-cancer vaccines could improve outcomes.

Program: Career Development Program
Project Term: Start Date: January 1, 2021 End Date: December 31, 2025
Rong Lu

Rong Lu, PhD

University of Southern California

Los Angeles, California
United States

Dissecting the heterogeneity of leukemic and pre-leukemic clonal expansion to identify genes associated with leukemia relapse and genesis

My research investigates the heterogeneity of leukemic and pre-leukemic clonal expansion to identify genes associated with leukemia relapse and genesis. Contrary to conventional studies analyzing cell mixtures, my research uniquely probes the specific cells underlying leukemia development. We expect to identify the key cellular and molecular events that drive leukemia onset and relapse. These findings will help improve diagnosis and can serve as new therapeutic targets for treating leukemia.

Program: Career Development Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2024
Daniel Lucas

Daniel Lucas, PhD

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio
United States

Cellular Crosstalk In The Normal And Malignant Bone Marrow

We want to understand how leukemia inhibits blood production as this is one of the main causes of death in leukemia patients. We use new microscopy techniques developed by our group to image—for the first time—all types of blood cells and how they are eradicated by leukemia cells. Identification of the mechanisms through which leukemia inhibits blood production will be the foundation for new studies to develop drugs to maintain normal blood levels and prevent death in leukemia patients.

Program: Career Development Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2026
Jeffrey Magee

Jeffrey Magee, PhD, MD

Washington University School of Medicine in St. Louis

St. Louis, Missouri
United States

Neonatal origins of pediatric AML

Coming soon.

Program: Career Development Program
Project Term: Start Date: July 1, 2021 End Date: June 30, 2026
Ravindra Majeti

Ravindra Majeti, PhD, MD

Stanford

Palo Alto, California
United States

Clonal Evolution of Pre-Leukemic Hematopoietic Stem Cells in Human Myeloid Malignancies

It has been demonstrated that most cases of AML are associated with mutations in multiple genes. Dr. Majeti's studies will provide novel insights into the genetic events and other factors such as the microenvironment that affect in the development of myeloid malignancies, particularly AML. This study will have significant implications for the prevention and treatment of myeloid malignancies, particularly AML.

Program: Discovery
Project Term: Start Date: July 1, 2020 End Date: June 30, 2024
Ravindra Majeti

Ravindra Majeti, PhD, MD

Stanford

Palo Alto, California
United States

Personalized Metabolic Targeting of Epigenetic AML Mutations Through the Alpha-Ketoglutarate Pathway

AML is characterized by founder mutations in epigenetic regulators that perturb alpha-ketoglutarate flux to block differentiation and rewire metabolism exposing new druggable vulnerabilities. By integrating bioenergetics and 5hmC profiling in primary cells, we have discovered unexpected 2-hydroxyglutarate-independent vulnerabilities for TET2, IDH1, IDH2, WT1, and CEBPA mutations. Here, we propose mutation-directed drug development for AML through targeting of the alpha-ketoglutarate pathway.

Program: Translational Research Program
Project Term: Start Date: October 1, 2020 End Date: September 30, 2023
Kasey Leger

Kasey Leger, MD

Seattle Children's Hospital

Seattle, Washington
United States

Cardioprotective Strategies and Cardiotoxicity Prediction in Children with Acute Myeloid Leukemia

We seek to reduce the adverse cardiac effects of chemotherapy in pediatric AML patients. We are assessing markers of heart function and injury to compare two clinical strategies for prevention of chemotherapy-induced heart injury. We are also developing a tool using these markers of heart function to characterize a child’s risk for cardiac dysfunction, which is critical to guiding safe chemotherapy delivery. By reducing the toxicity of therapy on the heart we hope to optimize delivery of effective chemotherapy and contribute to long-term leukemia cure without the burden of life-threatening heart disease during survivorship.

Program: Career Development Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2024
Sami Malek

Sami Malek, MD

Regents of the University of Michigan

Ann Arbor, Michigan
United States

Targeting v-ATPase mutations and activated autophagic flux in follicular lymphoma

In this proposal we seek a mechanistic understanding how mutations in ATP6V1B2 in FL activate autophagic flux and also maintain mTOR in an active state. Given that 25-30% of FL harbor mutations in various v-ATPase subunits and regulators (ATP6V1B2, APT6AP1, VMA21) we will extend our studies to these genes. We will clarify how and under what circumstances activated autophagy can be targeted in FL, why it works, and what the best molecular targets and drugs are.

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Shannon McKinney-Freeman

Shannon McKinney-Freeman, PhD

St. Jude Children's Research Hospital

Memphis, Tennessee
United States

Improving hematopoietic stem cell transplantation by defining novel regulators of engraftment

Blood-forming stem cells are routinely transplanted into patients to treat blood cancers. We discovered that multiple members of the GASP (G-protein coupled receptor Associated Sorting Proteins) family inhibit the function of blood-forming stem cells during transplantation. Our goal is to determine exactly how GASP family members inhibit these critical cells in order to inform our efforts to improve the efficiency of blood stem cell transplantation.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Dan Landau

Dan Landau, PhD, MD

Weill Cornell Medicine

New York, New York
United States

Defining the role of DNA methylation modifier mutations in reshaping blood differentiation topology

Coming soon.

Program: Career Development Program
Project Term: Start Date: July 1, 2021 End Date: June 30, 2026
Soheil Meshinchi

Soheil Meshinchi, PhD, MD

Fred Hutchinson Cancer Research Center

Seattle, Washington
United States

Multi-modal Immunotherapeutic Targeting of AML-restricted Targets in Infants and Children

Advances in understanding and management of AML in children has been stagnant for decades. Observed improvements in survival are more directly linked to improvements in supportive care or risk identification rather than advances in therapeutics. Excitement around FDA approval of two new IDH1/2 inhibitors did not reach the pediatric oncology community given paucity or absence of such mutations in children. This also highlights the stark differences between AML in older adults and that in younger patients. Thus, “trickle down therapeutics” where therapies that are developed in older adults are used effectively in children is a flawed concept. Discoveries and therapeutic development in younger patients must be prioritized if meaningful advances are to be made in curing AML in younger patients. Given that AML in children is not a priority for the pharmaceutical companies, alternate mechanisms for advancing therapeutics in children and young adults should be implemented.

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2026
Soheil Meshinchi

Soheil Meshinchi, PhD, MD

Fred Hutchinson Cancer Research Center

Seattle, Washington
United States

Novel immunotherapeutic strategies in infants with high risk AML

Treatment of AML in infants is especially challenging given unique genetic make-up of the disease as well as specific susceptibilities of the host. We will leverage the RNA Seq data from over 2000 patients to discover and validate novel targets (cell surface proteins), and in collaboration with Dr. Correnti (Protein Scientist) and Dr. Fry (CART development expert) generate and test novel antibodies, ADCs, BiTEs and CARTs directed against leukemia-specific targets in infants.

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Larry Kwak

Larry Kwak, PhD, MD

Beckman Research Institute of the City of Hope

Duarte, California
United States

Delivering unique immunotherapeutics for treatment of mantle cell lymphoma

City of Hope has a reputation for innovative translational research, and multiple researchers in the proposed application are prominent in the lymphoma field. The institutional commitment to translational science is evident in City of Hope’s investment in research support/regulatory affairs infrastructure and campus GMP manufacturing facilities. Since patients with mantle cell lymphoma (MCL) have poor outcomes after autologous transplantation, our researchers have been developing new immunotherapeutic strategies to combat this disease. This RFA was timely, as our team was preparing several innovative projects specifically focused on MCL. Our projects are unified by a focus on specific cell and pathway targeting, and antibody-based biologic agents. In fact, 3 of the proposed agents to be tested in this grant were developed here and will be manufactured at City of Hope. The immunotherapies proposed here target a range of antigens, including a unique MCL-specific antigen, and employ novel mechanisms of action, including B-cell receptor (BCR) feedback control, T cell killing and antibody-dependent cytotoxicity. Tumor target specificity is crucial to the safety and tolerability of any immunotherapy. However even with perfect specificity, targeting a single antigen or pathway is frequently insufficient due to antigen- and immune-escape mechanisms. Therefore we are exploring combining our antibody-based agents with inhibitors of B cell signaling (BTK, PI3K, Akt), as well as combining them between projects, in order to cut off tumor escape routes. Developing therapeutics with both high specificity and high potency against MCL is a lofty goal, but one that we aim to achieve. Project 1: Development of a unique tumor-specific, antibody therapy against mantle cell lymphoma (L Kwak, H Qin, L Chen). We have utilized a live cell-based phage display platform to target low-abundance, unique cell markers, discovering an antibody light chain binding domain specific to human MCL. We have further engineered a light chain antibody that binds highly specifically to MCL (MCLC-Ab), with no binding to other subtypes of B-cell lymphomas, nor to normal blood cells. This MCLC-Ab shows potent anti-tumor activity in xenograft MCL models. In Project 1, we will identify the MCLC-Ab target and confirm the antibody specificity for MCL by immunohistochemistry and flow cytometry (SA1). The MCLC-Ab will then undergo preclinical development as both an MCL diagnostic antibody (SA2) and as a potent, MCL-specific therapeutic (SA3). Project 2: Combining CAR T cells with signaling modulators for treatment of relapsed/refractory mantle cell lymphoma (S Forman, X Wang, E Budde, S Blanchard). CD19 chimeric antigen receptor (CAR) T cell therapy is limited by suboptimal response rates in non-Hodgkin lymphoma (NHL), persistent B cell aplasia, and a high risk of cytokine release syndrome (CRS). To improve the remission rates for patients with MCL, we propose combining CAR T cells with 3 oral agents that modulate B and T cell signaling: the BTK inhibitor ibrutinib, the Akt inhibitor MK-2206, and the PI3K inhibitor TGR-1202. First we propose a clinical trial of ibrutinib for relapsed MCL, followed by CD19CAR T cell infusion (SA1). We expect that ibrutinib will enhance response rates to CAR T cell therapy and may also decrease cytokine production, reducing severe CRS. This trial is built on our established clinical platform for CD19CAR T cell therapy for NHL. We will also optimize and pre-clinically develop the MCLC-Ab from Project 1 as a CAR, with the potential to avoid persistent B cell aplasia (SA2). Finally, we plan to test the use of Akt and PI3K inhibitors as part of CAR T cell manufacturing to improve T cell persistence and potency, and in vivo as combined therapy with CAR T cells (SA3). Project 3: Targeting oncogenic B cell receptor (BCR)-feedback control in refractory mantle cell lymphoma (M Muschen, V Ngo, R Chen, L Chen). Project 3 proposes to target the CD25 surface antigen present on both regulatory T cells (Tregs) and MCL cells, using a new CD25 antibody-pyrrolobenzodiazepine conjugate (ADCT-301). In SA1, in a humanized mouse model, we will use the CD25-ADC to pre-deplete immunosuppressive Tregs and enhance the activity of Project 1’s MCLC-Ab and Project 2’s CD19 CAR T cells. We have discovered that MCL cell surface CD25 recruits inhibitory SHIP1, attenuating oncogenic BCR signaling strength. CD25 normally cycles from cytoplasm to surface of MCL cells, but can be forced to remain on the cell surface via CD19 engagement or PI3K/Akt inhibition. In SA2, we will combine CD19 antibody or CD19 CAR T cells with CD25-ADC to force CD25 surface expression, enhancing ADCT-301 targeting. In SA3, we will stimulate CD25 surface accumulation using Akt and PI3K inhibitors to maximize targeting. Core A: Pathology and Tissue Bank Core (WC Chan, J Song). Core A will provide tissue bank services, screen MCLC-Ab to validate its specificity (FFPE sections, flow cytometry) and diagnostic utility (Project 1), provide MRD and residual tumor assessment for the clinical trial (Project 2), and assess immune reconstitution in humanized mice (Project 3). Core B: Translational Core (S Thomas, C Matsumoto). Core B will provide project management, clinical trial design, clinical protocol development, IND preparation, scientific writing and regulatory support services. Synergy: Our researchers are extremely collaborative as evidenced by the interactions that weave the individual projects into a cohesive team-science program. Project 1 + Project 2: Development of MCLC-CAR T cells. Project 2 + Project 3: CD19 stimulation of CD25 surface expression prior to ADC therapy, PI3K/Akt inhibition studies. Project 3 + Project 2 + Project 1: Regulatory T cell depletion with CD25-ADC prior to CAR T cell therapy or MCLC-Ab. Core A and Core B will provide services for all 3 projects as described above.

