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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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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: October 1, 2022 - 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: October 1, 2022 - 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: July 1, 2022 - 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: October 1, 2022 - 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: October 1, 2022 - 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: October 1, 2022 - September 30, 2025
Dr. Godley

Lucy Godley, MD PhD

University of Chicago

Chicago, 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: October 1, 2022 - 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: October 1, 2022 - 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: October 1, 2022 - September 30, 2025
Dr. Smith

Clayton Smith, MD

University of Colorado Denver, Anschutz Medical Campus

Denver, Colorado
United States

Increasing access to blood cancer care in Colorado and surrounding regions

The University of Colorado (CU) Division of Hematology/UCHealth Blood Disorders Center (BDCTC) is the only academic program serving patients with hematologic malignancies in the Rocky Mountain Region. This program sees ~1000 new patients annually and operates a dedicated Hematology Clinical Trials Unit (HCTU) that provides clinical trials to persons throughout the Rocky Mountain Region and beyond. Despite opening many clinical trials, it is clear that underserved populations (economically disadvantaged, rural, and/or underrepresented minorities) have low levels of trial enrollment. It is also clear that more proactive efforts are needed in order to more effectively deliver the therapeutic benefits of clinical trials to underserved populations. In order to accomplish this goal, we propose to work with regional community oncology centers on three complementary efforts to increase enrollment of underserved populations throughout the Colorado front range major population centers (metro Denver, Fort Collins, Colorado Springs) as well as rural Colorado and the Rocky Mountain region.

Program: IMPACT
Project Term: October 1, 2022 - September 30, 2027
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: October 1, 2022 - 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: October 1, 2022 - September 30, 2025
Dr. Jones

Courtney Jones, PhD

Princess Margaret Cancer Centre, University Health Network

Toronto
Canada

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: October 1, 2022 - 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: October 1, 2022 - 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: June 1, 2022 - 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: June 1, 2022 - 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: June 1, 2022 - 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: 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. 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: July 1, 2022 - December 9, 2022
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
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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - 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: July 1, 2022 - June 30, 2025
Dr. Morelli

Eugenio Morelli, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

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

Homa Rahnamoun, PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Examining the functional crosstalk between MLL-fusion and MOZ in acute myeloid leukemia

Small molecule inhibitors that target the Menin-MLL-fusion interaction have emerged as therapeutic opportunities for MLL1-r leukemias and are currently in clinical trials. We are now focused on identifying other factors that modulate sensitivity and resistance to Menin inhibition using complementary genomic and biochemical assays. Our goal is to find other druggable dependencies that can further sensitize leukemic cells to this epigenetic therapy and devise more effective treatment strategies.

Program: Career Development Program
Project Term: July 1, 2022 - 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: 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. 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: July 1, 2022 - 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: October 1, 2022 - 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: 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. 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: June 1, 2022 - December 9, 2022
Dr. Buhrlage

Sara Buhrlage, PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

JOSD1 as a novel targeted therapy for JAK20V617F dependent myeloproliferative neoplasms

Mutations in JAK2 are the most prevalent genetic event in myeloproliferative neoplasms (MPNs). Drugs that inhibit mutated JAK2 provide clinical benefit, however their impairment of non-mutated JAK2, which normal cells require, limits their clinical usefulness. We propose a strategy to target mutated JAK2 for degradation, using the cell's intracellular machinery to do so, while sparing non-mutated JAK2.

Program: Special Grants
Project Term: March 2, 2022 - March 1, 2023
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: Special Grants
Project Term: March 1, 2022 - February 29, 2024
Faron logo

Faron Pharmaceuticals, LTD

TAP Partner

Turku
Finland

A phase 1/2 study of Bexmarilimab, an anti-Clever1 monoclonal antibody, in combination with azacitidine or azacitidine/venetoclax in patients with AML, MDS or CMML

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

Faron (AIM: FARN, First North: 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 1 study in AML (BEXMAB) has been cleared by the FDA and Finnish Medicines Agency is currently enrolling patients.

Program: Therapy Acceleration Program
Project Term: June 30, 2022 - December 9, 2022
ImCheck

ImCheck Therapeutics, INC

TAP Partner

Marseille
France

A phase 1 study of ICT01, an anti-BTN3A monoclonal antibody, 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.

As demonstrated by lead clinical-stage program ICT01, which has a mechanism of action to simultaneously modulate innate and adaptive immunity, ImCheck's “first-in-class” activating antibodies may be able to produce superior clinical results as compared to the first-generation of immune checkpoint inhibitors and, when used in combination, to overcome resistance to this group of agents.

Program: Therapy Acceleration Program
Project Term: June 13, 2022 - December 9, 2022
Dr. Ritchie

David Ritchie, PhD

University of Melbourne

Melbourne
Australia

Merging immune and molecular signals in HCL for improved prognosis and treatment decision making

Our research consortium of diagnostic, translational and clinical researchers will undertake an integrated and novel exploration of the immune and genomic landscape in hairy cell leukemia (HCL) and correlate those data with response to both conventional and newly emerging therapies. We will apply our innovative platforms of digital spatial profiling, whole genome sequencing and circulating tumor DNA to provide highly novel data from our already collected sample bank from over 60 patients with HCL.

 

Program: HCL2025
Project Term: October 1, 2021 - September 30, 2023
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: April 1, 2022 - 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: April 1, 2022 - 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: October 1, 2021 - 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: October 1, 2021 - 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: October 1, 2021 - September 30, 2026
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
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: October 1, 2021 - 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: October 1, 2021 - 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 Key Studies with STAT3 Protein Degraders for Future Development in Hematological Patients." Kymera received this strategic investment from LLS TAP to advance work in an emerging approach to cancer therapy, called “targeted protein degradation.” 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. Kymera received FDA clearance to begin the clinical study and patient enrollment is ongoing.

Program: Therapy Acceleration Program
Project Term: March 11, 2020 - December 9, 2022
Biotheryx

BioTheryX, INC

TAP Partner

San Diego, California
United States

A phase 1 study of BTX-1188, a dual target protein degrader, in patients with AML or NHL

In November 2010, LLS made an equity investment in BioTheryX originally to support the development of a promising LLS-funded project with Toronto-based University Health Network and is currently supporting "An Open Label, Escalating Multiple Dose Study to Evaluate the Safety, Toxicity, Pharmacokinetics, and Preliminary Activity of BTX-1188 in Subjects With Advanced Malignancies." BioTheryX has a technology platform in the field of targeted protein degradation. This technology utilizes the body's own protein disposal system to selectively degrade and remove disease-causing proteins. It has potential applicability to a very broad range of disease targets, including a wide range of targets that have to date been considered "undruggable." BXT-1188 is an oral, dual target protein degrader specifically engineered to degrade GSPT1 and IKZF1/3. A clinical study of BTX-1188 in patients with relapsed or refractory AML or NHL is currently enrolling.

Program: Therapy Acceleration Program
Project Term: November 16, 2010 - December 9, 2022
Gongwei Wu

Gongwei Wu, PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Mechanisms and targeting of TP63-rearrangements in lymphoma

Chromosomal rearrangements involving a gene called TP63 have been found in 5-10% of several subtypes of lymphomas and patients with TP63-rearrangements have dismal outcomes, with nearly 0% of patients surviving 5 years after diagnosis. We investigate the oncogenic mechanisms of TP63-rearrangements to find the unique cancer cell vulnerabilities to this rearrangement using different models. Our study will develop an effective therapeutic strategy for patients with TP63-rearranged lymphomas.

Program: Career Development Program
Project Term: July 1, 2019 - June 30, 2022
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: October 1, 2021 - 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: July 1, 2018 - June 30, 2023
Caribou

Caribou Biosciences, INC

TAP Partner

Berkeley, California
United States

Supporting allogeneic CD371 (CLL-1) CAR development for 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." LLS is supporting the preclinical development of CB-012, Caribou’s third allogeneic CAR-T cell therapy, an allogeneic anti-CD371 CAR-T cell therapy for the treatment of relapsed or refractory acute myeloid leukemia (AML). CD371 is expressed on the surface of AML tumor cells and leukemic stem cells, but it is not expressed on normal hematopoietic stem cells, which makes it a compelling target for the treatment of AML. Caribou is applying their genome editing expertise to armor the CB-012 CAR-T product in order to drive persistence and seek maximum patient benefit.

