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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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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: July 1, 2022 - 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: July 1, 2022 - 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: June 30, 2022 - 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: July 1, 2022 - June 30, 2025
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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - June 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - June 30, 2025
Dr. Lentzsch

Suzanne Lentzsch, MD

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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - June 30, 2025
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: October 1, 2021 - September 30, 2024
Catherine Bollard

Catherine Bollard, MD

Children's Research Institute

Washington, District of Columbia
United States

Novel Combination Immunotherapies for High Risk Hodgkin's Lymphoma

Hodgkin’s Lymphoma (HL) is unique that the tumor cells are surrounded by an inhibitory environment that is able to evade effective anti-tumor responses. Understanding this environment may be a window into effective combination immunotherapies. The goal of this project is to determine if current immunotherapies can change this tumor environment sufficiently to unleash pre-existing anti-tumor T-cell immune responses to allow a more successful incorporation of HL specific cytotoxic T cells.

Program: Translational Research Program
Project Term: October 12, 2017 - September 30, 2021
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: November 1, 2021 - October 31, 2024
Stephen Nutt

Stephen Nutt , PhD

Walter & Eliza Hall Institute of Medical Research

Parkville, Victoria
Australia

Therapeutic targeting of IRF4 to treat multiple myeloma

Multiple myeloma is an incurable malignancy derived from transformed plasma cells. The transcription factor IRF4 is essential for the survival of myeloma and thus represents an excellent potential drug target. We have devised a strategy to identify the key amino acid residues, binding surfaces and protein partners of IRF4 and now aim to screen for small molecule inhibitors of this factor. Lead molecules will be developed that either directly inhibit IRF4 function or promote its degradation.

Program: Translational Research Program
Project Term: July 1, 2019 - June 30, 2022
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: July 1, 2019 - June 30, 2022
Ivan Maillard

Ivan Maillard, PhD, MD

The Trustees of the University of Pennsylvania, Medical Center

Philadelphia, Pennsylvania
United States

Preclinical Notch inhibition to prevent graft-versus-host disease in mice and non-human primates

We have identified peri-transplant blockade of individual Notch ligands as a new therapeutic strategy to prevent graft-versus-host disease (GVHD) in mice. In a non-human primate model, a single dose of an antibody targeting the Notch ligand DLL4 markedly increased GVHD-free survival as a single agent. Building on the highly conserved role of Notch signaling in GVHD, we propose to identify and characterize the most promising combination therapeutic strategies for clinical translation to patients.

Program: Translational Research Program
Project Term: July 1, 2019 - June 30, 2022
Ravindra Majeti

Ravindra Majeti, PhD, MD

Board of Trustees of the Leland Stanford Junior University

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: October 1, 2020 - September 30, 2023
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: July 1, 2019 - June 30, 2022
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: July 1, 2019 - June 30, 2022
Gareth Morgan

Gareth Morgan, PhD, MD, FRCPath, FRCP

New York University School of Medicine

New York, New York
United States

Structural chromosomal rearrangements and the multi-step progression of multiple myeloma

Two newly identified structural DNA changes, termed chromothripsis and chromoplexy, result in the formation of new chromosomal structures where multiple genes can be deregulated simultaneously. These events involve the relocation of super-enhancers to the sites of oncogenes, which provides a strong drive for cancer progression, an association with high-risk status, adverse prognosis, and punctuated evolution.

Program: Translational Research Program
Project Term: July 1, 2019 - June 30, 2022
Charles Mullighan

Charles Mullighan, MD

St. Jude Children's Research Hospital

Memphis, Tennessee
United States

Improving therapy for CRLF2-rearranged Ph-like acute lymphoblastic leukemia

CRLF2-rearranged ALL is the most common subset of Ph-like ALL, has a very poor prognosis and lacks effective therapy. This project will use two novel approaches to improve treatment. The first is developing proteolysis-targeting chimeras to degrade JAK2 and inhibit constitutive JAK-STAT signaling. In the second approach, we will use CRISPR/Cas9 activating and inhibitory genomic screens to identify cellular dependencies, vulnerabilities and synthetic lethal opportunities for therapy.

Program: Translational Research Program
Project Term: July 1, 2019 - June 30, 2022
Ryotaro Nakamura

Ryotaro Nakamura, MD

Beckman Research Institute of the City of Hope

Duarte, California
United States

CMV-CD19 bi-specific CAR T cells with CMV vaccine as post-transplantation immunotherapy for ALL

We propose to develop an innovative adaptive cellular immunotherapy (ACIT) utilizing Chimeric Antigen Receptor (CAR)-engineered T cells, which respond to both CD19+ cells and cytomegalovirus (CMV) antigen, namely CMV-CD19 bi-specific T cells, followed by CMV vaccine to further expand the T cells in vivo. We aim to address the unmet need to improve high relapse rate in patients with ALL undergoing hematopoietic cell transplantation (HCT) from a matched or mismatched unrelated/related donors.