Program: Mantle Cell Lymphoma Research Initiative
Project Term: Start Date: January 1, 2018 End Date: December 31, 2022
Rajni Kumari

Rajni Kumari, PhD

Albert Einstein College of Medicine

Bronx, New York
United States

Role of HLX in leukemia induction and maintenance

We and others have shown how HLX overexpression keeps blood cells more immature by blocking their differentiation and promoting their proliferation, a characteristic which is inherent to AML. However, whether there is a causative role of HLX in the induction of AML is still unclear. Hence, the aim of my study is to better understand, using genetically engineered mice models, retroviral models, and human AML patient samples, how HLX drives AML at molecular level. This study will uncover potential therapeutic strategies for AML treatment in future.

Program: Career Development Program
Project Term: Start Date: April 1, 2021 End Date: March 31, 2024
Gareth Morgan

Gareth Morgan, PhD, MD, FRCPath, FRCP

New York University School of Medicine

New York, New York
United States

Using mutographs to define the molecular landscape and cell of origin of Waldenstrom's Macroglobulinemia

Coming soon.

Program: Special Grants
Project Term: Start Date: February 1, 2023 End Date: February 1, 2025
Alison Moskowitz

Alison Moskowitz, MD

Memorial Sloan Kettering Cancer Center

New York, New York
United States

JAK/STAT inhibition as a therapeutic strategy in T-cell lymphoma

Given the high rate of JAK/STAT pathway dysregulation in T-cell lymphomas, we aim to develop new personalized therapies with JAK inhibitors for T-cell lymphoma. Our recent study with ruxolitinib (a JAK inhibitor) showed that activation of a parallel oncogenic pathway, PI3-kinase, predicts for poor response to ruxolitinib in T-cell lymphoma. Building upon this observation, we are assessing whether dual inhibition of JAK and PI3-Kinase will lead to higher efficacy in T-cell lymphoma.

Program: Career Development Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2024
Daisuke Nakada

Daisuke Nakada, PhD

Baylor College of Medicine

Houston, Texas
United States

Synergistic targeting of metabolic and epigenetic vulnerabilities in leukemia stem cells

Our lab is focused on identifying unique features that distinguishes acute myeloid leukemia (AML) stem cells from normal blood-forming stem cells. The cells that make more AML cells than others are called AML stem cells, and these cells need to be eradicated to achieve deep therapeutic responses. We believe targeting metabolism may achieve this goal and found strategies to target AML stem cell metabolism without harming normal stem cells. We hope that our study will lead to improved therapies against AML targeting metabolism to achieve deep remission with little toxicity.

Program: Career Development Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2024
Lakshmi Navak

Lakshmi Nayak, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

PD1 blockade alone and in combination with BTK/ITK inhibition in patients with refractory and recurrent primary central nervous system lymphoma

We study a rare and aggressive brain cancer called primary central nervous system lymphoma (PCNSL). We are using an emerging knowledge of the genetic basis of PCNSL to develop novel clinical trials exploring the use of targeted and immunotherapy agents in PCNSL patients. These trials include assessment of the activity of a PD-1 inhibitor by itself and in combination with a BTK inhibitor in PCNSL patients, as well as identifying any mechanisms of treatment resistance that may develop. The goal of our clinical research is to enhance survival and improve neurologic function in PCNSL patients.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Sattva Neelapu

Sattva Neelapu, MD

The University of Texas MD Anderson Cancer Center

Houston, Texas
United States

CD79b as a novel target for CAR T-cell therapy in B-cell malignancies

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 induces durable remissions in a significant proportion of patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphomas (NHL). However, relapse or progression occurs in ~60% of patients with majority of them experiencing CD19 loss in their tumors. Here, we will characterize the mechanism of CD19 loss in NHLs and develop CD79b CAR T-cell therapy as a novel approach to overcome CAR T resistance due to CD19 loss.

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Stephen Nimer

Stephen Nimer, MD

University of Miami

Coral Gables, Florida
United States

Targeting Epigenetics in Myeloid Malignancies

We have a highly collaborative team of investigators, whose goal is to develop novel therapeutic approaches to MDS and AML as well as to improve current therapies for these diseases based on a detailed understanding of how epigenetic dysregulation contributes to myeloid neoplasia. We are focusing on the clonal MDS or AML cell and on the bone marrow microenvironment (BMME), including immune cells that could contribute to or limit the progression of these disorders. Our Center brings together chemists, biochemists, cellular biologists and molecular biologists, who are supported by three core facilities, including an Administrative core, an Epigenomics core and a Bioinformatics and Big data sharing core. To advance our Center’s ability to implement personalized therapies for patients with myeloid malignancies, we have generated and will generate novel reagents, and utilize state-of-the-art in vitro and in vivo assays to identify key modulators of drug sensitivity or resistance. We will focus on so-called “epigenetic-focused” therapy, realizing that many of the enzymes that regulate epigenetic control of cell fate, influence signal transduction pathways, RNA splicing events, and the activity of key cellular proteins, such as BCL2 family members and p53.

The genetic mutations that underlie myeloid malignancies have been identified, and we and others have generated mouse models that have pinpointed the role that these genes and their mutations play in normal and malignant hematopoiesis. Our institutions have biospecimen banks with large numbers of MDS and AML samples, and active clinical trial portfolios, that have led to FDA approval of a variety of novel agents, including IDH1/2 inhibitors. The next step in delineating the pathogenesis and Achilles’ heel of these disorders is to better define the role of epigenetic abnormalities play in disease initiation and progression, and to define how targeting LSD1, the CoREST complex, PRMT5 and inflammation signals may advance current treatment strategies (e.g. VEN/AZA), and to enhance the activity of promising agents currently under investigation (menin inhibitors, etc.). Identifying the dependencies and vulnerabilities created by genetic or epigenetic abnormalities will allow us to more rationally advance the treatment of myeloid malignancies, a disease focus where headway is beginning to be made.

Defining the crosstalk between different epigenetic regulators, and how they affect cellular and extracellular processes other than histone proteins, may identify unique sensitivities that can increase the therapeutic index for novel, epigenetic-focused treatments, and identify potentially synthetic-lethal combination therapies. The individual projects in our Center, cover three key aspects of gene regulation and chromatin structure. Project 1 is focused on the LSD1 demethylase, which plays a role in myeloid differentiation, Project 2 is focused on the role of PRMT5 in regulating LSC self-renewal, proliferation and survival, and the expression of potential immunogens, and Project 3 is focused on the interaction between the BMME and the epigenome in mediating sensitivity to epigenetic agents in CMML and MDS. Thus, our center will span the continuum from basic mechanisms of disease initiation and progression, to clinical issues related to therapeutic sensitivity vs. resistance.

Ramin Shiekhattar first discovered that MAO inhibitor antidepressants such as tranylcypromine (TCP), can inhibit the LSD1 demethylase. This finding led to a recently published clinical trial of AZA + TCP in MDS and AML patients led by Justin Watts, and to a new clinical program, that will be continued at Sylvester and MSKCC. They will work with Phil Cole, who founded a biotech company in 2011 that is synthesizing novel epigenetic-focused therapies, to examine how targeting the CoREST complex can synergize with clinically available MDS/ AML cells differentiation- or apoptosis-inducing agents. Several lead compounds are now being tested in the Shiekhattar and Nimer labs.

Omar Abdel-Wahab and Stephen Nimer have discovered several oncogenic functions of PRMT5, an arginine methyltransferase targeted by several small molecule inhibitors that are now in clinical trials for MDS or AML patients at Sylvester and MSKCC. They will work with Luisa Cimmino to exploit their work implicating PRMT5 in regulating homologous recombination, RNA splicing and p53 function. Maria Figueroa has extensively studied predictors of the clinical response to DNA hypomethylating agents (HMA) and has identified critical mediators of HMA resistance originating in the BMME. She will work with Ross Levine, a leader in delineating the molecular pathogenesis of hematologic malignancies, to evaluate how signals from the BMME impact the responsiveness of MDS and CMML cells to HMA combinations as well as how to overcome primary resistance to HMA by targeting key signals in the niche.

Three Cores will enable the efficient completion of our collaborative studies. Core A, the Administrative Core, will be housed at UM; it will provide infrastructure support, to optimize interactions between the various labs represented here, handle all financial and reporting aspects of the grant, assist with the SCOR site visit and the annual meeting of the Center, and maintain regulatory compliance for the Center (e.g. assuring access to bio-specimens, handling IRB and IACUC approvals, etc.). Both UM and MSKCC continue to collect MDS/AML/MPN bio-specimens. Core B, the Epigenomics Core, led by Sion Williams and Lluis Morey, will perform various NGS-based assays to assess genome-wide changes in gene expression, DNA methylation, and histone post-translational modifications. Core C, the Bioinformatics and Big Data Core, led by Stephan Schürer, will provide bioinformatics support and ensure complete and efficient sharing of data for all three projects in the SCOR.

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2022 End Date: September 30, 2027
Robert Kridel

Robert Kridel, PhD, MD

University Health Network

Toronto, Ontario
Canada

Delineation of the molecular heterogeneity underlying treatment failure in follicular lymphoma

A proportion of follicular lymphoma patients will experience early treatment failure and premature death. We will delineate the molecular features that underlie treatment failure from a recent randomized trial (BIONIC) & Canadian cohort via 3 aims: 1) confirm the prognostic significance of prior reported biomarkers (eg, m7-FLIPI, etc); 2) establish the genetic taxonomy of FL via integrated genomic analyses and consensus clustering; and 3) determine the prognostic value of circulating tumor DNA.

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Grzegorz Nowakowski

Grzegorz Nowakowski, MD

Mayo Clinic, Rochester

Rochester, Minnesota
United States

REACH: Recruitment Expansion through community Access to Clinical trials in Hematologic malignancies

Mayo Clinic Rochester (MCR) is a tertiary center with 35,000 blood cancer visits annually. Circa 70% of patients referred to MCR come from 5 states: MN, WI, IA, SD and ND inhabited by 10,483,946 people living primarily in a rural setting. To improve local care access, MCR has developed the Mayo Clinic Health System (MCHS), a network of 17 community sites of which 7 have oncology care. In 2018, the MCR joined with the University of Minnesota to establish the Minnesota Cancer Clinical Trials Network (MCCTN) that includes 18 sites. These 2 networks encompass large areas of rural, economically disadvantaged populations and unrepresented minorities, including Native Americans, Latinos and African Americans. The MCR is actively supporting clinical research at MCHN sites, including access to clinical trials (CTs) portfolio. Oncology CTs are open in some of MCHS sites but of the 25 currently open, only 2 CTs target blood cancers. The University of Iowa/Mayo Clinic Lymphoma SPORE has opened epidemiological trials in the MCHS. The MCCTN is new and none of the 3 open CTs are hematologic. Lymphoma study accruals from the MCHS include 42 patients (1 therapeutic; 41 lymphoma epidemiology). The robust epidemiology trial accrual demonstrates that these new lymphoma patients are being seen at these sites and are willing to consent. While many patients from rural communities are seen at MCR for initial diagnosis, these patients often are unable to enroll into trials due to distance from MCR. Feedback from providers from both Networks identified barriers to accrual to lymphoma CTs: i) lack of local lymphoma trials; ii) competition with the more common solid tumor CTs for scarce resources; iii) very busy clinical practices that limits dedicated time for enrollment of intensive complex hematology patients. The practice pressure particularly affects patients requiring language or financial assistance. In this proposal, we outline our plans to address the 3 barriers identified.