 

Program: Therapy Acceleration Program
Project Term: February 28, 2021 - December 9, 2022
Caribou

Caribou Biosciences, INC

TAP Partner

Berkeley, California
United States

Supporting allogeneic BCMA CAR development for multiple myeloma

In February 2021, LLS made an equity investment in Caribou Biosciences to "Support allogeneic BCMA CAR development for multiple myeloma." LLS is supporting the preclinical development of CB-011, Caribou’s second allogeneic CAR-T cell therapy, an allogeneic anti-BCMA CAR-T cell therapy for the treatment of relapsed or refractory multiple myeloma (MM). It is the first allogeneic CAR-T cell therapy immune-cloaked to prevent both T- and NK-mediated immune rejection. Caribou's immune cloaking strategy is expected to drive CAR-T cell persistence, enabling more durable antitumor activity.

Program: Therapy Acceleration Program
Project Term: February 28, 2021 - December 9, 2022
NexImmune

NexImmune, INC

TAP Partner

Gaithersburg, Maryland
United States

A phase 1/2 study of adoptively transferred autologous T cells in patients with multiple myeloma

In October 2017, NexImmune benefitted from an initial TAP investment and now in 2021 received a second investment as part of the company’s initial public offering to support "A Phase 1 / 2 Study to Evaluate the Safety, Tolerability and Initial Anti-Tumor Activity of Adoptively Transferred Autologous T Cells in Patients With Relapsed Refractory Multiple Myeloma." The antigen-specific T-cell immunotherapy from NexImmune is designed to target multiple tumor antigens associated with MM (NEXI-002). The initial goal of these early clinical trials is to demonstrate safety, T-cell persistence, and determine preliminary patient benefit.

Program: Therapy Acceleration Program
Project Term: October 6, 2017 - December 9, 2022
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
E. Anders Kolb

E. Anders Kolb, MD

Nemours Alfred I. duPont Hospital for Children

Wilmington, Delaware
United States

E. Anders Kolb 2022 PedAL grant

Coming soon.

Program: Dare to Dream
Project Term: September 1, 2021 - August 31, 2024
Andreas Strasser

Andreas Strasser, PhD, MSc, FAA

Walter & Eliza Hall Institute of Medical Research

Melbourne, Victoria
Australia

Directly targeting the Cell Death Machinery to Treat Hematopoietic Malignancies

These multidisciplinary, collaborative grants bring together teams of researchers to solve difficult challenges in the blood cancers. We are working to understand why and how it is that if cells in the body don’t die when they should, cancer is able to develop,” This SCOR paves the way for therapies that harness the body's own cell death machinery, called apoptosis, the normal process that causes impaired cells to self-destruct. When the process goes awry, cancer cells do not die as readily. The team was instrumental in the discovery of the first approved apoptosis-targeted agent called venetoclax (Venclexta) for use in chronic lymphocytic leukemia and, more recently, for elderly patients with acute myeloid leukemia (AML). The team is now testing multiple new approaches to boost apoptosis in other leukemias, as well as lymphoma and myeloma.

Program: Specialized Center of Research Program
Project Term: October 1, 2017 - September 30, 2022
David Weinstock

David Weinstock, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
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 acting 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: October 1, 2021 - September 30, 2026
Forty Seven

Forty Seven, INC

TAP Partner

Menlo Park, California
United States

A phase 1b/2 study of magrolimab, an anti-CD47 monoclonal antibody, in combination with rituximab in patients with B-cell NHL

In March 2017, LLS began its partnership with Forty Seven to support "A Phase 1b/2 Trial of Hu5F9-G4 in Combination With Rituximab or Rituximab + Chemotherapy in Patients With Relapsed/Refractory B-cell Non-Hodgkin's Lymphoma." LLS funded Stanford University researchers and founders of Forty Seven, Irv Weissman, MD, and Ravi Majeti, MD, PhD, to study seminal work in macrophages. This is a type of immune cell that patrols the body and chews up damaged cells. If a macrophage latches onto a normal cell, a protein known as CD47 sends a “don’t eat me” signal. But lymphoma and leukemia cells are clever and use CD47 to trick the macrophages into ignoring them and letting them grow as cancer. In preclinical mice models, Drs. Weissman and Majeti used an antibody to block the “don’t eat me” signal and stimulate the immune system to recognize the cancer cells as invaders. When they added rituximab as an “eat me” signal, the therapy delivered a one-two punch.

Gilead Sciences acquired Forty Seven in April 2020 and continues to develop magrolimab in multiple clinical studies in patients with myelodysplastic syndrome, acute myeloid leukemia, non-Hodgkin lymphoma, and solid tumors.

Program: Therapy Acceleration Program
Project Term: March 1, 2017 - April 7, 2020
Kura

Kura Oncology, INC

TAP Partner

San Diego, California
United States

A phase 1/2 study of KO-539, a menin-MLL(KMT2A) inhibitor, in patients with 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. KO-539 is a potent and selective menin inhibitor that is currently in a Phase 1/2 clinical trial (KOMET-001) and targeting patients with relapsed/refractory acute myeloid leukemia, including patients with NPM1 mutations or KMT2A rearrangements.

Program: Therapy Acceleration Program
Project Term: December 22, 2014 - December 9, 2022
Immune-Onc

Immune-Onc Therapeutics, INC

TAP Partner

Palo Alto, California
United States

A phase 1 study of IO-202, an antibody targeting LILRB4, 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." 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. The lead candidate, called IO-202, a first-in-class antibody targeting the Leukocyte Immunoglobulin-Like Receptor subfamily B (LILRB) member 4 (LILRB4), has entered a phase 1 clinical trial for the treatment of advanced acute myeloid leukemia and chronic myelomonocytic leukemia.

Program: Therapy Acceleration Program
Project Term: March 5, 2021 - December 9, 2022
Biotheryx

BioTheryX, INC

TAP Partner

San Diego, California
United States

A phase 1 study of BTX-A51, a multi-kinase inhibitor, in patients with AML or high-risk MDS

In November 2010, LLS made an equity investment in BioTheryX originally to support the development of a promising LLS-funded project with Toronto-based University Health Network and is currently supporting "A First-In-Human, Open-Label, Escalating Multiple-Dose Study to Evaluate the Safety, Toxicity, and Pharmacokinetics of BTX-A51 Capsules in Patients With Relapsed or Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome." BTX-A51 appears to block a specific leukemic stem cell target (CK1-alpha) as well as super enhancer targets (CDK7/CDK9) preventing transcription of key oncogenic genes. BTX-A51 has demonstrated preclinical animal efficacy implying the eradication of AML stem cells and the potential for use in multiple malignancies. A clinical study of BTX-A51 in patients with relapsed or refractory AML or high-risk MDS is currently enrolling.

Program: Therapy Acceleration Program
Project Term: November 16, 2010 - December 9, 2022
Ryvu

Ryvu Therapeutics, SA

TAP Partner

Krakow
Poland

A phase 1b study of RVU120, a novel CDK8 inhibitor, in patients with AML or 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." SEL120 (RVU120) is a highly selective first-in-class CDK8/CDK19 inhibitor that was discovered with the Ryvu Therapeutics discovery engine platform. CDK8 plays a unique and critical role in gene regulation and is implicated in the development of numerous hematological malignancies and solid tumors. In preclinical studies, SEL120 has shown strong proof of concept for the treatment of AML, a disease with a poor prognosis. Ryvu is conducting an open-label, dose-escalation study at multiple sites in the United States to evaluate the safety, tolerability and preliminary activity of SEL120 and to establish a recommended dose for further clinical development.

Program: Therapy Acceleration Program
Project Term: August 7, 2017 - December 31, 2023
X4 Pharmaceuticals

X4 Pharmaceuticals, INC

TAP Partner

Boston, Massachusetts
United States

A phase 1b study of mavorixafor, an oral CXCR4 antagonist, in combination with ibrutinib in patients with waldenstrom's macroglobulinemia expressing mutations in MYD88 and CXCR4

In April 2019, LLS entered into a partnership with X4 Pharmaceuticals to support "A Phase 1b Trial of Mavorixafor, an Oral CXCR4 Antagonist, in Combination With Ibrutinib in Patients With Waldenstrom's Macroglobulinemia (WM) Whose Tumors Express Mutations in MYD88 and CXCR4." The company’s lead candidate, mavorixafor, is a first-in-class, small molecule antagonist of chemokine receptor CXCR4 being developed as a once-daily oral therapy. The efficacy and safety of mavorixafor, dosed once daily, is currently being evaluated in a global Phase 3 clinical trial in patients with WHIM syndrome, and in two Phase 1b clinical trials – in combination with ibrutinib in patients with Waldenström’s macroglobulinemia, and as monotherapy in patients with severe congenital neutropenia.