Program: Translational Research Program
Project Term: July 1, 2019 - June 30, 2022
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: July 1, 2019 - June 30, 2022
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: July 1, 2019 - June 30, 2022
Justin Kline

Justin Kline, MD

The University of Chicago

Chicago, Illinois
United States

Molecular regulation of PD-L1 expression and anti-tumor immunity in diffuse large B cell lymphoma

Copy gains of the chromosomal region (9p24.1) containing the PD-1 ligands, PD-L1 and PD-L2, are a recurring genomic alteration in DLBCL, and we have found that the presence of PD-L1 gene alterations are a genetic biomarker of DLBCLs that harbor a T cell-inflamed phenotype.

Program: Translational Research Program
Project Term: July 1, 2019 - June 30, 2022
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: October 1, 2021 - September 30, 2024
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: October 1, 2021 - September 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: July 1, 2021 - 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: October 1, 2021 - September 30, 2024
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: September 1, 2021 - August 31, 2024
John Pimanda

John Pimanda, PhD

The University of New South Wales (UNSW)

, New South Wales
Australia

Optimising azacitidine responsiveness in myelodysplasia and acute myeloid leukaemia

Our research aim is to improve outcomes for high-risk myelodysplastic syndrome and associated acute myeloid leukaemia patients who are refractory to azacitidine or its derivative decitabine, the most effective pharmacotherapeutics for these blood cancers. To this end, we will identify and evaluate therapeutic alternatives for this population of patients by leveraging discoveries and using clinical samples collected from an on-going investigator initiated clinical trial.

Program: Translational Research Program
Project Term: January 1, 2021 - December 31, 2023
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: July 1, 2018 - June 30, 2021
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: July 1, 2019 - June 30, 2022
Rizwan Romee

Rizwan Romee, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

CIML NK cell immunotherapy for relapse after haploidentical hematopoietic cell transplantation

Relapse remains major risk after hematopoietic cell transplantation, with limited effective treatment options and extremely poor prognosis. We described human cytokine induced memory-like (CIML) NK cells with enhanced anti-leukemia activity. CIML NK cells were safe and with promising clinical activity in our phase 1 clinical trial. Here we propose to test the safety and potential efficacy of CIML NK cells in patients with myeloid malignancies relapsed after haploidentical donor transplantation.

Program: Translational Research Program
Project Term: July 1, 2019 - June 30, 2022
Davide Rossi

Davide Rossi, PhD, MD

Foundation for the Institute of Oncology Research (IOR)


Switzerland

Treatment tailoring by optimized early residual disease assessment in classic Hodgkin lymphoma

Incorporation of circulating tumor DNA (ctDNA) monitoring into clinical trials of classic Hodgkin lymphoma (cHL), which is the primary objective of this proposal, will allow to: i) precisely define ctDNA accuracy in anticipating disease course; and ii) test if ctDNA results can be used to guide treatment decisions. The project results can translate ctDNA monitoring as a routine response assessment tool for cHL.

Program: Translational Research Program
Project Term: July 1, 2019 - June 30, 2022
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: July 1, 2019 - 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: July 1, 2019 - June 30, 2022
Dr. Shanmugam

Mala Shanmugam, PhD

Emory University

Atlanta, Georgia
United States

Deciphering the metabolic basis for t(11;14) multiple myeloma venetoclax sensitivity

The BCL-2 antagonist venetoclax is highly cytotoxic in a subset of t(11;14) multiple myeloma (MM). In investigating the metabolic basis for the sensitivity of t(11;14) MM to venetoclax, we determined that sensitive cells exhibit significantly reduced succinate ubiquinone reductase (SQR) activity. In addition, inhibition of SQR sensitizes resistant MM to venetoclax. Our proposal seeks to investigate SQR as a diagnostic and therapeutic target to broaden the application of this potent BH3 mimetic.

Program: Translational Research Program
Project Term: July 1, 2018 - June 30, 2021
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: July 1, 2019 - June 30, 2022
Jolanta Grembecka

Jolanta Grembecka, PhD

Regents of the University of Michigan

Ann Arbor, Michigan
United States

ASH1L degradation as a new treatment for acute leukemia

This project is focused to develop small molecule degraders of ASH1L histone methyltransferase as a treatment for aggressive sub-types of AML and ALL with high expression of HOXA genes by utilizing the PROTAC (proteolysis targeting chimera) approach. Optimization of ASH1L degraders and their comprehensive evaluation in in vitro and in vivo leukemia models are proposed. We expect these studies will lead to new therapeutics for aggressive acute leukemias with high HOXA expression.

Program: Translational Research Program
Project Term: July 1, 2019 - June 30, 2022
Terry Fry

Terry Fry, MD

University of Colorado-Denver

Aurora, Colorado
United States

Rational development of multi-targeted CAR-T cell constructs in pediatric acute myeloid leukemia

We propose to rationally select targets for and design multi-antigen CAR constructs for pediatric acute myeloid leukemias with the intent of generating durable responses and reducing off-tumor toxicity. This will be achieved using two complimentary approaches 1) the identification of markers expressed on pediatric AML stem cells (LSC); and, 2) phenotypic interrogation of AML evolution under single antigen CAR targeting in both preclinical models and in patients treated with a CD33 CAR trial.