Program: IMPACT
Project Term: Start Date: April 1, 2021 End Date: March 31, 2026
Thomas Koehnke

Thomas Koehnke, MD

Board of Trustees of the Leland Stanford Junior University

Palo Alto, California
United States

The role of truncating ASXL1 mutations in disease initiation and progression of human myeloid malignancies

N/A

Program: Career Development Program
Project Term: Start Date: July 1, 2021 End Date: June 30, 2024
Stephen Oh

Stephen Oh, PhD, MD

Washington University in St. Louis

St. Louis, Missouri
United States

Leveraging dysregulated signaling networks for therapeutic benefit in myeloproliferative neoplasms

The objective of this project is to decipher mechanisms driving transformation of myeloproliferative neoplasms (MPNs) to secondary acute leukemia (sAML). We have identified increased expression of DUSP6 and RSK1 in sAML patient cells. Genetic/pharmacologic targeting suggest a role for DUSP6 and RSK1 in MPN development. We thus propose studies to determine how DUSP6 and RSK1 contribute to MPN pathogenesis, and to evaluate the therapeutic potential of DUSP6 and/or RSK1 inhibition for MPN patients.

Program: Translational Research Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2024
Robert Orlowski

Robert Orlowski, PhD, MD

The University of Texas MD Anderson Cancer Center

Houston, Texas
United States

SCOR in High Risk Plasma Cell Dyscrasias

Dr. Orlowski assembled an experienced, collaborative group of researchers who work in a multidisciplinary manner on projects focusing on basic, translational, and clinical aspects of smoldering multiple myeloma (SMM) and multiple myeloma (MM). Both high risk SMM and MM represent important and urgent unmet medical needs for the development of novel, more effective therapies.

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2017 End Date: September 30, 2023
Bruno Paiva

Bruno Paiva, PhD

Universidad de Navarra

Pamplona
Spain

Systematic multiomic profiling of tumor and immune cells for non invasive detection of early myeloma

Multiple myeloma remains largely incurable and there is consensus that the pathway to cure cancer involves treating patients earlier. Thus, there is an unmet need to develop methods for early detection of pre-malignant disease and to help tailoring treatment for patients with smoldering myeloma. We aim to develop new methods for minimally invasive characterization of patients with smoldering myeloma in order to treat disease causation instead of symptomatology and increase curability rates.

Program: Translational Research Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2024
Eirini Papapetrou

Eirini Papapetrou, PhD, MD

Icahn School of Medicine at Mount Sinai

New York, New York
United States

Studying the biology and therapeutic vulnerabilities of leukemia stem cells using AML-iPSCs

Acute myeloid leukemia (AML) is an aggressive blood cancer that still lacks effective therapies. Our goal is to identify therapeutic vulnerabilities for long-lasting remission or cure of AML by targeting the leukemia stem cells (LSCs), the cells that maintain the disease and re-grow it upon relapse. To this end, we leverage unique model systems of AML LSCs that we have developed using induced pluripotent stem cell (iPSC) technology. Our study may open new avenues for the therapy of AML.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Sameer Parikh

Sameer Parikh, MBBS

Mayo Clinic, Rochester

Rochester, Minnesota
United States

Immunogenicity and safety of commercially available vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with hematologic malignancies and associated precursor conditions

Mass immunization campaigns are underway in the US after the emergency use authorization of highly effective vaccines against SARS-CoV-2. Despite the efficacy of these measures, patients with B cell malignancies and associated precursor conditions remain at a high risk of adverse outcomes due to COVID-19 infection. These patients were excluded from pivotal vaccination trials that tested the efficacy in the general population. Historically, patients with hematologic malignancies have a 20-50% rate of immunogenicity to routine vaccinations – either due to the underlying malignancy itself or due to immunosuppressive therapies. We are currently enrolling patients in an observational study (NCT04748185) to assess the immunogenicity and safety of commercially available vaccines against SARS-CoV-2 in patients with B cell malignancies and associated precursor conditions such as monoclonal B cell lymphocytosis (MBL). Eligible patients who those with a diagnosis of a B cell malignancy (without regard to treatment status of the underlying malignancy). In collaboration with the Mayo Vaccine Center, we will determine immunogenicity of SARS-CoV-2 vaccination by: a) measuring antibody response (including anti-spike antibody, anti-nucleocapsid antibody, and blocking antibody titers); and b) measuring cell mediated immune response (including T cell ELISpot assay).

Program: Special Grants
Project Term: Start Date: June 1, 2021 End Date: December 31, 2021
Alex Kentsis

Alex Kentsis, PhD, MD

Memorial Sloan Kettering Cancer Center

New York, New York
United States

Targeting kinase-dependent dysregulation of transcription factor control in acute myeloid leukemia

Defining mechanisms of dysregulated gene control are central to understanding cancer and the development of effective therapies. Our research is focused on the mechanisms of gene control dysregulation in acute myeloid leukemia (AML), a refractory form of blood cancer that affects both children and adults. Using new methods for manipulating proteins, we are defining essential mechanisms by which AML cells enable cancer-causing gene expression. This work also allowed us to develop new drugs to specifically block this in cancer, but not healthy cells. Ongoing work aims to define precise mechanisms of cancerous gene control and develop definitive treatments for its control.

Program: Career Development Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2024
Michael Keller

Michael Keller, MD

Children's Research Institute

Washington, District of Columbia
United States

T-cell immunotherapy for prevention of COVID-19 following bone marrow transplantation

SARS-Cov-2 infections may be prolonged in cancer patients and may enable intrahost development of virulent viral variants. Adoptive immunotherapy with virus-specific T-cells has been an effective treatment for refractory viral infections in immunocompromised patients following HSCT. We propose to study the functionality of coronavirus-specific T-cells (CSTs) from healthy donors, and utilize CSTs as preventative therapy for patients undergoing bone marrow transplant in a phase I study.

Program: Translational Research Program
Project Term: Start Date: July 1, 2021 End Date: June 30, 2024
Lev Kats

Lev Kats, PhD

The University of Melbourne

Parkville, Victoria
Australia

Targeting DCAF1 as a novel treatment strategy for therapy resistant multiple myeloma

We have identified the multi-domain protein DCAF1 as a genetic dependency in multiple myeloma and developed a series of potent on-target DCAF1 inhibitors that have a unique mode of action compared with existing therapies. In this proposal we will continue the detailed molecular characterization of our lead compound Vpr8. In parallel, using Vpr8 as the scaffold, we will develop a new series of PROTAC drugs that engage the ubiquitin ligase activity of DCAF1-containing E3 complexes.

Program: Translational Research Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2024
Jonas Jutzi

Jonas Jutzi, PhD, MD

Brigham and Women’s Hospital

Boston, Massachusetts
United States

Unfolding selective pathway dependencies of CALR mutated myeloproliferative neoplasms

The goal of this study is to selectively eradicate blood cancer cells carrying mutations in a gene called calreticulin. Genes and corresponding proteins required for cancer cell survival but not for the survival of healthy cells will first be targeted in mice, both genetically and by using drugs. Validated drugs will then be tested on patient samples. This study will lay the foundation to the development of tailored treatments for patients with calreticulin-mutated blood cancer.

Program: Career Development Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2024
Carl June

Carl June, MD

The Trustees of the University of Pennsylvania, Medical Center

Philadelphia, Pennsylvania
United States

Pan-heme CAR: Anti-CD38 CAR T cells for myeloid, lymphoid and plasma cell malignancies

Our SCOR team has a razor-sharp focus on an exciting new treatment modality for blood cancers: chimeric antigen receptor (CAR) T cells. T cells can be trained to target cancer cells by genetic modification. In fact, previous support from the Leukemia & Lymphoma Society allowed us to successfully develop CAR T cells targeted to CD19, a pan-B cell marker. This treatment, generically called CART-19, was approved by the FDA in 2017 for the treatment of B-cell acute lymphoid leukemia (B-ALL) and in 2018 for some non-Hodgkin lymphoma (NHL), with promising results in other B cell malignancies such as chronic lymphocytic leukemia (CLL). Thus, the development of a single therapy for a single disease (initially, CLL) paid handsome dividends when translated to a broader range of CD19-expressing malignancies (ALL, NHL).

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2019 End Date: May 31, 2025
Dr. Jordan

Craig Jordan, PhD

University of Colorado Denver, Anschutz Medical Campus

Aurora, Colorado
United States

Therapeutic targeting of AML stem cells 2018

Our SCOR team seeks to fundamentally reinvent the ways in which physicians diagnose and treat acute myeloid leukemia (AML). For over 40 years, AML has been treated with a combination of chemotherapy drugs that have major side effects and usually only provide short-term benefit to patients. Indeed, survival rates for most AML patients are dismal, and quality of life for these patients is poor. Consequently, improved strategies for AML are a huge priority for the field. We believe that the lack of progress against AML is due to a single, fundamental failure of existing therapies: While current therapies attack leukemia cells, they fail to act against the real root of the problem, namely leukemia stem cells. It’s like mowing over weeds in a lawn. If the roots are not removed, the weed (disease) will grow back. And like eradicating the roots of weeds, AML stem cells have proved difficult to treat. This is primarily due to the fact that AML stem cells within a given patient can exist in multiple forms, each of which has a differing response to therapy. In other words, while various drugs can often kill some AML stem cells in a patient, completely eradicating all the AML stem cells can be very difficult.

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2018 End Date: September 30, 2024
Hao Jiang

Hao Jiang, PhD

University of Virginia

Charlottesville, Virginia
United States

Dissecting the role of a key epigenetic modulator in Mixed Lineage Leukemia

We study how a protein called Dpy30 controls blood cancers by regulating chromatin, the physical structure where our genes reside. We study how this protein controls addition of a specific chemical group onto chromatin, thereby regulating expression of genes for leukemia in cells and animals. We are also developing chemicals to inhibit Dpy30’s activity in leukemia. We hope to better understand the role of Dpy30 in leukemia and identify Dyp30-inhibiting chemicals for leukemia treatment.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Piers Patten

Piers Patten, PhD

King's College London

London
United Kingdom

Understanding SARS-Cov-2 evolution in haemato-oncology patients

Through phenotypic and functional studies of immune cells, proteomic mapping of immune responses and genomic studies of variant strains, this project will assess the evolution of natural SARS-CoV-2 infection and COVID-19 vaccine responses in hemato-oncology patients. Integration of immunological profiles and genomic outcomes with clinical characteristics will inform future best patient management, especially for those patients at risk of prolonged infection with long term viral shedding.

Program: Translational Research Program
Project Term: Start Date: September 1, 2021 End Date: August 31, 2024
Daniel Pollyea

Daniel Pollyea, MD

University of Colorado Denver, Anschutz Medical Campus

Aurora, Colorado
United States

Targeting Leukemia Stem Cells in the Clinical Setting: The Development of A Comprehensive Program

My focus is to develop a program in which novel therapies targeting leukemia stem cells (LSCs) are tested in clinical trials. This is achieved via partnership with laboratory-based colleagues who identify vulnerabilities in LSCs. Once recognized, we find or develop drugs to exploit these weaknesses through clinical trials for acute myeloid leukemia patients. The goal is to bring forward new therapies that result in deep and durable responses, which also have the potential to cure this disease.