Program: Therapy Acceleration Program
Project Term: April 12, 2019 - December 9, 2022
Verastem

Verastem Oncology, INC

TAP Partner

Needham, Massachusetts
United States

A phase 2 study of duvelisib, a dual PI3K(delta/gamma) inhibitor, in patients with PTCL

In October 2018, LLS began a partnership with Verastem to support two clinical trials, "A Multi-Center, Phase 2, Open-label, Parallel Cohort Study of Efficacy and Safety of Duvelisib in Patients With Relapsed or Refractory Peripheral T Cell Lymphoma (PTCL)" and "A Phase I Trial of Duvelisib in Combination With Either Romidepsin or Bortezomib in Relapsed/Refractory T-cell Lymphomas." Verastem sold its global commercial and development rights to COPIKTRA (duvelisib) to Secura Bio in September 2020. Secura Bio continues to develop duvelisib in PTCL as enrollment was recently completed in the Phase 2 PRIMO clinical trial evaluating the efficacy and safety of duvelisib in adult patients with histologically confirmed relapsed or refractory PTCL.

In December 2020, Copiktra (duvelisib) was included in the National Comprehensive Cancer Network® T-Cell Lymphoma Guidelines® for the treatment of all subtypes of PTCL. Clinical data that supported the NCCN Guidelines inclusion was presented during the 2021 ASH meeting.

Program: Therapy Acceleration Program
Project Term: October 29, 2018 - September 30, 2020
Kymera

Kymera Therapeutics, INC

TAP Partner

Watertown, Massachusetts
United States

A phase 1 study of KT-413, a dual degrader of IRAK4 and IMiD substrates, in patients with DLBCL

In March 2020, LLS made an equity investment in Kymera Therapeutics to "Support Key Studies with IRAK4 Protein Degraders for Future Development in Hematological Patients." Kymera received this strategic investment from LLS TAP to advance work in an emerging approach to cancer therapy, called “targeted protein degradation.” 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. Kymera received FDA clearance to begin the clinical study and patient enrollment is ongoing.

Program: Therapy Acceleration Program
Project Term: March 11, 2020 - December 9, 2022
Constellation

Constellation Pharmaceuticals, INC

TAP Partner

Cambridge, Massachusetts
United States

A phase 3 randomized study of pelabrasib (CPI-0610), a BET inhibitor, and ruxolitinib in JAK inhibitor treatment naive MF patients

In July 2012, LLS began its partnership with Constellation to support three first-in-human Phase 1 clinical trials for blood cancer patients and is currently supporting "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 developed CPI-0610 inhibits members of the BET family of chromosome-binding proteins to selectively inactivate various cancer-promoting genes, including MYC, a master control gene that plays a role in many cancers. Inhibiting BET can kill a broad range of blood cancers. Pelabresib (CPI-0610) is currently in a registration-enabling clinical trial for the treatment of myelofibrosis.

MorphoSys acquired Constellation in July 2021 and continues to develop pelabresib in multiple clinical studies in patients with myeloproliferative neoplasms.

Program: Therapy Acceleration Program
Project Term: July 31, 2012 - December 9, 2022
Travera

Travera, INC

TAP Partner

Medford, Massachusetts
United States

Supporting mass accumulation rate (MAR) as a predictive biomarker in multiple myeloma

In June 2018, LLS made an equity investment in Travera to support "Mass Accumulation Rate (MAR) as a Predictive Biomarker in Multiple Myeloma." Travera has developed a universal cancer biomarker with the potential of matching cancer patients to virtually any available cancer drug or combination of drugs. Travera uses a proprietary technology that was developed at MIT to measure the weight change (called mass response) of a patients’ cancer cells (tested outside the body) in response to a variety of cancer drugs. In the future, this mass response may enable oncologists to quickly determine which drugs to prescribe based on the actual responses of their patients’ tumor cells to candidate drugs, regardless of the mechanism of action. Travera is studying the use of its biomarker test in patients with relapsed and/or refractory multiple myeloma (RRMM) and are working with prominent academic institutions to enroll study participants.

Program: Therapy Acceleration Program
Project Term: June 27, 2018 - December 9, 2022
Carisma

Carisma Therapeutics, INC

TAP Partner

Philadelphia, Pennsylvania
United States

Supporting CAR-engineered macrophage (CAR-M) development for blood cancers

In February 2021, LLS made an equity investment in Carisma Therapeutics to "Support CAR Macrophage Development for Blood Cancers." Carisma Therapeutics is a spin out company from the University of Pennsylvania (Penn), founded by Saar Gill, M.D., Ph.D. and Michael Klichinsky, PharmD, Ph.D., SVP of Research. Early work at Penn was supported in part by LLS grants. Based on preclinical studies, the company’s highly differentiated CAR-macrophage (CAR-M) platform may have the potential to overcome challenges encountered by other cell therapies such as trafficking limitations to the tumor site, immunosuppressive tumor microenvironments and the heterogeneous expression of tumor-associated antigens. Carisma is working closely with LLS TAP to develop one or more CAR-M therapies for blood cancers.

Program: Therapy Acceleration Program
Project Term: February 22, 2021 - December 9, 2022
Immunitas

Immunitas Therapeutics, INC

TAP Partner

Waltham, Massachusetts
United States

Supporting translational and clinical development of the lead IMT-009 program for lymphoma indications

In August 2021, LLS made an equity investment in Immunitas Therapeutics to provide "Support of Translational and Clinical Development of the Lead IMT-009 Program for Lymphoma Indications." IMT-009, a first-in-class NK and T cell modulator targeting CD161, is being developed for the treatment of solid tumors and hematological malignancies. Immunitas is also advancing IMT-073, a dual-target NK and T cell modulator. The company was founded by Longwood Fund with leading scientists from Dana-Farber, MGH, the Broad, and MIT.

Program: Therapy Acceleration Program
Project Term: August 10, 2021 - December 9, 2022
Affimed

Affimed, NV

TAP Partner

Heidelberg
Germany

A phase 2 study of AFM13, a bispecific cell engager targeting CD30 and CD16A, in patients with CD30-positive PTCL or transformed mycosis fungoides

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 II Open-label Multicenter Study to Assess the Efficacy and Safety of AFM13 in Patients With Relapsed or Refractory CD30-positive Peripheral T-cell Lymphoma or Transformed Mycosis Fungoides (REDIRECT)." AFM13 is bispecific tetravalent Innate Cell Engager (ICE®) targeting CD30 on tumor cells and CD16A on NK cells and macrophages. Building on the success of the two trials in HL, the company received FDA approval to enroll patients in a Phase 2 registration-directed study of AFM13 as a monotherapy in relapsed or refractory CD30-positive peripheral T-cell lymphoma. Concurrently, the study is enrolling patients with transformed mycosis fungoides, an aggressive subtype of cutaneous T-cell lymphoma. The REDIRECT clinical trial is currently enrolling patients. 

Program: Therapy Acceleration Program
Project Term: August 26, 2013 - June 30, 2020
OncoPep

OncoPep, INC

TAP Partner

North Andover, Massachusetts
United States

A phase 1b study of PVX-410, a multi-peptide cancer vaccine, and citarinostat, an HDAC inhibitor, with and without lenalidomide for patients with smoldering myeloma

In August 2014, LLS made an equity investment in OncoPep which is currently supporting "A Phase 1b Study of PVX-410, a Multi-Peptide Cancer Vaccine, and Citarinostat (CC-96241), a Histone Deacetylase Inhibitor (HDAC) With and Without Lenalidomide for Patients With Smoldering Multiple Myeloma." Smoldering multiple myeloma is the asymptomatic stage of multiple myeloma that has a high risk of progressing to full-blown multiple myeloma. PVX-410 is made of multiple peptides to target the tumor cell heterogeneity observed in all cancers, particularly MM, and decrease the likelihood of tumor cells developing resistance by targeting multiple antigens found on the surface of MM cells simultaneously. Furthermore, targeting multiple antigens increases the probability of an immune response in the target patient population. Citarinostat is an orally active, small-molecule histone deacetylase (HDAC) inhibitor which is being combined here to further augment the immune activity of the vaccine. The FDA has approved lenalidomide as a treatment option for SMM. Lenalidomide is being added to the combination of the vaccine and Citarinostat because it is hypothesized that co-administration would further enhance the T cell-mediated immune response induced by PVX-410.