Program: Translational Research Program
Project Term: July 1, 2019 - June 30, 2022
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: July 1, 2019 - June 30, 2022
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: July 1, 2021 - 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: October 1, 2021 - September 30, 2024
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: April 1, 2021 - March 31, 2023
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: October 1, 2021 - September 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: October 1, 2021 - 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: October 1, 2021 - September 30, 2024
Dan Vogl

Dan Vogl, MD

The Trustees of the University of Pennsylvania, Medical Center

Philadelphia, Pennsylvania
United States

Targeting the myeloma bone marrow microenvironment through S100A9 inhibition with tasquinimod

We propose laboratory and clinical studies to understand the mechanisms of anti-myeloma activity of tasquinimod, a small molecule inhibitor of S100A9. This proposal is part of an ongoing collaboration between Dr. Yulia Nefedova, whose laboratory studies the myeloma bone marrow microenvironment and its immunosuppressive effects, and Dr. Dan Vogl, whose clinical and translational research program focuses on novel therapies for relapsed and refractory myeloma.

Program: Translational Research Program
Project Term: July 1, 2019 - June 30, 2022
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: July 1, 2019 - June 30, 2022
Margaret Shipp

Margaret Shipp, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Matching genetic signatures and targeted combination therapy in high-risk DLBCL

Current strategies for the treatment of DLBCL do not reflect the genomic complexity of the disease. We propose to change the DLBCL treatment paradigm by linking newly defined comprehensive genetic signatures of discrete DLBCL subsets with matched targeted combination therapies. The most promising combination therapies will be evaluated in patients with relapsed DLBCL and the appropriate genetic signatures.

Program: Translational Research Program
Project Term: July 1, 2019 - June 30, 2022
Patrick Brown

Patrick Brown, MD

The Johns Hopkins University School of Medicine

Baltimore, Maryland
United States

The immunobiology of blinatumomab response and resistance in relapsed pediatric B-ALL

Responses to blinatumomab in B-ALL are binary, with some patients having a striking response and deep remission, while others show no response at all, despite the presence of CD19 expression on leukemic cells and adequate numbers of CD3+ T-cells. This project will identify biomarkers to predict which patients will respond to blinatumomab. We have an agreement to use blinatumomab for research and a cohort of pediatric samples from the ongoing Children’s Oncology Group study for relapsed B-ALL.

Program: Translational Research Program
Project Term: July 1, 2019 - June 30, 2022
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: July 1, 2021 - 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: July 1, 2018 - June 30, 2021
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: July 1, 2021 - June 30, 2024
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: July 1, 2019 - 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: July 1, 2019 - 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: October 1, 2021 - September 30, 2024
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: July 1, 2021 - 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: October 1, 2021 - September 30, 2024
Loren Walensky

Loren Walensky, PhD, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Precision targeting of BFL-1 and MCL-1 in pediatric leukemias to overcome treatment resistance

Pediatric leukemia cells hijack the BCL-2 family signaling network to overexpress a range of anti-apoptotic proteins, including BFL-1 and MCL-1, and thereby enforce cellular immortality and cause treatment resistance. Here, we will harness novel and unique stapled peptides with the capacity to selectively target BFL-1, MCL-1, and importantly, both targets simultaneously, in order to reactivate the cell death pathway in MCL-1 and BFL-1 dependent pediatric leukemias.

Program: Translational Research Program
Project Term: July 1, 2019 - June 30, 2022
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: July 1, 2019 - 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: July 1, 2019 - June 30, 2022
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: October 1, 2021 - 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: July 1, 2018 - June 30, 2022
Scott Armstrong

Scott Armstrong, PhD, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Selective BRD4 degradation in pediatric leukemia

There exists compelling rationale for targeting BRD4 therapeutically in acute leukemia yet currently available inhibitors lack selectivity and demonstrate toxicity. We have developed a selective degrader molecule that can specifically bind and degrade BRD4. Here we propose to chemically optimize our BRD4-degrader and evaluate its mechanisms and anti-cancer effects in models of leukemia to determine if it is a novel therapeutic for the treatment of pediatric acute leukemia.

Program: Translational Research Program
Project Term: July 1, 2019 - June 30, 2022
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: October 1, 2021 - June 30, 2024
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: October 1, 2021 - 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: July 1, 2021 - June 30, 2024
Iannis Aifantis

Iannis Aifantis, PhD

New York University School of Medicine

New York, New York
United States

Targeting the stress response machinery in pediatric T cell acute lymphoblastic leukemia (T-ALL)

Current intensive chemotherapy regimens to T cell acute lymphoblastic leukemia (T-ALL) patients come at the cost of serious side effects while a significant percentage of patients experience relapse. We have recently demonstrated that T-ALL is addicted to the function of a stress response pathway activated in the presence of proteotoxic stress. Here, we present a novel approach to exploit the altered dependency of T-ALL on stress responses and target leukemia-specific vulnerabilities.

Program: Translational Research Program
Project Term: July 1, 2019 - June 30, 2022
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: July 1, 2019 - June 30, 2022