Program: Career Development Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2024
Sean Post

Sean Post, PhD

The University of Texas MD Anderson Cancer Center

Houston, Texas
United States

Understanding the mechanisms and developing novel therapies for a high-risk DLBCL population

The most aggressive forms of DLBCL are marked by alterations that result in MYC and BCL2/6 activation. In cases without genetic alterations at these loci, the mechanisms underpinning their overexpression remains largely unknown. Herein, we will examine how a putative driver of DLBCL (hnRNP K) impacts disease progression through its direct regulation of these critical oncogenes and evaluate treatment responses using clinical samples and animal models for this high-risk DLBCL patient population.

Program: Translational Research Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2021
Zhijian Qian

Zhijian Qian, PhD

University of Florida

Gainesville, Florida
United States

The role of FOXM1 downregulation in the development of clonal dominance in del(5q) MDS

Our research focuses on identifying the molecular mechanism underlying the development of a dominant population of abnormal stem cells in myelodysplastic syndrome (MDS) patients. We will employ mouse genetic models and MDS patient samples to elucidate the role of FOXM1 in the development of a dominant population of abnormal stem cells in vivo. This research program may lead to the identification of new effective therapeutic strategies for the treatment of early stages of MDS patients.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Christiane Querfeld

Christiane Querfeld , PhD, MD

Beckman Research Institute of the City of Hope

Duarte, California
United States

Unraveling the mechanisms of immune checkpoint dysfunction in cutaneous T cell lymphoma

Cutaneous T-cell lymphoma (CTCL) is a disfiguring, incurable malignancy profoundly affecting patients’ appearances, quality of life, and relationships. Standard treatments only benefit 30% of patients with limited duration. Rather than focusing on the tumor alone, we target the adjacent tumor microenvironment, which nourishes tumor growth. We have begun a clinical trial of durvalumab, which is an inhibitor of the checkpoint protein receptor PD-L1. We are currently investigating how immune checkpoint proteins together with the immune booster lenalidomide affect CTCL growth. This research will benefit not only those with CTCL but many other cancers.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Peng Ji

Peng Ji, PhD, MD

Northwestern University

Chicago, Illinois
United States

Targeting Plek2 for the treatment of myeloproliferative neoplasms

Current therapy for MPNs remains suboptimal with ongoing risks for thrombosis. Newer drug such as JAK inhibitor has toxicity and is not curative. New targeted therapy with less side effects is urgently needed in the field. This project focuses on the inhibitors of Plek2, a novel target of MPNs. We have identified lead compounds of Plek2 through screening and medicinal chemistry. We propose to further study the mechanisms of action of the inhibitors and perform in vivo studies using MPN models.

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Peng Ji

Peng Ji, PhD, MD

Northwestern University

Chicago, Illinois
United States

The role of Plek2 in the pathogenesis of myeloproliferative neoplasms

Our research focuses on the study of a novel therapeutic target, named Plek2, in the development of myeloproliferative neoplasms (MPNs). MPNs can progress to leukemia and there are currently no cures. We use animal models and patient samples to study how elevated levels of Plek2 causes the disease and identify approaches to suppress the function of Plek2. Our goal is to use the knowledge from this study to develop novel therapies to treat MPNs.

Program: Career Development Program
Project Term: Start Date: July 1, 2017 End Date: June 30, 2022
Catriona Jamieson

Catriona Jamieson, PhD, MD

University of California, San Diego

La Jolla, California
United States

Detection and Targeting of Enzymatic Base Editing Deregulation in Leukemia Stem Cells

Dr. Jamieson is examining the role of two enzymes (APOBEC3 and ADAR1) known to mutate DNA and RNA, and their role in acute myeloid leukemia (AML) and disease relapse, particularly in elderly patients.

Program: Discovery
Project Term: Start Date: July 1, 2020 End Date: June 30, 2024
Caron Jacobson

Caron Jacobson, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

CAR T-cell therapy in central nervous system (CNS) lymphoma: a study in safety and efficacy and a model in which to study mechanisms of neurotoxicity

CAR T-cells are highly effective in lymphoma but limited by a profound and potentially fatal toxicity involving the central nervous system (CNS). Little is known about how CAR T-cells eliminate lymphoma cells in the CNS nor how this therapy causes toxicity. I will study CAR T-cells in patients with CNS lymphomas with the goal of expanding CAR T-cell indications. I will also examine serial blood and CNS samples to understand neurologic toxicity to inform new therapies to control this toxicity.

Program: Career Development Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2026
Kerry Rogers

Kerry Rogers , MD

The Ohio State University

Columbus, Ohio
United States

Improving BTK Inhibitor Therapy in Chronic Lymphocytic Leukemia Through Rational Combination Strategies

Ibrutinib is a targeted oral treatment for CLL that is safe and highly effective, however it must be given indefinitely which leads to chronic side effects and allows resistance to develop. We are conducting two clinical trials that add a second drug to ibrutinib to eliminate the remaining leukemia or ibrutinib-resistant leukemia cells. If these trials are successful, people taking CLL with or without resistance may be able to stop treatment in remission after taking an ibrutinib combination.

Program: Career Development Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2024
Dr. Ito

Keisuke Ito, PhD, MD

Albert Einstein College of Medicine

Bronx, New York
United States

Targeting mitophagy of leukemia stem cells for therapy

Enhancing the commitment of leukemia stem cells (LSCs) is a promising therapeutic strategy against blood cancer, but tracking the division pattern of individual cells has proved difficult. We have established a novel technical regimen to assess the behavior of individual LSCs and their cell fate in vivo. Genetic mouse models and mouse models engrafted with leukemia patient samples are also used. Our project seeks to elucidate the role of mitophagy in the control of LSC division balance, which may facilitate new therapy targeting these cells.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Helen Heslop

Helen Heslop, MD

Baylor College of Medicine

Houston, Texas
United States

Immunotherapy of Hematologic Malignancies

The overall goal of this SCOR proposal is to develop and clinically validate T-cell immunotherapies designed to produce antitumor activity without the toxicities associated with intensive chemotherapy. The effectiveness of T-cell immunotherapy for leukemia and lymphoma has now been amply demonstrated. Studies conducted in our previous SCOR have already led to multicenter trials and orphan drug designation of EBV-specific T cells for the treatment of EBV-positive NHL and to commercial licensing of our genetically modified T cells and a genetic safety switch engineered into effector T cells.

Program: Specialized Center of Research Program
Project Term: Start Date: October 1, 2018 End Date: September 30, 2023
Rizwan Romee

Rizwan Romee, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Cytokine induced memory-like NK cell immunotherapy to target post transplant relapse

Coming soon.

Program: Career Development Program
Project Term: Start Date: July 1, 2021 End Date: June 30, 2026
Michael Rout

Michael Rout, PhD

Rockefeller University

New York, New York
United States

Engineering nanobodies for lymphoma immunotherapeutics

This project will generate optimized single-chain antibodies (nanobodies) against HVEM and BTLA, two cell receptors that are misregulated in ~75% of follicular lymphomas. We will select for nanobodies that inhibit lymphoma tumor growth through restoration of HVEM or BTLA activity. We will further engineer lymphoma-targeted CAR-T cells, which have shown anti-tumor activity in other malignancies, to secrete these anti-HVEM or anti-BTLA nanobodies, in an alternative combination therapy approach.

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Kathleen Sakamoto

Kathleen Sakamoto, PhD, MD

Stanford University

Palo Alto, California
United States

Niclosamide for the treatment of relapsed pediatric acute myeloid leukemia

Niclosamide is an FDA approved anti-parasitic drug that is well tolerated in adults and children. AML cells are sensitive to niclosamide, act synergistically with chemotherapy in vitro, and inhibit the proliferation of primary AML stem cells in vivo. We propose to examine the effects of niclosamide in combination with chemotherapy in animal models of AML and study the mechanism of action of niclosamide in AML cells in anticipation of a clinical trial in children with relapsed AML.

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Michael Savona

Michael Savona, MD

Vanderbilt University Medical Center

Nashville, Tennessee
United States

Manipulation of cell fate in myeloid disease

Apoptosis is a normal cellular process of getting rid of extra cells that is co-opted by cancer cells to enhance their own survival, and we aim to better understand this process in myelodysplastic syndromes (MDS). Pevonedistat (PEV) is a novel therapy presumed to function, in part, through its effects on apoptosis. Our clinical trial will combine PEV with the standard of care therapy for MDS, azacitidine, in order to keep cancer cells from hijacking apoptosis, and we will study patient samples to match responses with molecular changes in the cancer cells. We seek to determine the suitability of this approach for MDS, and the ability to predict which patients may respond to PEV-based therapy.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Michael Savona

Michael Savona, MD

Vanderbilt University Medical Center

Nashville, Tennessee
United States

Reaching out to underserved & minority patients with hematological diseases in the southeastern US

Vanderbilt-Ingram Cancer Center (VICC) is the only NCI designated cancer center that serves both adult and pediatric populations in TN, one of the highest cancer-mortality states in the country. In fact, TN rural dwellers encompass about 30-50% of the states’ population, many with lower per-capita income and high school graduation rates. Influencing cancer care by facilitating underserved and minority populations to access therapeutic clinical trials as well as those focused on screening and prevention strategies remains a cornerstone objective. The Vanderbilt Health Affiliated Network (VHAN) serves as the largest provider for an organized network of hospitals, clinics, and health systems across TN. This network encompasses 12 health systems and 61 hospitals. Within VHAN, the VICC has had a formal affiliation with Baptist Memorial Healthcare Corporation (BMHCC) since 2012. BMHCC is affiliated with 22 hospitals and provides care for 8000 new cancer patients (pts) annually covering 111 counties totaling 4.3 million people. This includes 44% of the 252 counties and parishes in the Delta Regional Authority, congressionally acknowledged as the most indigent population in the US. The primary objective of the VICC community center affiliation with BMHCC is to enhance the regional level of cancer care and to advance cancer research efforts. VICC has provided guidance on a regular basis to assist BMHCC in the establishment and implementation of the Minority and Underserved National Cancer Institute Community Oncology Research Program (NCORP) grant as a successful and sustainable program. BMHCC has become amongst the top recruitment sites for NCORP, with steady growth in the proportion of rural pts seen across the health system. VICC continues to be a resource for BMHCC on providing consultations, training, and best practices for specialized services such as clinical research, radiation oncology, cancer screening, stem cell transplantation and community engagement.

Program: IMPACT
Project Term: Start Date: April 1, 2021 End Date: March 31, 2026
Susan Schwab

Susan Schwab, PhD

New York University School of Medicine

New York, New York
United States

T cell acute lymphoblastic leukemia accumulation in the central nervous system

T cell acute lymphoblastic leukemia (T-ALL) has a strong tendency to infiltrate the central nervous system (CNS). The goal is hope to develop strategies to treat CNS disease in T-ALL with less neurotoxicity and more efficacy than current chemotherapy.

Program: Discovery
Project Term: Start Date: July 1, 2020 End Date: June 30, 2024
Marc Seifert

Marc Seifert, PhD

Institute of Cell Biology (Tumor Research) at the Medical school Essen


Germany

Exploiting metabolic dependencies, tumor plasticity and their consequences for drug response of HCL

We have long standing experience in the field of HCL research. The aim of this research proposal is to characterize HCL on single cell level across multiple layers to uncover interactions of HCL with its microenvironment, which supports HCL cell survival. We will further explore metabolic and functional dependencies of primary HCL cells, and we hypothesize that their attenuation compromises HCL cell survival. Finally, we aim to pharmacologically disrupt these pro-survival pathways in HCL cells.