Program: Therapy Acceleration Program
Project Term: August 18, 2014 - December 9, 2022
NexImmune

NexImmune, INC

TAP Partner

Gaithersburg, Maryland
United States

A phase 1/2 study of adoptively transferred T lymphocytes targeting WT1, PRAME and Cyclin A1 in AML or MDS patients with relapsed disease after matched allogeneic HCT

In October 2017, NexImmune benefitted from an initial TAP investment and now in 2021 received a second investment as part of the company’s initial public offering to support "A Phase 1 / 2 Study to Evaluate the Safety, Tolerability and Initial Anti-Tumor Activity of Adoptively Transferred T Lymphocytes in AML or MDS Patients With Relapsed Disease After Matched Allogeneic HCT." The antigen-specific T-cell immunotherapy from NexImmune is designed to target multiple tumor antigens associated with  AML (NEXI-001). Moreover, in AML patients, CAR-T therapies have yet to demonstrate significant antitumor activity and immunocheckpoint inhibitors have shown only marginal efficacy when given as a monotherapy in blood cancers outside of Hodgkin lymphoma. The initial goal of these early clinical trials is to demonstrate safety, T-cell persistence, and determine preliminary patient benefit.

Program: Therapy Acceleration Program
Project Term: October 6, 2017 - December 9, 2022
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 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 to develop an in vivo chimeric antigen receptor (CAR) T platform based on a non-replicating gammaretrovirus. 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: November 3, 2020 - December 9, 2022
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." CB-010, Caribou’s lead allogeneic CAR-T cell program, targets CD19 and is being evaluated in a Phase 1 clinical trial for patients with relapsed/refractory B cell non-Hodgkin lymphoma. It is the first clinical-stage allogeneic CAR-T cell therapy in which PD-1 was genetically disrupted in the CAR-T genome. The goal of the PD-1 knockout is to boost the persistence of CAR-T cell antitumor activity, which is believed to have the potential to reduce CB-010 exhaustion and potentially confer a better therapeutic index compared to other allogeneic CAR-T cells. CB-010 is the first allogeneic CAR-T cell therapy with a PD-1 knockout in clinical studies, and it is being evaluated in the ongoing, open-label, multicenter Phase 1 ANTLER clinical trial in the United States in adults with relapsed or refractory B cell non-Hodgkin lymphoma. 

Program: Therapy Acceleration Program
Project Term: February 28, 2021 - December 9, 2022
Forty Seven

Forty Seven, INC

TAP Partner

Menlo Park, California
United States

A phase 3 randomized study of magrolimab, an anti-CD47 monoclonal antibody, in combination with azacitidine in treatment-naïve patients with higher risk MDS

In July 2019, LLS expanded its partnership with Forty Seven by making an equity investment to support "ENHANCE: A Randomized, Double-blind, Multicenter Study Comparing Magrolimab in Combination With Azacitidine Versus Azacitidine Plus Placebo in Treatment-naïve Patients With Higher Risk Myelodysplastic Syndrome." LLS funded Stanford University researchers and founders of Forty Seven, Irv Weissman, MD, and Ravi Majeti, MD, PhD, to study seminal work in macrophages. This is a type of immune cell that patrols the body and chews up damaged cells. If a macrophage latches onto a normal cell, a protein known as CD47 sends a “don’t eat me” signal. But lymphoma and leukemia cells are clever and use CD47 to trick the macrophages into ignoring them and letting them grow as cancer. In preclinical mice models, Drs. Weissman and Majeti used an antibody to block the “don’t eat me” signal and stimulate the immune system to recognize the cancer cells as invaders. 

Gilead Sciences acquired Forty Seven in April 2020 and continues to develop magrolimab in multiple clinical studies in patients with myelodysplastic syndrome, acute myeloid leukemia, non-Hodgkin lymphoma, and solid tumors.

Program: Therapy Acceleration Program
Project Term: July 17, 2019 - April 7, 2020
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: April 1, 2021 - March 31, 2026
Sutro

Sutro Biopharma, INC

TAP Partner

South San Francisco, California
United States

A phase 1 study of STRO-001, an anti-CD74 antibody drug conjugate, in patients with advanced B-cell malignancies

In August 2018, LLS partnered with Sutro Biopharma to support "A Phase 1 Open-Label, Safety, Pharmacokinetic and Preliminary Efficacy Study of STRO-001, an Anti-CD74 Antibody Drug Conjugate, in Patients With Advanced B-Cell Malignancies." STRO-001 is a CD74-targeting ADC currently being investigated in a Phase 1 clinical trial of patients with advanced B-cell malignancies, including multiple myeloma and non-Hodgkin lymphoma. STRO-001 is a new generation of ADC with more efficient homogeneous ADC design, which has the potential to minimize unwanted toxicity and improve clinical impact over prior technologies.

Program: Therapy Acceleration Program
Project Term: August 10, 2018 - December 31, 2023
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
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: January 1, 2021 - 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: July 1, 2019 - 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: October 1, 2021 - 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: July 1, 2021 - June 30, 2026
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

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: July 1, 2020 - June 30, 2023
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
Ravindra Majeti

Ravindra Majeti, PhD, MD

Board of Trustees of the Leland Stanford Junior University

Palo Alto, California
United States

Development of CAR T Cells Targeting AML Stem Cells

AML is an aggressive cancer of blood progenitors with poor clinical outcomes. We propose to develop and test in pre-clinical models chimeric antigen receptor (CAR)-modified T cells directed against CD93 expressed on human AML stem cells. We recently discovered expression of CD93 on a variety of AML cells, but not on blood stem and progenitor cells or most normal tissues, making it a good CAR T cell target. Our goal is to develop a CAR T cell candidate that can be brought into clinical trials.

Program: Translational Research Program
Project Term: July 1, 2018 - June 30, 2021
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: July 1, 2019 - 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: July 1, 2019 - 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: July 1, 2018 - June 30, 2023
Ari Melnick

Ari Melnick, MD

Weill Cornell Medicine

New York, New York
United States

SIRT3 targeted therapy for B-cell lymphomas

Our goal is to develop curative therapeutic regimens for the most aggressive forms of B-cell lymphoma, without unacceptable toxicity and in a manner that is widely applicable to patients regardless of access to the highest complexity health care. We propose that SIRT3 targeted therapy is important step to achieve this goal. Our preliminary data show that i) DLBCLs are broadly dependent on SIRT3 to maintain their survival regardless of genetic backgrounds and subtype, ii) SIRT3 expression is linked to inferior clinical outcome in DLBCL patients, iii) SIRT3 is required for lymphomagenesis in vivo, yet dispensable for normal B-cells. Mechanistically we showed that SIRT3 is the master regulator of anaplerotic metabolism in DLBCL, required to drive production of metabolic precursors through the TCA cycle to support the massive biosynthetic needs of lymphoma cells. Loss of SIRT3 function causes a precipitous drop in production of metabolic precursors in DLBCL cells, forcing them to engage in destructive autophagy which in turn triggers apoptosis.

Program: Special Grants
Project Term: December 31, 2019 - December 30, 2021
Johanna Melo-Cardenas

Johanna Melo-Cardenas, PhD

St. Jude Children's Research Hospital

Memphis, Tennessee
United States

Evolution of megakaryocyte abnormalities in the progression of primary myelofibrosis

My studies are in primary myelofibrosis, a blood cancer characterized by a buildup of fibrous tissue that impairs the bone marrow’s ability to produce normal blood cells. I am studying alterations in large cells in the bone marrow called megakaryocytes and exploring how changes in the bone marrow microenvironment contribute to disease progression. By knowing more about this process, we can uncover new ways to treat the disease before it progresses to a more severe phase.

Program: Career Development Program
Project Term: January 1, 2021 - December 31, 2023
C. Ola Landgren

C. Ola Landgren, PhD, MD

Memorial Sloan Kettering Cancer Center

New York, New York
United States

CD38-targeted immuno-PET imaging to detect early myeloma

The objective of this study is to prevent relapse by ruling out presence of last residual disease, and thereby facilitate the development of curative treatment strategies for multiple myeloma, which currently is viewed as an incurable disease.

Program: RTFCCR/LLS Prevention
Project Term: July 1, 2019 - June 30, 2020
Soheil Meshinchi

Soheil Meshinchi, PhD, MD

Fred Hutchinson Cancer Research Center

Seattle, Washington
United States

Novel Immunotherapeutic Development in Childhood AML

Dr. Soheil Meshinchi is taking a personalized medicine approach to identify immunotherapies for specific subsets of pediatric acute myeloid leukemia (AML). Pediatric AML remains a devastating disease with only a 60% survival rate. Survivors often have long-term quality of life issues related to the toxic chemotherapy used to treat their disease. A better knowledge of the molecular basis of pediatric AML will help identify targets for therapeutic intervention. Some of these targets may be mutants of normal genes, while others may be overexpression of normal genes, which would provide a therapeutic window in which targeting the overexpressed gene product may preferentially kill tumor cells. Dr. Meshinchi has surveyed the gene expression spectrum of pediatric AML and has identified several targets which are overexpressed in pediatric AML. One protein, CD74, is highly expressed in a subset of AMLs. Another target is CD70, which is highly expressed in about half of all pediatric AML cases that include a fusion of the MLL protein. Patients with MLL fusions have a worse outcome. Lastly, some infant AML patients have another kind of fusion protein paired with overexpression of the FOLR1 protein. All three proteins that Dr. Meshinchi has identified as being highly expressed in subsets of pediatric AML have much lower expression in healthy cells. Therefore, targeting these proteins is a logical choice. These three proteins are all expressed on the surface of the cell, making them accessible to targeting by special therapeutic antibodies called “antibody drug conjugates” (ADCs). ADCs have a toxic payload attached to them. When the antibody binds to its target on the cell surface, the cell takes in the ADC releasing the toxic payload, which then kills the cell. This immunotherapy approach is a highly specific, personalized approach for treating cancer. ADCs to each of the protein targets identified by Dr. Meshinchi are being clinically evaluated in other diseases, providing the opportunity to potentially repurpose those drugs for pediatric AML. Therefore, Dr. Meshinchi proposes to evaluate these ADCs in laboratory models of pediatric AML. Should any of these drugs show promise in these laboratory models, Dr. Meshinchi will propose clinical trials in pediatric patients through LLS’s Pediatric Acute Leukemia (PedAL) Master Clinical Trial. If any of the targets do not have an effective drug in the laboratory models, Dr. Meshinchi will create new ADCs using proven expertise currently available in his laboratory. Therefore, these studies present the possibility of new, targeted immunotherapy for specific subsets of pediatric AML patients, either rapidly through drug repurposing, or through the development of new ADCs. The goal is to improve the survival and quality of life for these vulnerable blood cancer patients.

Program: Dare to Dream
Project Term: October 1, 2020 - September 30, 2022
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: July 1, 2021 - June 30, 2026
Jatinder Lamba

Jatinder Lamba, PhD

University of Florida

Gainesville, Florida
United States

Personalizing CD33-directed immunotherapy for pediatric AML

Acute myeloid leukemia remains a refractory disease with dismal outcome. Recent approval of CD33-directed gemtuzumab ozogamicin (GO) is a significant step in AML treatment. We recently identified a genetic variant in CD33 resulting loss if the domain that is recognized by GO. Presence of this variant significantly impacts patient’s GO response. The proposed research seeks to perform mechanistic evaluation of CD33 variant to improve our ability to personalize CD33-directed immunotherapy in AML.

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

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: October 1, 2021 - 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: July 1, 2019 - 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: January 1, 2018 - December 31, 2022
Constantine Mitsiades

Constantine Mitsiades, PhD, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

CRISPR-based functional characterization of WM cells: insights into therapeutic vulnerabilities and strategies to overcome resistance

This project represents the first, to our knowledge, systematic effort to apply CRISPRCas9-based functional genomics approaches to determine in an unbiased manner (i) which genes are essential for survival/proliferation of Waldenström's Macroglobulinemia (WM) cells and have distinct vs. shared roles for WM vs. other hematologic malignancies (e.g. multiple myeloma, MM); and (ii) which genes drive WM cell resistance to established or investigational therapies.

Program: Special Grants
Project Term: October 1, 2019 - October 1, 2021
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: April 1, 2021 - March 31, 2024
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
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: July 1, 2019 - June 30, 2024
Ann Mullally

Ann Mullally, MD

Brigham and Women’s Hospital

Boston, Massachusetts
United States

Enhancing the clonal selectivity of current drug therapies in myeloproliferative neoplasms

Our research is focused on developing less toxic, more efficacious treatments for a type of blood cancer called, myeloproliferative neoplasms (MPN). We are using CRISPR genome editing and single-cell RNA sequencing to uncover new biological insights into MPN that can be exploited for therapeutic gain. The goal of our research is to advance the understanding and treatment of MPN and in doing so to lessen the burden these diseases place on patients with MPN and on their loved ones.

Program: Career Development Program
Project Term: July 1, 2017 - 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
Markus Muschen

Markus Muschen, PhD, MD

Yale University

New Haven, Connecticut
United States

Mechanisms of tumor-initiation in B-lymphoid malignancies

Dr. Müschen studies mechanisms of tumor-initiation in B-cell malignancies, including acute lymphoblastic leukemia, mantle cell lymphoma and diffuse large B-cell lymphoma. These studies focus on negative regulators of the WNT/b-catenin pathway as potential diagnostic marker and therapeutic target.

Program: Discovery
Project Term: July 1, 2020 - June 30, 2023
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: July 1, 2019 - June 30, 2024
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
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: July 1, 2018 - 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: July 1, 2019 - June 30, 2022
Stephen Nimer

Stephen Nimer, MD

University of Miami

Coral Gables, Florida
United States

Interventional Epigenetics in Myeloid Malignancies

Myeloid malignancies like acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN) arise due to a combination of genetic mutations and epigenetic abnormalities that sustain the abnormal behavior of cancer cells. The genetic material of the cell is the “hard drive” full of instructions that allow cells to grow, have unique functions, and ultimately live or die. Epigenetics is the “software” of the cell, allowing access to the information from the hard drive in a controlled manner. This interplay between the hardware and the software culminates in gene expression, allowing the genetic material to be read and interpreted. Targeted therapy in other myeloid cancers only works for a fraction of patients. Most myeloid cancers have a constellation of mutations that, in combination, likely determine the outcome of patients. The genetic mutations in myeloid cancers often occur in genes that control the epigenetic regulation of gene expression. While it is not possible to correct the genetic abnormalities in cancer cells, it is becoming possible to target and reverse the epigenetic abnormalities, and either kill the cancer cell or make it behave more normally. The goal of this SCOR is to analyze basic mechanisms of disease in order to arrive at novel therapeutic strategies and develop biomarkers that can predict the likelihood of a therapeutic response.

Program: Specialized Center of Research Program
Project Term: October 1, 2017 - September 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
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: April 1, 2021 - 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: July 1, 2021 - June 30, 2024
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
Ryan O'Connell

Ryan O'Connell, PhD

The University of Utah

Salt Lake City, Utah
United States

MicroRNAs in myeloid leukemia development and resistance to chemotherapy

My lab studies a novel class of molecules, called microRNAs, which are altered in blood disorders such as acute myeloid leukemia (AML). We propose to study how these molecules cause disease, and determine if blocking microRNAs can reduce AML in pre-clinical animal models. This work will provide novel insights into the contribution of microRNAs to different aspects of AML, and inform the development of next generation microRNA therapeutics that can be used to treat this devastating condition.

Program: Career Development Program
Project Term: July 1, 2017 - 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
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: October 1, 2017 - September 30, 2022
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 Kharas

Michael Kharas, PhD

Memorial Sloan Kettering Cancer Center

New York, New York
United States

Uncovering the dysregulated RNA binding protein network in normal and malignant hematopoiesis

The research focuses on discovering the driving factors in leukemia cells that control translation of RNAs into protein. Our studies explore these RNA regulators with a myriad of approaches including genetic mouse models, human leukemia cell lines, and human acute myeloid leukemia samples. Our ultimate goal is to discover new mechanisms and targets that are essential for leukemia cell survival and thus creating new therapeutic strategies for patients with myeloid leukemia.