Program: HCL2025
Project Term: Start Date: October 1, 2021 End Date: December 31, 2026
Kevin Shannon

Kevin Shannon, MD

The Regents of the University of California, San Francisco

San Francisco, California
United States

Co-targeting BET bromodomain proteins and aberrant Ras signaling in pediatric AML

We will test rational drug combinations in accurate preclinical model systems that reflect the distinct genomic features of pediatric AML. The use of genetically accurate mouse models to inform clinical translation is particularly important in pediatric AML given its relatively low incidence and difficulties inherent in testing drug combinations in children. Our preliminary studies have identified combined BET and MEK inhibition as a particularly promising combination for pediatric AML.

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Alex Herrera

Alex Herrera, MD

Beckman Research Institute of the City of Hope

Duarte, California
United States

Novel combination strategies to enhance brentuximab vedotin efficacy in relapsed/refractory Hodgkin Lymphoma

New, non-chemotherapy treatments that use a patient’s own immune system have transformed the treatment of Hodgkin lymphoma (cHL). Typically used in patients with cHL that is resistant to standard treatment, these immune therapies can control the disease for months to years. However, in the long run, most patients will not be cured and will have immunotherapy-resistant cHL. My research evaluates strategies for reversing resistance to brentuximab vedotin (BV) immunotherapy for cHL by combining BV with other treatments in clinical trials.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Michael Green

Michael Green, PhD

The University of Texas MD Anderson Cancer Center

Houston, Texas
United States

Investigating the role of CREBBP mutations and epigenetic crosstalk in B-cell lymphoma

We seek to understand the genetic and epigenetic etiology of B-cell lymphoma and how deregulation of normal epigenetic programs perturb developmental programs and immune interactions. We approach this using a variety of genomic technologies to interrogate primary human tumors, CRISPR-engineered cell lines, patient-derived xenograft models and transgenic mouse models with different genetic lesions. We hope to understand how genetic and epigenetic changes associated with B-cell lymphoma create dependencies or characteristics that can be targeted through rational therapeutic interventions to improve patient outcomes.

Program: Career Development Program
Project Term: Start Date: October 1, 2020 End Date: September 30, 2025
Mitchell Geer

Mitchell Geer, PhD

New York University School of Medicine

New York, New York
United States

Role of ERK isoforms in normal hematopoiesis and leukemia

Current therapies for cancers driven by “RAS/ERK’ pathway mutations, such as juvenile myelomonocytic leukemia (JMML), are either high risk (bone marrow transplant) or ineffective (targeted inhibitors). We have identified a unique dependency of JMML cell growth for a group of ERK targets, which are not required for normal blood cell growth. We are investigating this further and aim to identify the ERK targets responsible, which may provide new drug targets to treat JMML and other cancers.

Program: Career Development Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Alfred Garfall

Alfred Garfall, MD

Perelman School of Medicine at the University of Pennsylvania

Philadelphia, Pennsylvania
United States

Enhancing CAR T cell therapy for multiple myeloma

My overall focus is to improve CAR T cell therapy for multiple myeloma. Our clinical trial uses CAR T cells targeting BCMA as first line therapy for high-risk multiple myeloma to assess whether early use of CAR T cells is safer and more effective than use in patients with relapsed disease. Half of patients will also receive CAR T cells targeting CD19 to assess whether this can improve the duration of response to anti-BCMA CAR T cells. Our goal is to evaluate whether early use of CAR T cells is a safer and more effective way to use CAR T cells for multiple myeloma patients.

Program: Career Development Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2024
David Fruman

David Fruman, PhD

University of California, Irvine

Irvine, California
United States

Preclinical optimization of statin/BH3 mimetic combinations in multiple myeloma

This project will evaluate a novel two-drug combination to improve killing of multiple myeloma (MM) cells. First, we will test the hypothesis that statins increase killing of MM cells by BH3 mimetics including venetoclax and the MCL-1 inhibitor AMG 176. Second, we will identify biomarkers that predict response. This project will have significant positive impact on two fields: repurposing statins for blood cancer, and application of BH3 mimetics to improve health and survival of MM patients.

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Maria Figueroa

Maria "Ken" Figueroa, MD

University of Miami

Coral Gables, Florida
United States

Epigenetic Deregulation of Hematopoietic Cells with Aging and Disease

Our lab is focused on understanding how age-related epigenetic deregulation contributes to driving the functional decline of the hematopoietic system we see as we age. We are using genome-wide sequencing approaches to understand the changes in human hematopoietic stem and progenitor cells (HSPC) with aging at epigenomic level, along with in vitro and in vivo modeling of key changes that we hypothesize are the responsible drivers of the aging decline phenotype. Our overarching goal is to identify key drivers of functional HSPC decline to ultimately develop methods for modulating these drivers and achieve HSC rejuvenation.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Jonathan Licht

Jonathan Licht, MD

University of Florida

Gainesville, Florida
United States

Targeting Enhancer Dysfunction in Hematological Malignancy

Blood cancers such as leukemia, lymphoma and myeloma may be caused by abnormal regulation of genes that control normal cell growth and development. Genes that are normally active can be silenced and/or genes normally not present in a blood cell are abnormally activated. The result can be an uncontrolled signal for continued cell growth or survival. Our group studies the molecular basis of this gene deregulation using cells cultured in the laboratory, human specimens, and animal models.

Program: Specialized Center of Research Program
Project Term: Start Date: January 1, 2019 End Date: September 30, 2024
Areej El-Jawahri

Areej El-Jawahri, MD

Massachusetts General Hospital

Boston, Massachusetts
United States

Randomized Trial of a Sexual Dysfunction Intervention for Hematopoietic Stem Cell Transplant Survivors

Our goal is to improve sexual function and quality of life for patients with blood cancers undergoing hematopoietic stem cell transplantation. We will conduct a clinical trial to evaluate whether a multi-component intervention to address sexual health and intimacy concerns can improve sexual function and satisfaction as well as quality of life and mood in hematopoietic stem cell transplant survivors. We will also explore whether improvement in sexual function leads to improvement in quality of life in this population. By developing an innovative and potentially scalable model of care to address sexual health issues, we aim to improve the quality of life and survivorship care for patients with blood cancers.

Program: Career Development Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2024
Gianpietro Dotti

Gianpietro Dotti, MD

The University of North Carolina at Chapel Hill

Chapel Hill, North Carolina
United States

Targeting cathepsin G in acute myeloid leukemia

We developed a chimeric antigen receptor (CAR) targeting an epitope of the myeloid associated antigen cathepsin G that is processed and presented in the contest of the MHC complex in myeloid leukemic cells. T cells expressing the cathepsin G specific CAR (CG1.CAR) recognize HLA-A2+ myeloid target cells expressing cathepsin G. We intend to study efficacy and safety of CG1.CAR-T cells in preclinical models in preparation of a phase I clinical study in patients with relapsed/refractory AML.

Program: Translational Research Program
Project Term: Start Date: July 1, 2021 End Date: June 30, 2024
Lei Ding

Lei Ding, PhD

Columbia University Medical Center

New York, New York
United States

Targeting the interaction of leukemia stem cells with their niche to treat myelofibrosis

Bone marrow scar formation (fibrosis) is a hallmark of myelofibrosis and contributes significantly to the disease progression. We use mouse genetics to model myelofibrosis and understand the cellular and molecular makeup of the diseased microenvironment. We aim to understand the composition and alteration of the bone marrow microenvironment in myelofibrosis. This may provide novel therapeutic targets for myelofibrosis.

Program: Career Development Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2024
Courtney DiNardo

Courtney DiNardo, MD

The University of Texas MD Anderson Cancer Center

Houston, Texas
United States

Targeted therapy for AML expressing mutant RUNX1

Clinical outcome of high-risk Myelodysplastic Syndrome (MDS) and AML with mutant (mt) RUNX1 is relatively poor. Supported by our preclinical data, we propose a Phase Ib clinical trial of omacetaxine mepisuccinate (OM) and venetoclax along with correlative science studies in patients with relapsed MDS or AML exhibiting mtRUNX1. Studies proposed will also determine pre-clinical activity of novel, OM-based combinations against mtRUNX1-expressing, patient-derived, pre-treatment AML cells.

Program: Translational Research Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2024
Courtney DiNardo

Courtney DiNardo, MD

The University of Texas MD Anderson Cancer Center

Houston, Texas
United States

A precision-based all-oral combination of venetoclax, oral decitabine, and IDH1/2 targeted inhibition for patients with IDH1 or IDH2 mutated AML

My ultimate goal is to develop more effective, better tolerated, and individualized treatment for patients with AML. This project focuses on AML patients with IDH1 or IDH2 mutations, with a clinical trial evaluating a combination of three agents which are effective in IDH-mutated AML. While these therapies are not curative on their own, my hope is that this combination will lead to a practice changing all-oral, outpatient, and well-tolerated curative strategy for patients with IDH-mutated AML.

Program: Career Development Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2026
Timothy Ley

Timothy Ley, MD

Washington University School of Medicine in St. Louis

St. Louis, Missouri
United States

Improving risk assessment of AML with a precision genomic strategy to assess mutation clearance

We will enroll transplant-eligible patients with intermediate-risk AML, and define mutation clearance after recovery from induction using deep exome sequencing. Patients who clear all mutations will be consolidated with chemotherapy only (HiDAC). Patients who fail to clear all mutations will be offered an allogeneic transplant. This prospective study may improve outcomes for intermediate-risk patients by more precisely using transplantation in first remission.

Program: Translational Research Program
Project Term: Start Date: April 1, 2021 End Date: March 31, 2023
Madhav Dhodapkar

Madhav Dhodapkar, MBBS

Emory University

Atlanta, Georgia
United States

Improving targeted adoptive cell therapy of myeloma

Dr. Madhav Dhodapkar, M.D., of Winship Cancer Institute of Emory University, Atlanta, leads a multi-institutional, multi-disciplinary LLS Specialized Center of Research team focused on advancing new immunotherapies for patients with multiple myeloma. Their goal is to improve the effectiveness of CAR T-cell immunotherapy, which engineers the patient’s T cells to find and kill cancer cells. The CAR-T they are studying targets a protein called BCMA found on the surface of all myeloma cells. BCMA-targeting therapies are showing tremendous promise for treating myeloma patients in clinical trials, but many patients eventually relapse. Dr. Dhodapkar’s group is working to understand the mechanisms that cause some patients to be resistant to the treatment. They are also investigating another type of immunotherapy that relies on natural killer T cells. His team includes researchers at Emory as well as Fred Hutchinson Cancer Center in Seattle.

Program: Specialized Center of Research Program
Project Term: Start Date: January 1, 2020 End Date: December 31, 2024
Alexey Danilov

Alexey Danilov, PhD, MD

Beckman Research Institute of the City of Hope

Duarte, California
United States

Enhancing efficacy of cyclin-dependent kinase inhibitors in diffuse large B-cell lymphoma

Nearly half of patients with diffuse large B-cell lymphoma (DLBCL), ultimately fail current therapies and die from their disease. Selective targeting of cyclin-dependent kinase 9 (CDK9) is a promising strategy, as evidenced by potent anti-tumor effects in preclinical models of DLBCL. Yet tumors evade therapy by developing resistance. This proposal seeks to both elucidate and circumvent the oncogenic events underlying this resistance in order to offer novel therapeutic approaches to treat DLBCL.