Program: Career Development Program
Project Term: July 1, 2017 - June 30, 2022
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: July 1, 2018 - 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: June 1, 2021 - 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: July 1, 2019 - 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: 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
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: October 1, 2021 - 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: October 1, 2019 - September 30, 2024
Craig Jordan

Craig Jordan, PhD

University of Colorado Denver, Anschutz Medical Campus

Aurora, Colorado
United States

Therapeutic targeting of AML stem cells

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: October 1, 2018 - September 30, 2023
Ricky Johnstone

Ricky Johnstone, PhD

The University of Melbourne

Parkville, Victoria
Australia

Targeting deregulated epigenetic mechanisms in B-cell lymphomas

Diffuse large B-cell lymphomas (DLBCL) are aggressive tumors characterized by profound epigenetic alterations. In this proposal, we seek to investigate novel epigenetic therapies to treat this type of lymphomas. Specifically, we propose to explore the use of histone deacetylases inhibitors, alone or in combination with hypomethylating agents, as a precision medicine approach to treat lymphomas that present mutations in TET2, a protein involved in DNA demethylation that is highly mutated in DLBCL

Program: Translational Research Program
Project Term: July 1, 2019 - June 30, 2022
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: July 1, 2018 - June 30, 2023
Christopher Park

Christopher Park, PhD, MD

New York University School of Medicine

New York, New York
United States

microRNA regulation of leukemia stem cells

We are investigating the mechanisms by which microRNAs regulate stem cells in acute myeloid leukemia (AML). We are utilizing patient cells and mouse models of AML to determine if microRNAs regulate leukemia stem cells by virtue of their presence in different parts of the cell (cytoplasm vs nucleus). Given the important role of microRNAs in AML , better understanding how microRNAs regulate leukemia stem cells will identify novel targets for therapy.

Program: Career Development Program
Project Term: July 1, 2017 - June 30, 2022
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
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: July 1, 2019 - June 30, 2024
Joel Pomerantz

Joel Pomerantz, PhD

The Johns Hopkins University School of Medicine

Balitmore, Maryland
United States

Evaluation of BRD1 as a novel therapeutic target for diffuse large B cell lymphoma

Antigen receptor signaling to NF-kappaB is frequently dysregulated in Diffuse Large B Cell Lymphoma (DLBCL) and required for lymphoma cell proliferation. Using a novel genome-wide loss-of-function screen, we identified the chromatin regulatory protein BRD1 as a factor required in this pathway. We propose to test our hypothesis that BRD1 is a novel therapeutic target for the treatment of DLBCL and other lymphomas that depend upon chronic antigen receptor signaling to NF-kappaB.

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

Shan Lin, PhD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Identification of therapeutic targets sensitizing acute myeloid leukemia to BCL2 inhibitors

Venetoclax is a medication that can induce cell death of acute myeloid leukemia (AML), but its effectiveness needs to be further improved to benefit more patients. We are conducting a functional genetic screen to identify cooperating targets that enhance the efficacy of venetoclax and investigate the underlying molecular mechanism. Our study will provide valuable insights for understanding cell death regulation in AML and facilitating the clinical application of venetoclax for AML treatment.

Program: Career Development Program
Project Term: July 1, 2019 - June 30, 2022
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: July 1, 2018 - 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: July 1, 2018 - June 30, 2023
Clara Reglero

Clara Reglero, PhD

Columbia University Medical Center

New York, New York
United States

Targeting chemotherapy resistance in relapsed leukemia.

Acute lymphoblastic leukemia (ALL) represents the most frequent type of cancer in children and displays high rates of relapse. In this context, mutations in NT5C2 act as major drivers of resistance to chemotherapy with 6-mercaptopurine and are associated with early relapse and progression. Our project aims to investigate the regulation of this protein and design NT5C2 inhibitors that would prevent and improve the treatment of relapsed leukemia patients.

Program: Career Development Program
Project Term: October 1, 2021 - September 30, 2023
Christopher Reilly

Christopher Reilly, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

The impact of telomere maintenance on intestinal mucosal injury and regeneration during allogeneic stem cell transplantation for myeloid malignancies.

Short telomeres, the protective caps at the ends of DNA, are associated with increased risk of fatal toxicity among stem cell transplant recipients. We will determine 1) the relationship between recipient telomere length and intestinal injury after transplant and 2) how telomere length influences intestinal healing in a transplant mouse model. The goal of this work is to identify transplant patients at increased risk of toxicity and design therapies to improve patient survival.

Program: Career Development Program
Project Term: October 1, 2021 - September 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: July 1, 2019 - 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: July 1, 2017 - June 30, 2022
Babal Jha

Babal Jha, PhD

Cleveland Clinic Foundation

Cleveland, Ohio
United States

Synthetic lethality of a-ketoglutarate antagonists in TET2 mutant leukemias

This project investigates therapeutic inhibition of dioxygenase activity in TET2MT MDS cells to produce synthetic lethality. We have generated TET inhibitors (TETi) derived from a-ketoglutarate with a higher activity than the natural inhibitor 2-hydroxyglutarate. TETi displayed selective toxicity in TET2MT cells and in vivo led to their elimination in competitive repopulation models. This project will advance the goal of establishing a new class of targeted therapeutics for TET2MT leukemias.

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

Catriona Jamieson, PhD, MD

The Regents of the 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: July 1, 2020 - June 30, 2023
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: October 1, 2021 - 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: July 1, 2019 - June 30, 2024
Keisuke 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: July 1, 2018 - 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: October 1, 2018 - 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: July 1, 2021 - June 30, 2026
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
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: July 1, 2018 - 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: April 1, 2021 - 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: July 1, 2020 - June 30, 2023
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: October 1, 2021 - September 30, 2024
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
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: July 1, 2018 - June 30, 2023
Balazs Halmos

Balazs Halmos, MD

Albert Einstein College of Medicine

Bronx, New York
United States

Safety and efficacy of booster doses of BNT162b2 vaccine in immunocompromised patients with a cancer diagnosis

It is now well-established that COVID-19 in patients with cancer carries a higher morbidity and mortality, especially in patients with hematologic malignancies (Kuderer et al, Lee et al). Effective vaccines have been developed and authorized by the FDA to combat this pandemic (Pfizer NEJM, Moderna NEJM, J&J NEJM). However, emerging data suggests that despite these vaccines inducing high levels of immunity in the general population, patients with hematologic malignancies have lower rates of seroconversion for the SARS-CoV-2 Spike antibody (Thakkar et al Cancer cell, Dimpy Shah cancer cell, Sheeba Irshad cancer cell). Evidence has also suggested that specific therapies, such as anti-CD20 antibodies, BTK-inhibitors and stem cell transplantation have an association with lower rates of seroconversion (Thakkar et al Cancer cell, Thakkar et al Nature cancer, Herishanu at al blood 2021). Novel immunization strategies such as booster dosing are urgently needed to protect this high-risk patient population. We propose a study to administer a third dose of the BNT162b2 mRNA vaccine to patients with cancer who have a negative SARS-CoV-2 Spike IgG at least 14 days after 2 doses of the BNT162b2 vaccine

Program: Special Grants
Project Term: August 1, 2021 - July 31, 2022
Annamaria Gulla

Annamaria Gulla, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Optimizing mechanisms for induction of immunogenic cell death to improve clinical outcome in high risk multiple myeloma patients

Immune evasion drives myeloma progression and hampers a long-term clinical response. We are using functional studies and genomic profiling to characterize the specific gene alterations driving tumor immune escape. We are also developing therapeutic combinations to stimulate the patient’s immune system against their own myeloma. Overall, this study will provide proof-of-concept for the rapid clinical translation of novel therapeutic approaches to improve the outcome of myeloma patients.

Program: Career Development Program
Project Term: July 1, 2019 - June 3, 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
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: October 1, 2020 - September 30, 2025
Christina Glytsou

Christina Glytsou, PhD

New York University School of Medicine

New York, New York
United States

Targeting mitochondrial dynamics in venetoclax-resistant acute myeloid leukemia

Although new targeted therapies have been discovered and approved for the treatment of various types of leukemia, in many cases patients do not respond or develop resistance to treatments. My LLS-funded studies shed light on the mitochondria adaptations which enable cancer cells escape cell death induced by the treatments, while suggesting novel therapeutic strategies.

Program: Career Development Program
Project Term: July 1, 2021 - June 30, 2023
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: July 1, 2019 - 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: July 1, 2019 - June 30, 2024
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
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: July 1, 2018 - 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: January 1, 2019 - 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: July 1, 2019 - June 30, 2024
Takeshi Egawa

Takeshi Egawa, PhD, MD

Washington University School of Medicine in St. Louis

St. Louis, Missouri
United States

Protection of proliferating B lymphocytes from transformation by a c-MYC-induced tumor suppressive program

Our research focuses on defining mechanisms by which genes with essential function in normal cells turn to causative drivers of leukemia and lymphomas. Specifically, we study the gene named c-MYC, which is essential for normal cells but causes cancers. We combine genome-wide studies of patient samples and genetic studies in mouse models and identified genes deregulated in MYC-driven cancers. They can be used as biomarkers to identify high-risk patients and potentially targeted for therapies.

Program: Career Development Program
Project Term: July 1, 2017 - 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
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: July 1, 2019 - 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
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: October 1, 2021 - 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: April 1, 2021 - 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: January 1, 2020 - December 31, 2024
Matthew Davids

Matthew Davids, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Optimizing ibrutinib combination strategies to achieve minimal residual disease negativity in CLL

We seek to optimize combination therapy for chronic lymphocytic leukemia with ibrutinib. We will address this question through 2 clinical trials combining ibrutinib with chemoimmunotherapy or an antibody. We will also examine the biology of CLL cells at a genetic and functional level to predict who will have the best response to therapy and to identify resistance mechanisms. Our goal is to develop curative combinations for CLL and to understand resistance in the patients who are not cured.

Program: Career Development Program
Project Term: July 1, 2018 - June 30, 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
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: July 1, 2018 - June 30, 2023
Ronald Levy

Ronald Levy, MD

Board of Trustees of the Leland Stanford Junior University

Palo Alto, California
United States

Stanford study of COVID-19 vaccine responses in patients with B-cell lymphoma

We are conducting a study analyzing blood samples from B-NHL patients before and at timepoints after SARS-CoV-2 vaccination for several aspects of immune system responses, compared to similarly-aged participants without lymphoma. These analyses aim to answer a few key questions: (1) Do B-NHL patients respond as well as healthy controls to the SARS-CoV-2 vaccines?  (2) Does B-NHL subtype and/or treatment history, particularly the use of CD20-targeted therapies such as rituximab and BTK-targeted therapies such as ibrutinib, affect vaccine response? And (3) is it a good strategy to try to vaccinate patients before they start anti-lymphoma therapy, in cases where this is reasonable to do? An understanding of which B-NHL patients are most likely to have suboptimal responses to SARS-CoV-2 vaccines and what in their response is lacking will help focus strategies for protecting these patients from a potentially fatal infection.

Program: Special Grants
Project Term: June 1, 2021 - December 31, 2021
Ronald Levy

Ronald Levy, MD

Board of Trustees of the Leland Stanford Junior University

Palo Alto, California
United States

In vivo generation of Chimeric Antigen Receptor cells to treat hemopoietic malignancies

This project is aimed at investigating a pre-clinical “off-the-shelf” CAR (chimeric antigen receptor) T-cell immunotherapy approach where the CAR cells are generated directly in the patient’s body. Importantly, this product will be a truly off the shelf therapy that is ready instantaneously and can be used repeatedly without the restriction of time-consuming manufacturing processes.

Program: Discovery
Project Term: July 1, 2020 - 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: 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
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: July 1, 2021 - June 30, 2026
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
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: January 1, 2018 - 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: July 1, 2018 - 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: October 1, 2021 - 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: July 1, 2019 - June 30, 2022
Jianjun Chen

Jianjun Chen, PhD

Beckman Research Institute of the City of Hope

Duarte, California
United States

The oncogenic role and underlying mechanism of TET1 in acute myeloid leukemia

Acute myeloid leukemia (AML) is a type of very fatal disease (>70% of patients cannot survive 5 years with current therapies) and improved therapies are urgently needed. Here we will conduct a series of studies to define the role of TET1, a DNA demethylase (“eraser”), in the pathogenesis of AML, and to reveal the underlying molecular mechanisms. The success of our study will not only provide novel insight into AML pathogenesis, but may also lead to the development of improved novel therapies.

Program: Career Development Program
Project Term: July 1, 2017 - June 30, 2022
Dr. Shi

Xiangguo Shi, PhD

Baylor College of Medicine

Houston, Texas
United States

AMPK links energy metabolism and histone acetylation in leukemia-initiating cell

How leukemia cell coordinates cellular energy metabolism and the epigenetic landscape is a fundamental question with significant clinical implications. We employ interdisciplinary approaches including molecular biology, genome engineering, disease modeling, and high-throughput sequencing technologies to discover new mechanisms of the role of AMPK in metabolic and epigenetic regulation in leukemia-initiating cells. This project will explore the potential of targeting AMPK to safely treat acute myeloid leukemia.

Program: Career Development Program
Project Term: July 1, 2019 - June 30, 2022
Chun-Chin Chen

Chun-Chin Chen, PhD

Massachusetts Institute of Technology

Cambridge, Massachusetts
United States

Mechanisms of aberrant DNA double-strand break repair leading to lymphoid malignancy

The aim of this project is to address why Down syndrome children are prone to leukemia. We establish a model system using stem cells derived from Down syndrome patients to study early development of blood cells and identify the genomic aberrations in these processes. We hope to help understand why the genetic alterations in Down syndrome promote mutations in blood cells that drive leukemia development.

Program: Career Development Program
Project Term: July 1, 2019 - June 30, 2022
Margaret Shipp

Margaret Shipp, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Discovery and characterization of an immunosuppressive tumor microenvironmental (TME) niche in classic Hodgkin lymphoma

Dr. Shipp and her colleague, Scott J. Rodig, MD, Ph.D., are mapping the immune microenvironment in classical Hodgkin lymphoma.

Program: Discovery
Project Term: July 1, 2020 - June 30, 2023
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
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: July 1, 2018 - 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: July 1, 2018 - 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: July 1, 2018 - June 30, 2023
Robert Signer

Robert Signer, PhD

The Regents of the University of California, San Diego

, California
United States

Targeting leukemia stem cells by disrupting translational fidelity

Dr. Signer is investigating how the process of building defective proteins (inaccurate protein synthesis) plays a role in the development of a type of blood cancer called acute myeloid leukemia (AML) in the hopes of developing targeted therapies to treat this condition.

Program: Discovery
Project Term: July 1, 2020 - June 30, 2023
Sylvain Simon

Sylvain Simon, PhD

Fred Hutchinson Cancer Research Center

Seattle
United States

Deciphering immune cell heterogeneity and transcriptomic changes associated with CRS development and severity in CAR-T cell treated patients

We seek to understand the mechanisms of Cytokine Release Syndrome (CRS), the most common and potentially life-threatening toxicity associated with CAR-T cell therapies. We are using cutting-edge approaches to determine the cascade of events leading to the development of CRS and therefore define new candidates for CRS prevention and/or resolution. We will describe a cellular and molecular atlas associated with CRS development and severity, thus providing more specific and reliable candidates for therapeutic targeting. These findings may inform strategies to prevent CRS of cancer patients receiving CAR-T therapies.

Program: Career Development Program
Project Term: January 1, 2021 - December 31, 2023
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
Robert Bradley

Robert Bradley, MD

Fred Hutchinson Cancer Research Center

Seattle, Washington
United States

The biological and therapeutic consequences of SF3B1 mutations in myelodysplastic syndromes

My lab studies how common mutations affecting RNA splicing, a critical step during expression of most human genes, give rise to myelodysplastic syndromes, leukemias, and other malignancies. We combine experimental and computational studies to create new models of these disorders and thereby understand their molecular origins. In the long term, our goal is to identify new therapies for treating these disorders, which currently have limited treatment options.

Program: Career Development Program
Project Term: July 1, 2017 - 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
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: October 1, 2021 - September 30, 2024
Marcel Spaargaren

Marcel Spaargaren, PhD

Academic Medical Center Amsterdam


Netherlands

Towards a rational targeted therapy for Waldenstrom's Macroglobulinemia by kinome-centered loss-of-adhesion and synthetic lethality screens

We have previously demonstrated that disrupted retention of the malignant B cells within lymphoid organs is a key mechanism of action of the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, underlying its unprecedented high clinical efficacy in the treatment of chronic lymphocytic leukemia, mantle cell lymphoma and Waldenström’s Macroglobulinemia (WM). Unfortunately, apart from innate (primary) resistance, a significant subset of patients who receive prolonged treatment with ibrutinib develop (secondary) therapy resistance. Considering microenvironment-dependence as the Achilles’ heel of WM cells, we hypothesize that induction of homelessness by targeting localization (homing and retention) as well as survival/proliferation of WM cells in their lymphoid organ microenvironment by combination therapy may overcome innate (primary) resistance and prevent acquired (secondary) drug-resistance, providing a powerful strategy to cure WM. Therefore, our aims are: 1) to identify the signaling pathways and kinases (given their druggability) that control WM cell retention and outgrowth; 2) to identify kinases whose inhibition sensitizes WM cells to the anti-adhesive and growth-inhibitory effects of ibrutinib, and 3) to explore and exploit their potential as therapeutic targets for development of novel targeted (combination) therapy for WM patients.