Program: Translational Research Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2023
Alexey Danilov

Alexey Danilov, PhD, MD

Beckman Research Institute of the City of Hope

Duarte, California
United States

Overcoming ibrutinib resistance in mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive blood cancer which affects about 3,000 individuals in the United States annually. Despite advances of novel therapies in blood cancers, MCL remains incurable, and patients ultimately succumb to disease. We seek to evaluate longitudinal samples from patients with MCL treated with novel therapies to understand the mechanisms of drug resistance. We identify novel targets, with a particular focus on protein turnover pathways, to overcome drug resistance and improve survival of patients with MCL.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Brian Dalton

Brian Dalton, PhD, MD

Johns Hopkins University

Baltimore, Maryland
United States

Therapeutic modulation of serine availability for SF3B1-mutant myeloid malignancies

Mutations in the spliceosome gene SF3B1 are common in myeloid malignancies, but they are currently untargetable. Our previous work has shown that SF3B1 mutations reprogram energy metabolism and create vulnerability to restriction of the nonessential amino acid serine. Here we propose a preclinical project studying PEGylated cystathioinine beta synthase (pCBS), a recombinant enzyme that catabolizes serine, as a treatment for SF3B1-mutant myeloid malignancies.

Program: Translational Research Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2024
Riccardo Dalla-Favera

Riccardo Dalla-Favera, MD

Columbia University Medical Center

New York, New York
United States

Targeting the NAD salvage pathway in GCB-DLBCL

Novel therapies are needed for ~40% of Diffuse Large B-Cell Lymphoma (DLBCL) patients who do not respond to the standard immune-chemotherapy regimen. Repurposing for DLBCL FDA-approved drugs and other targeted compounds in clinical development may offer a fast-track route to the clinic. Toward this end, we identified inhibitors of the enzyme NAMPT as active against a subset of DLBCL. The goal of this proposal is to thoroughly develop the pre-clinical rationale for NAMPT inhibition against DLBCL.

Program: Translational Research Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2024
Jaehyuk Choi

Jaehyuk Choi, PhD, MD

Northwestern University

Chicago, Illinois
United States

Identification of novel therapeutic strategies for aggressive subtypes of CTCL

Coming soon.

Program: Career Development Program
Project Term: Start Date: July 1, 2021 End Date: June 30, 2026
Selina Chen-Kiang

Selina Chen-Kiang, PhD

Weill Cornell Medicine

New York, New York
United States

Longitudinal functional genomics in mantle cell lymphoma therapy and drug resistance

Overview Title: Longitudinal functional genomics in mantle cell lymphoma therapy and drug resistance Weill Cornell Medicine and Ohio State University PI: Selina Chen-Kiang, Ph.D. co-PI: Peter Martin, M.D. Despite the plethora of therapies available for mantle cell lymphoma (MCL), it remains incurable due to the development of drug resistance. Moreover, each successive treatment failure is associated with a more rapidly proliferating disease and fewer practical treatment options. For example, the BTK inhibitor (BTKi) ibrutinib has unprecedented activity but failure is virtually universal and is associated with dismal outcomes. Understanding the genomic basis and mechanisms for drug resistance in MCL is therefore urgently needed. Our goal is to develop superior therapies for MCL that are practical, well tolerated and amenable to patient stratification, by defining the genomic and the molecular and immunological mechanisms for drug resistance in the context of rationally designed clinical trials with targeted agents. Targeting the cell cycle represents a rational approach to MCL therapy, as dysregulation of CDK4 and aberrant cyclin D1 expression underlie unrestrained proliferation in disease progression. We have demonstrated that induction of prolonged early G1 arrest (pG1) by inhibiting CDK4 with palbociclib not only prevented proliferation of primary MCL cells but also reprogrammed them for killing by clinically relevant targeting agents including ibrutinib and PI3K inhibitors (PI3Ki)s. By longitudinal functional genomics of serial biopsies from MCL patients treated with either palbociclib or ibrutinib we discovered a close association of clinical response with inactivation of PI3K and activation of the tumor suppressor transcription factor FOXO1. Moreover, chromatin remodeling appeared to be the proximal event that reprograms MCL cells in response to CDK4 inhibition. Collectively, our findings suggest that through regulation of PI3K and FOXO1 and the epigenome, induction of pG1 by CDK4 inhibition reprograms MCL for a deeper and more durable clinical response to BTKi and PI3Ki. Supporting this hypothesis, in our phase 1 clinical trial of palbociclib + ibrutinib (PALIBR) in recurrent MCL (N=27) the overall response rate was 67% with 43% complete responses. The responses were rapid and durable; only 2 responding patients have progressed in the 32 months since the trial opened. To further accelerate the development of targeted MCL therapies, we have developed a novel inhibitor for protein arginine methyl transferase 5 (PRMT5), which is dysregulated in MCL and many other human cancers. Inhibition of PRMT5 reverses PRMT5 catalyzed epigenetic marks, restores regulatory pathways and enhances survival of preclinical models of MCL and kills ibrutinib-resistant primary MCL cells. Building on these novel findings and capitalizing on the upcoming multi-center phase 2 PALIBR in recurrent MCL, we propose to investigate drug resistance and develop new strategies that circumvent drug resistance in three integrated projects. Project 1: Development of rational treatment strategies for new and recurrent MCL (PI: Peter Martin, M.D.; co-PI: Jia Ruan, M.D., Ph.D., and Kami Maddocks, M.D.). We aim to develop regimens that can be targeted to the appropriate patient subset, are well tolerated, and can be administered in the community. We will conduct a multicenter feasibility trial of lenalidomide + rituximab (R2)+ durvalumab in untreated MCL with real-time monitoring of MRD. We will explore whether durvalumab can overcome immune-mediated resistance to R2 and whether using MRD to modify therapy improves tolerability and practicality without compromising efficacy. We will also conduct a multicenter phase 2 trial of PALIBR in previously treated MCL to better define patients most likely to benefit from this therapy while providing information on mechanisms of resistance in collaboration with Project 2 and 3. Project 2: Functional genomics and mechanism of drug resistance in MCL (PI: Selina Chen-Kiang, Ph.D.; co-PI: Olivier Elemento, Ph.D., and Lewis Cantley, Ph.D.) The clinical response from the phase 1 clinical trial of PALIBR supports our hypothesis that induction of pG1 by CDK4 inhibition reprograms MCL for a deeper and more durable clinical response. To understand the underlying mechanism, we aim to identify the genomic resistance biomarkers by longitudinal functional genomics in the context of the clinical response to PALIBR in the phase 2 clinical trial in collaboration with Project 1. We will further elucidate the mechanism of pG1 reprograming for ibrutinib vulnerability, and target the therapy vulnerability conferred by the genomic resistance biomarkers discovered in this study, such as targeting PRMT5 in collaboration with Project 3. Project 3: Targeting the epigenome in MCL (PI: Jihye Paik, Ph.D., co-PI: Robert Baiocchi, M.D., Ph.D.). Based on our collective evidence, we hypothesize that dysregulation of PRMT5 and FOXO1 causes epigenetic and gene expression changes promoting MCL proliferation and survival. Thus, targeting PRMT5-regulated epigenome may restore FOXO1-mediated cytotoxic gene expression and induce MCL killing. Our goal is to characterize the epigenetic recruitment of PRMT5 and FOXO1 for mechanism-based targeting of MCL epigenome. We aim to identify direct targets of PRMT5 necessary for MCL proliferation and survival, and to define the role of FOXO1 in killing of MCL cells by targeting the epigenome, in collaboration with Projects 1 and 2. These innovative studies are supported by the Administrative Core, Pathology Core and Genomics, Bioinformatics & Biostatistics Core (organization table appended). In addition, WCM has pledged a match of 1.7 million for the proposed studies as indicated in the letters from Drs. Augustine Choi, Dean of WCM, John Leonard, Interim Chairman of Medicine and Lewis Cantley, Director of the Meyer Cancer Center (appended).

Program: Mantle Cell Lymphoma Research Initiative
Project Term: Start Date: January 1, 2018 End Date: December 31, 2022
Jianhua Yu

Jianhua Yu, PhD

Beckman Research Institute of the City of Hope

Duarte, California
United States

All-in-one for myeloma: a single therapy to combine CAR T cells and bispecific antibodies to engage both innate and adaptive immune responses

This project is designed to develop a novel cell therapy to treat relapse/refractory multiple myeloma (MM), an incurable cancer. We target BCMA, a protein highly expressed on MM compared to normal cells, with CAR T cells that also secrete a bispecific antibody that can engage all cytolytic cells, including various endogenous T cells, natural killer (NK) cells, and NKT cells to kill MM cells. We aim to complete all preclinical studies so that the therapy is ready for future clinical studies.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Sisi Chen

Sisi Chen, PhD

Memorial Sloan Kettering Cancer Center

New York, New York
United States

Aberrant LZTR1 and RIT1 signaling as a driver of clonal hematopoietic disorders

Our research focuses on a novel mechanism of RAS protein regulation via the protein LZTR1, which is altered in leukemia and hinders the effectiveness of leukemia therapies. We will utilize mouse models and functional genomic studies to uncover how altered RAS degradation drives leukemia and identify novel drug targets. This effort will help us identify the clinical impact of alterations in this novel RAS pathway in patients and potential means to improve leukemia treatment.

Program: Career Development Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2024
Aditi Shastri

Aditi Shastri, MD

Albert Einstein College of Medicine

New York, New York
United States

Antisense inhibition of STAT3 as a therapeutic strategy against leukemic stem cells

STAT3 is over-expressed in highly purified leukemic stem & progenitor cells and its expression is associated with a worse prognosis. Inhibition of STAT3 by an anitsense oligonucleotide AZD9150 leads to decreased viability of leukemic stem cells in in vitro & in vivo models. In the proposed studies, we will comprehensively examine the role of STAT3 in AML stem cell dynamics, identify the mechanisms of its actions and determine the efficacy of clinically available STAT3 inhibitors.

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Grant Challen

Grant Challen, PhD

Washington University in St. Louis

St. Louis, Missouri
United States

Synergism of cell-intrinsic and cell-extrinsic factors in the clonal evolution of pre-malignant HSCs

We study the mechanisms of clonal hematopoiesis (CH), a process by which mutations provide hematopoietic stem cells (HSCs) with a fitness advantage. CH can precede the development of blood cancer. We use cutting-edge techniques to understand the effects of these mutations on HSC behavior. Our long-term goal is to identify ways to inhibit the growth of these mutant HSCs while sparing normal HSCs in people with CH. This may someday provide a blood cancer prevention method by eliminating the cells which carry the initial cancer-driving mutations.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Liran Shlush

Liran Shlush, PhD, MD

Weizmann Institute of Science


Israel

Early diagnosis and treatment of pre-leukemia

In the current study we propose, based on our preliminary results, that we can reliably identify pre-AML cases out of the many individuals with age related clonal hematopoiesis (ARCH) based on clinical parameters thereby limiting the population that needs to undergo molecular testing. We have also developed a predictive model that can identify pre-AML cases years before diagnosis. We now propose to utilize this knowledge to treat high-risk individuals with ARCH, at a time point before they have developed disease, by targeting the driving alterations most associated with AML development.