Program: Special Grants
Project Term: March 1, 2020 - March 1, 2022
Daniel Starczynowski

Daniel Starczynowski, PhD

Cincinnati Children's Hospital Medical Center

, 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: July 1, 2020 - June 30, 2023
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: October 1, 2020 - September 30, 2022
Alexandra Stevens

Alexandra Stevens, MD

Baylor College of Medicine

Houston, Texas
United States

Pediatric AML PDX Models and Drug Testing-Gateway to Novel PedAL Trials

Pediatric AML is a disease with poor outcomes and a need for improved therapeutic options. Pediatric AML is characterized by diverse lesions that often do not overlap with adult AML, which therefore means therapeutic development must be done using pediatric AML models. Recent advances in patient derived xenograft (PDX) modeling have made possible the successful development of PDX models of diverse pediatric AML subtypes.

Program: Dare to Dream
Project Term: July 1, 2021 - June 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: July 1, 2021 - June 30, 2024
Karin Tarte

Karin Tarte, PhD

National Institute of Health and Medical Research (INSERM)

Rennes
France

Characterizing and targeting the follicular lymphoma microenvironment

This proposal will explain how follicular lymphoma (FL) arises from normal B-cell activation. Using the first mouse models that reflect the true biology of FL integrated with sophisticated analyzes of primary human FL, we will define the nature and evolution of the FL tumor microenvironment in relationship with the main FL-specific genetic alterations and identify key therapeutic vulnerabilities that will lead to a new class of precision-targeted therapy for this otherwise incurable tumor.

Program: Translational Research Program
Project Term: July 1, 2019 - June 30, 2022
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: October 1, 2021 - 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: July 1, 2018 - 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: Special Grants
Project Term: October 1, 2021 - September 30, 2024
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: January 1, 2021 - 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: October 1, 2021 - 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: July 1, 2019 - June 30, 2022
Saad Usmani

Saad Usmani, MD

Memorial Sloan Kettering Cancer Center

New York, New York
United States

Optimizing Risk and Response Adaptive Strategies using Immunotherapy in Multiple Myeloma

Despite great improvement in survival outcomes over the last 20 years, multiple myeloma (MM) remains an incurable disease. As anti-myeloma therapeutics continue to expand, it is becoming more crucial to personalize treatment approaches that provide the most value to a specific patient. We are applying this approach in three clinical trials for newly diagnosed MM testing various immunotherapeutic approaches with associated correlative studies. Together, these studies may provide new therapeutic approaches as well as better MRD assessment to better understand a patient’s response.

Program: Career Development Program
Project Term: July 1, 2017 - June 30, 2022
Geoffrey Uy

Geoffrey Uy, MD

Washington University in St. Louis

St. Louis, Missouri
United States

Targeting Leukemia Stromal Interactions in T-ALL

My research is focused on understanding how a protein, CXCR4, promotes the growth and survival of T-cell acute lymphoblastic leukemia. We are conducting a clinical trial in patients with T-ALL to test if a CXCR4 inhibitor, BL-8040, can increase the effectiveness of chemotherapy. Additional studies seek to understand how BL-8040 causes the death of tumor cells and to test novel agents in combination with BL-8040 with an overall goal of improving clinical outcomes in T-ALL.

Program: Career Development Program
Project Term: July 1, 2017 - June 30, 2022
Santosha Vardhana

Santosha Vardhana, PhD, MD

Memorial Sloan Kettering Cancer Center

New York, New York
United States

T-cell profiling of hematologic malignancy patients undergoing COVID-19 vaccination

Early during the COVID-19 pandemic, it became rapidly apparent that patients with cancer, and in particular patients with blood cancers, were at particularly high risk of complications and death from COVID-19 infection.  Over the past 18 months, our group has identified distinct roles for B-cells and T-cells in short and long-term control of COVID-19.  In recent work, we have also established that patients with blood cancers often mount poor antibody responses to COVID-19 vaccination.  The nature of T-cell responses to COVID-19 vaccination, and the impact of both cancer type and treatment on the ability to mount T-cell responses to vaccination remains undefined. To answer this question, we have banked longitudinal samples from over 500 patients with blood cancers undergoing vaccination against COVID-19.  We will use a multiparametric approach, including flow cytometry, sequencing and identification of COVID-specific T-cell receptors, and sequencing of the viral genome to understand the T-cell response to vaccination in these patients and how breakthrough infections might occur in the context of T-cell failure.

Program: Special Grants
Project Term: June 1, 2021 - December 31, 2021
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: July 1, 2020 - June 30, 2023
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: 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
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: October 1, 2021 - September 30, 2024
George Vassiliou

George Vassiliou, PhD, MD

Wellcome Trust Sanger Institute

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: July 1, 2018 - 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: 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
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: January 1, 2021 - December 31, 2023
Elvin Wagenblast

Elvin Wagenblast, PhD

University Health Network

Toronto, Ontario
Canada

Modeling the Initiation and Progression of Down Syndrome Associated Leukemia using CRISPR/Cas9 at Single Cell Resolution

Children with Down syndrome (Trisomy 21) have an increased risk of childhood leukemia and, in these cases, the initiating genetic alterations already occur during the development of the fetus. In 30% of newborns with Down syndrome, a pre-leukemia disease occurs, which in some cases can progress to acute myeloid leukemia. I am planning to determine why children with Down syndrome have an increased risk of developing leukemia with the goal to identify potential therapeutic targets.

Program: Career Development Program
Project Term: April 1, 2021 - March 31, 2023
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 Baker

Brian Baker, PhD

University of Notre Dame

Notre Dame, Indiana
United States

Safer and more effective T cells for immunotherapy of viral-associated hematological malignancies

T cells engineered with TCRs specific for tumor antigens provide exciting opportunities for immunotherapy, notably for hematological malignancies due to viral infection. A risk of TCRs, however, is their high cross-reactivity, which can be exacerbated by efforts to increase potency. We propose to combine structure-guided TCR engineering with manipulation of T cell signaling to develop more specific and more effective T cells for immunotherapy, targeting HTLV-1-associated T cell lymphoma.

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
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: July 1, 2018 - 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: 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
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: April 1, 2021 - 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: July 1, 2019 - June 30, 2024
Haopeng Yang

Haopeng Yang, PhD

The University of Texas MD Anderson Cancer Center

Houston, Texas
United States

Targeting dominant-negative CREBBP mutations in follicular lymphoma

CREBBP hotspot mutations frequently occurr in follicular lymphoma (FL) but their role in the disease remains largely unknown. We will use next generation sequencing and gene editing techniques to study the epigenetic consequences in lymphoma patients and cell line models with CREBBP hotspot mutations. We will also target CREBBP by testing the efficacy of a novel Cbp/p300 inhibitor on patient-derived xenograft models. This study could provide a biological explanation for how CREBBP mutations work in FL.

Program: Career Development 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
Philippe Armand

Philippe Armand, PhD, MD

Dana-Farber Cancer Institute

Boston, Massachusetts
United States

Checkpoint-Based Immunotherapy in Follicular Lymphoma

This project focuses on designing new immunotherapy approaches for the treatment of patients with follicular lymphoma. It is based on a clincal trial that tests combinations of antibodies, with the goal of making the patients’ own immune systems more effective at attacking their lymphoma. Through analysis of tumor and blood samples from the patients on the trial, we hope to gain a deeper understanding of the biology of follicular lymphoma and its vulnerability to immune attack, which will help to design the next generation of trials. The trial and sample collection are currently ongoing.

Program: Career Development Program
Project Term: July 1, 2018 - June 30, 2023
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: July 1, 2018 - 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: 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
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: July 1, 2019 - June 30, 2024
Robert Albero Gallego

Robert Albero Gallego, PhD

Columbia University Medical Center

New York, New York
United States

Role and mechanisms of enhancer deregulation in in T-ALL

My research focuses on the aberrant regulatory logic in acute lymphoblastic leukemia (ALL). Epigenetic analysis of human samples allowed us to dissect the alterations in the regulatory architecture of their normal counterparts. I characterized a group of DNA elements, known as enhancers, which lock ALL cells in a differentiation-arrested state. Targeting these regions and the proteins involved in their activation may lead to the development of new therapeutic options using pre-clinical leukemia models.

Program: Career Development Program
Project Term: July 1, 2019 - June 30, 2022
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
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: October 1, 2021 - September 30, 2025