Program: RTFCCR/LLS Prevention
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Jason Butler

Jason Butler, PhD

Hackensack Meridian Health

Edison, New Jersey
United States

Modulating Signaling Pathways in Endothelial Cells to Abate Leukemic Progression

We seek to elucidate the mechanisms by which aging of the vascular system contributes to the decline in blood stem cell function and leads to diseases such as hematopoietic malignancies. We have developed novel model systems that have led to the discovery of rejuvenation factors that can restore the functional capacity of an aging blood and vascular system. These studies lay the foundation for the development of therapeutic strategies to not only rejuvenate an aged blood system, but to also give a competitive advantage to non-malignant blood cells while directly targeting cancer cells following chemotherapy regimens commonly utilized to treat hematological malignancies.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Tomasz Skorski

Tomasz Skorski, PhD, MD, DSc

Temple University

Philadelphia, Pennsylvania
United States

Genetic roadmaps to synthetic lethality in myeloproliferative neoplasms (MPNs)

Myeloproliferative neoplasms (MPNs) carry JAK2(V617F), MPL(W515L) and mutations in calreticulin (CALRmut) often accompanied by mutations in TET2, ASXL1, DNMT3A, EZH2, and other genes. We will develop a strategy based on gene mutation profiling to identify MPNs displaying specific defects in DNA repair. These defects will be then explored by specific DNA repair inhibitors to eliminate quiescent and proliferating MPN stem and progenitor cells without affecting normal cells and tissues.

Program: Translational Research Program
Project Term: Start Date: July 1, 2021 End Date: June 30, 2024
Tomasz Skorski

Tomasz Skorski, PhD, MD, DSc

Temple University

Philadelphia, Pennsylvania
United States

Precision medicine-guided drugging of DNA repair to induce synthetic lethality in AMLs

We will test if Gene Expression and Mutation Analysis (GEMA) could be applied as personalized medicine tool to identify individual patients with AML displaying specific preferences for repairing spontaneous and drug-induced DNA damage. These preferences will predispose leukemia stem and progenitor cells to synthetic lethality triggered by already approved as well as novel DNA repair inhibitors.

Program: Translational Research Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2021
Amin Sobh

Amin Sobh, PhD

University of Florida

Gainesville, Florida
United States

Investigating the Role of Adenylate Kinase 2 in Multiple Myeloma

The goal of my research is to characterize the role of the cellular metabolic regulator AK2 in multiple myeloma (MM) pathogenesis and therapy resistance. A series of molecular, biochemical, and functional assays will be performed using laboratory models to define the basis of MM cell dependence on AK2 and elucidate its role in MM progression and drug resistance. This work will highlight novel metabolic vulnerabilities in MM that can be targeted to further enhance therapeutic outcomes.

Program: Career Development Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2024
Daniel Starczynowski

Daniel Starczynowski, PhD

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio
United States

Rational therapeutic targeting of oncogenic immune signaling states in myeloid malignancies

Dr. Starczynowski is investigating the role and potential benefit of therapeutic targeting of a protein called UBE2N in acute myeloid leukemia (AML).

Program: Discovery
Project Term: Start Date: July 1, 2020 End Date: June 30, 2024
Kimberly Stegmaier

Kimberly Stegmaier, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Advancing New Therapeutic Strategies for Pediatric Acute Leukemias

Dr. Kimberly Stegmaier is performing pre-clinical research to identify promising therapeutic strategies for pediatric leukemia. Pediatric blood cancers comprise about 40% of all pediatric cancers. The most common pediatric blood cancer is acute lymphoblastic leukemia (ALL), which is curable in most patients through the use of chemotherapy. Though beneficial in the short term, destroying the cancer through chemotherapy often leads to long term health problems. For those that do not respond to chemotherapy, there are fewer therapeutic options. Another pediatric blood cancer is acute myeloid leukemia (AML), which is a more aggressive and lethal disease. Therefore, many pediatric acute leukemia patients require better therapeutic options, and a precision medicine approach targeting specific mutations will likely lead to a better clinical benefit.

Program: Dare to Dream
Project Term: Start Date: October 1, 2020 End Date: September 30, 2023
Srividya Swaminathan

Srividya Swaminathan, PhD

Beckman Research Institute of the City of Hope

Duarte, California
United States

Development of natural killer (NK) cell-based therapies to treat MYC-high pediatric lymphoid cancers

Refractory pediatric B- and T- lymphoid cancers exhibit hyperactivation of MYC and its downstream pathways. Experimentally, MYC inactivation sustains tumor regression. However, MYC’s requirement in normal B/T-cells has hampered the development of MYC inhibitors. Recently, we showed that MYC-High B/T-Lymphoid Neoplasms (B/T-MLN) evade Natural Killer (NK) cell surveillance. Hence, we propose to develop targeted off-the-shelf NK therapies as an alternative to MYC inhibition for treating B/T-MLN.

Program: Translational Research Program
Project Term: Start Date: July 1, 2021 End Date: June 30, 2024
Sarah Tasian

Sarah Tasian, MD

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania
United States

Precision Medicine Inhibitor and Immunotherapy Approaches for High-Risk Childhood Leukemias

Dr Tasian’s scientific passion is successful development of precision medicine therapies for high-risk childhood leukemia. Her translational laboratory research program focuses upon investigation of kinase inhibitors and chimeric antigen receptor (CAR) T cell immunotherapies in childhood ALL and AML using primary patient specimens and patient-derived xenograft models. Through her laboratory and clinical research, she aspires to improve cure rates and minimize toxicities for children with leukemia.

Program: Career Development Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2026
Samuel Taylor

Samuel Taylor, PhD

Albert Einstein College of Medicine

Bronx, New York
United States

Pharmacological inhibition of the transcription factor PU.1 as a novel treatment for acute myeloid leukemia

Transcription factors are components of a cell which control our genetic information and are known to have altered function in diseases such as Acute Myeloid Leukemia (AML). I am investigating how we can better understand and use novel transcription factor drugs as therapy for AML. This involves using CLICK-chemistry drug localization studies and creating transcription factor occupancy maps of the genome. Overall, my work will help to understand the inner workings of transcription factors in disease and provide a new therapeutic option for the treatment of AML.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2021
Enrico Tiacci

Enrico Tiacci, MD

University of Perugia. Department of Medicine and Surgery


Italy

BRAF inhibition as an alternative to chemotherapy in the treatment strategy of hairy cell leukemia

Hairy cell leukemia (HCL) is very sensitive to chemotherapy, whose toxicity to the bone marrow and the immune system is however concerning. We have established vemurafenib plus rituximab as a very effective chemotherapy-free regimen in relapsed/refractory HCL (NEJM, in press). Here, we will test it in a clinical trial against a chemotherapy-based standard of care represented by cladribine plus rituximab, aiming at lower toxicity and similar efficacy.

Program: HCL2025
Project Term: Start Date: January 1, 2023 End Date: December 31, 2025
Jennifer Trowbridge

Jennifer Trowbridge, PhD

The Jackson Laboratory

Bar Harbor, Maine
United States

Discovery of Aging-Driven Mechanisms Causing Clonal Hematopoiesis (CH) and its Progression to Hematological Malignancy

My research focuses on why and how risk of acute myeloid leukemia (AML) increases with aging. Studying naturally aged mouse models in combination with mice engineered to express mutations commonly found in human blood stem cells with aging, we are investigating whether certain inflammatory factors that increase during aging increase the risk of leukemia. My goal is to identify biomarkers to assess risk of AML development in aging individuals and define new therapeutic targets to prevent AML.

Program: Career Development Program
Project Term: Start Date: January 1, 2021 End Date: December 31, 2025
Nathan Ungerleider

Nathan Ungerleider, PhD

Tulane University School of Medicine

New Orleans, Louisiana
United States

EBV promotes Burkitt's lymphoma progression through microprocessor sequestration.

This proposal aims to understand the molecular mechanisms underlying response to AZA therapy in MDS, as a basis for developing more effective therapies. A ribonucleotide, AZA’s effects on RNA remain unknown. Here, we will investigate the impact of in vivo AZA therapy on RNA alternative splicing and DNA demethylation in MDS patients. Secondly, we will investigate whether AZA treatment exposes neoepitopes in the dysplastic cells of patients, which could be exploited for cancer immunotherapy in MDS

Program: Career Development Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2023
Ashwin Unnikrishnan

Ashwin Unnikrishnan, PhD

The University of New South Wales (UNSW)

, New South Wales
Australia

Beyond azacitidine: investigating new therapeutic strategies for the treatment of MDS

This proposal aims to understand the molecular mechanisms underlying response to AZA therapy in MDS, as a basis for developing more effective therapies. A ribonucleotide, AZA’s effects on RNA remain unknown. Here, we will investigate the impact of in vivo AZA therapy on RNA alternative splicing and DNA demethylation in MDS patients. Secondly, we will investigate whether AZA treatment exposes neoepitopes in the dysplastic cells of patients, which could be exploited for cancer immunotherapy in MDS

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Robert Bradley

Robert Bradley, MD

Fred Hutchinson Cancer Research Center

Seattle, Washington
United States

Loss of the non-canonical BAF complex as a driver and therapeutic target in SF3B1-mutant MDS and leukemia

The most common cause of MDS is a genetic mutation occurring in blood cells that affects a process called “RNA splicing”. The most commonly mutated RNA splicing factor gene is called SF3B1. We now know that many patients with MDS carry mutations in SF3B1 but we do not know why these mutations cause disease. Dr. Bradley proposes to determine how mutations in SF3B1 cause MDS and potentially create new opportunities for treating this disease.

Program: Discovery
Project Term: Start Date: July 1, 2020 End Date: June 30, 2024
Juliette Bouyssou

Juliette Bouyssou, PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Understanding sex differences in myeloid and dendritic differentiation and function to target high-risk leukemias including BPDCN

There are widely recognized but unexplained sex differences in cancer incidence and outcomes, including in blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive leukemia that occurs over 3 times more frequently in men. We aim to identify male-female differences in plasmacytoid dendritic cells, the blood cell involved in BPDCN, to better understand this disease. Our goal is to use what we learn to improve the treatment of BPDCN and related blood cancers for both men and women.

Program: Career Development Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Katherine Borden

Katherine Borden, PhD

IRIC - Institute for Research in Immunology and Cancer

Montreal, Quebec
Canada

The oncogene eIF4E coordinates extracellular signalling in AML

The oncoprotein eIF4E is dysregulated in many cancers including AML. We show that eIF4E drives production of the glycosaminoglycan hyaluronan (HA). Further, HA elevation alters the surface architecture of high-eIF4E AML cells and this is required for eIF4E’s oncogenic activity. We will explore HA’s involvement in AML and the efficacy of depleting HA in patients using hyaluronidase in a Phase I trial in AML.

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2021
Catherine Bollard

Catherine Bollard, MD

Children's Research Institute

Washington, District of Columbia
United States

T cells with native and chimeric receptors against multiple tumor targets for acute myeloid leukemia

Adoptive T cell therapies for acute myeloid leukemia face numerous hurdles such as limited target antigens, immunosuppressive tumor environment as well as the loss of efficacy due to downregulation of the targeted antigen. The goal of our project is to address some of these challenges with a single T cell product targeting multiple tumor associated antigens that have limited expression on healthy tissues via a novel combination of native T cell receptor and gene engineered CAR targeting.

Program: Translational Research Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2024
Dane Vassiliadis

Dane Vassiliadis, PhD

The University of Melbourne

Parkville, Victoria
Australia

Targeting non-genetic mechanisms of therapeutic resistance in Acute Myeloid Leukaemia

Drug resistance in AML can develop via a non-genetic process which remains poorly understood. Using our novel cellular barcoding technology that can trace the growth of thousands of cancer cells, our research will identify genes that are switched on or off in AML cells that lead to drug resistance and relapse. This work will reveal the factors underpinning non-genetic drug resistance that may be targeted with new drugs to prevent relapse and ultimately improve quality of life and survival.

Program: Career Development Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2024
George Vassiliou

George Vassiliou, MBBS, PhD

University of Cambridge

Cambridge
United Kingdom

Prevention of myeloid cancers by understanding their pre-clinical evolution

Here we propose to study blood DNA from 1500 people who have had extensive genetic and aging-related tests over many years as participants of the "Immunoageing" study (http://www.immunoageing.eu/index.html). We propose to study these people for the presence of age-related clonal hematopoiesis (ARCH) to understand what factors are associated with ARCH and its expansion. Our aim is to use these findings to help prevent ARCH from progressing to myeloid cancer in at risk individuals identified by future screening programs, which we and others developing separately.

Program: RTFCCR/LLS Prevention
Project Term: Start Date: July 1, 2018 End Date: December 31, 2022
Matteo Bellone

Matteo Bellone, MD

Fondazione Centro San Raffaele

Lombardia
Italy

Gut microbiota modulation to prevent progression of smoldering multiple myeloma to active disease

Blocking the progression of smoldering multiple myeloma (SMM) to active MM is an unmet clinical need. In primary mouse models of MM, we aim at demonstrating that modulation of the gut microbiota by vaccination against the commensal Prevotella heparinolytica and/or colonization by P. melaninogenica, also in combination with anti-PD-L1 antibodies, inhibit the progression of asymptomatic MM to full-blown disease. Our findings are expected to provide the ground for clinical trials in SMM patients.

Program: Translational Research Program
Project Term: Start Date: July 1, 2021 End Date: June 30, 2024
Wendy Béguelin

Wendy Béguelin, PhD

Weill Cornell Medicine

New York, New York
United States

Preventing follicular lymphoma progression and transformation through precision therapy

Follicular lymphomas (FL) depend on stromal cells for survival and proliferation and evade T-cell immune surveillance. Although indolent, most FLs eventually undergo either progression or transformation to an aggressive lymphoma. Effective treatments to prevent this remain a critical unmet need. This proposal will develop novel, mechanism-based therapeutic regimens for FL that overcome defective immune surveillance, prevent FLs from receiving stromal support and prevent disease progression.

Program: Translational Research Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2024
Therese Vu

Therese Vu, PhD

University of Colorado Denver, Anschutz Medical Campus

Aurora, Colorado
United States

Evaluating a novel collaboration between NOTCH1 and MLL1 for improved targeted treatments in T-ALL

Most T cell acute lymphoblastic leukemia (T-ALL) patients respond to chemotherapy, however many relapse with limited therapy options. To address this problem, we are utilizing a newly-developed human T-ALL system to study two potential therapy targets (NOTCH1 and MLL1) and their interaction, to determine if they can be co-inhibited to eradicate disease. Since compounds that inhibit NOTCH1 and MLL1 are already in development, this novel combination strategy could lead to clinical approval sooner.

Program: Career Development Program
Project Term: Start Date: January 1, 2021 End Date: December 31, 2023
Brian Walker

Brian Walker, PhD

Indiana University

Indianapolis, Indiana
United States

The impact of non-coding somatic mutations on the prognosis and progression of multiple myeloma

Past studies of protein-coding regions have extensively characterized the genome of multiple myeloma (MM), but there has been little information on the prognostic impact of non-coding variants that may affect gene expression and regulation. Using a well-defined set of patient samples at different stages of disease progression we will define non-coding mutational hotspots in MM that contribute to progression and poor prognosis, identifying novel targets for alternative treatment strategies.

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Venkata Lokesh Battula

Venkata Lokesh Battula, PhD

The University of Texas MD Anderson Cancer Center

Houston, Texas
United States

Targeting immune checkpoint protein B7-H3 (CD276) in acute myeloid leukemia

We found that immune checkpoint protein B7-H3 is overexpressed in Acute Myeloid Leukemia (AML) cells compared to normal hematopoietic cells. We have developed four monoclonal antibodies (mAbs) which successfully block B7-H3 and activate NK cells to induce apoptosis in AML cells. In this proposal we propose to generate therapeutically relevant anti-B7-H3 chimeric recombinant mAbs and test their activity in vivo. In addition, we will identify the receptor for B7-H3 expressed on NK cells.

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
G. Greg Wang

G. Greg Wang, PhD

The University of North Carolina at Chapel Hill

Chapel Hill, North Carolina
United States

Decipher and Target AML Cell Dependency on Epigenetic Mutations

The goal of our program aims to understanding the general roles of DNA methylation machineries in epigenetic regulation and cancerous transformation seen in hematological cancers. Routinely, we take a set of integrated biochemical, genomics, oncology, and medicinal chemistry approaches to tackle the broad and critical questions in this field. Our findings shall not only promote current understanding of how hematological malignancies occur but also help develop novel therapeutic approaches.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Ryan Wilcox

Ryan Wilcox, PhD, MD

Regents of the University of Michigan

Ann Arbor, Michigan
United States

XPO-1 as a novel therapeutic target in GATA-3 expressing mature T-cell lymphomas

GATA-3 identifies high-risk subtypes of mature T-cell lymphomas (MTCL), as its target genes, which we have systematically identified, have significant cell-autonomous and non-cell-autonomous (by regulating constituents of the tumor microenvironment) roles in these MTCL. As our preliminary data suggests that XPO-1 inhibition is a novel, and largely unexplored, therapeutic strategy in these MTCL, we will examine its cell-autonomous (Aim #1) and non-cell-autonomous (Aim #2) role in GATA-3+ MTCL.

Program: Translational Research Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2024
Kirsten Williams

Kirsten Williams, MD

Emory University

Atlanta, Georgia
United States

Initiation of a novel immunotherapeutic to safely eradicate acute leukemia

We propose to develop a novel personalized immunotherapy to treat patients with refractory acute myeloid leukemia. We have shown that tumor-specific T cells (TAA-T) can diminish leukemia disease burden after allogeneic stem cell transplant. We now propose to augment the efficacy of the TAA-T products in the autologous setting using IL-15 backpacks to enhance TAA-T function and enhance efficacy without increased toxicity in vivo.

Program: Translational Research Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2022
Jennifer Woyach

Jennifer Woyach, MD

The Ohio State University

Columbus, Ohio
United States

Overcoming BTK Inhibitor Resistance in Chronic Lymphocytic Leukemia

Coming soon.

Program: Career Development Program
Project Term: Start Date: April 1, 2021 End Date: March 21, 2026
Jian Xu

Jian Xu, PhD

The University of Texas Southwestern Medical Center

Dallas, Texas
United States

Functional and mechanistic roles of BCAA metabolism in the progression of myeloproliferative neoplasms

The processes that control the progression of myeloproliferative neoplasms to leukemic transformation remain largely unknown. We have developed genetic mouse models that recapitulate leukemia progression in humans. We aim to discover new regulators and pathways controlling the propagation of leukemia stem cells as targetable vulnerabilities. Our study promises to provide critical insights into developing new and generalizable therapies to selectively eliminate leukemia stem cells.

Program: Career Development Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2024
Roberta Zappasodi

Roberta Zappasodi, PhD

Weill Cornell Medicine

New York, New York
United States

Restoring lymphoma immunosurveillance by combined EZH2 inhibition and immunotherapy

The project builds on evidence that mutations leading to persistent EZH2 activation drive germinal center B-cell lymphomagenesis by disrupting T-cell surveillance, and will test the hypothesis that EZH2 inhibition synergizes with immune checkpoint blockade and/or co-stimulation to eradicate these diseases. These results will provide the rationale for clinical development of precision-medicine immune-epigenetic combination therapies for lymphomas where these mechanisms are specifically altered.

Program: Translational Research Program
Project Term: Start Date: October 1, 2021 End Date: June 30, 2024
Amer Zeidan

Amer Zeidan, MBBS

Yale University

New Haven, Connecticut
United States

The use of immune checkpoint inhibitors to improve outcomes of patients with myeloid malignancies

We are testing whether the immune checkpoint inhibitor pembrolizumab can improve outcomes of patients. In MDS, we showed that entinostat reduces the number and activity of immune suppressive cells, thereby making the cancer susceptible to the killing effect of pembrolizumab. We are now testing this combination in a clinical trial. In CML, many patients cannot completely clear the disease despite tyrosine kinase inhibitor (TKI) therapy due to inability of their immune system to eradicate all CML cells. We therefore designed a clinical trial to augment the TKI impact on CML cells by adding pembrolizumab.

Program: Career Development Program
Project Term: Start Date: July 1, 2018 End Date: June 30, 2023
Carl Allen

Carl Allen, PhD, MD

Baylor College of Medicine

Houston, Texas
United States

Testing targeted therapy in LCH

We propose to the hypothesis that patients with LCH who fail initial chemotherapy will respond to a targeted strategy of blocking MAPK signaling through MEK inhibition.  This trial is a Phase 2 study to evaluate the safety and efficacy of cobimetinib in patients with refractory LCH.  Exploratory aims will evaluate response of lesions with specific mutations, ability of peripheral blood mononuclear cells to determine disease burden, and development of somatic mutations in patients who relapse.

Program: Translational Research Program
Project Term: Start Date: October 1, 2021 End Date: September 30, 2023
Alec Zhang

Alec Zhang, PhD

The University of Texas Southwestern Medical Center

Dallas, Texas
United States

Development of LILRB1-based immunotherapy for multiple myeloma treatment

LILRB1 is a human immune inhibitory receptor expressed on a variety of immune cells. Based on preliminary data, we hypothesize that blocking LILRB1 signaling in immune effector cells of myeloma patients will lead to increased anti-cancer activities of immune cells. We will identify subsets of myeloma patients with higher LILRB1 expression on immune cells, and determine whether anti-LILRB1 antagonizing antibodies can improve the function of immune cells for multiple myeloma treatment.

Program: Translational Research Program
Project Term: Start Date: July 1, 2021 End Date: June 30, 2024
Arash Alizadeh

Arash Alizadeh, PhD, MD

Board of Trustees of the Leland Stanford Junior University

Palo Alto, California
United States

Refining Molecular Risk Prediction & Individualized Lymphoma Therapy Using Circulating Tumor DNA

My group studies variation in clinical outcomes of patients with aggressive lymphomas and tries to capture the underlying basis for this variation. We then integrate insights from our studies into molecular prediction tools that inform the probable outcomes of individual patients when treated with therapeutic regimens that are currently available. We hope to build precise risk models that have high predictive value for clinical outcomes of patients with lymphoma. Our goal is to use these models to inform therapeutic trials of novel strategies to improve the outcomes of blood cancer patients.

Program: Career Development Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2024
Baochun Zhang

Baochun Zhang, PhD, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

A multiantigen-targeting cytotoxic CD4+ T cell approach for treating B cell malignancies

B cell malignancies comprise a large number of different types of lymphomas and leukemia, which collectively represent the sixth leading cause of cancer death in the US. These cancer cells are potential targets of the host immune system’s CD4+ T cells, however, the latter normally lack the ability to kill such cancer cells. In this project, we develop a novel approach to rapidly produce CD4+ T cells capable of killing B cell cancers, and advance this approach towards clinical trials.

Program: Translational Research Program
Project Term: Start Date: July 1, 2019 End Date: June 30, 2022
Omar Abdel-Wahab

Omar Abdel-Wahab, MD

Memorial Sloan Kettering Cancer Center

New York, New York
United States

Developing novel therapeutic approaches for classical and variant hairy cell leukemia

In this proposal, we have combined clinical and research expertise in HCL across Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, the University of Pennsylvania, and Yale University to develop newer targeted therapeutics for every stage and subtype of hairy cell leukemia. Capitalizing on this combined expertise, our proposal stands to significantly advance treatment strategies for hairy cell leukemia through the following aims: to test BRAF inhibition for initial treatment of classical hairy cell leukemia, test new oral inhibitors of the MAP kinase signaling pathway known as ERK inhibitors in both classical and variant hairy cell leukemia, evaluate totally new treatments that degrade BRAF, and develop T-cell immunotherapies for the first time in hairy cell leukemia.

Program: HCL2025
Project Term: Start Date: October 1, 2021 End Date: September 30, 2025