Research We Fund

Understanding Leukemia in Children with Down Syndrome to Develop Better Therapies

This Specialized Center of Research is focused on identifying the contributions of chromosome 21, which is present in three copies in individuals with Down syndrome (DS), to acute leukemia. Children with DS are at a 20-fold increased risk of leukemia compared to the overall pediatric population and frequently have other health issues that complicate leukemia treatment. Although acute myeloid leukemia in children with DS (ML-DS), which frequently evolves from transient abnormal myelopoiesis (TAM), has a better outcome than acute myeloid leukemia (AML) in children without DS, those who relapse following treatment face an extremely poor prognosis. Similarly, children with DS who develop B-ALL have a worse prognosis than those without DS due to excessive treatment-related mortality and increased risk of relapse. Our overarching, united goal is to develop novel therapies to cure DSassociated leukemias and to reduce the side effects of treatment in this vulnerable population. In addition to children with DS, our study has major implications in other cases of pediatric and adult leukemias. For example, chromosome 21 amplification is one of the most significant gains in several classes of malignancies, including certain subtypes of AML, hyperdiploid ALL, and iAMP21. Amplification of chromosome 21 is also a feature of the acute leukemia phase of a disease named myelofibrosis. Therefore, insights we gain from this research will impact a large group of patients with acute leukemia.

Targeting aberrant epigenetic condensates in myeloid malignancies

Genetic changes of ASXL1 are very frequent in human blood cancers. We found that the altered forms of ASXL1 protein promote blood cancers through forming tiny liquid-like droplets in the cell. In this project, we aim to develop a method to specifically break these droplets to inhibit its activity in driving blood cancers.

Targeting Microenvironment Determinants in Peripheral T-cell Lymphoma

Peripheral T-cell lymphomas are highly aggressive blood cancer that have very poor survival rate, highlighting the need for new therapies to improve patient survival. We aim to improve our understanding of the characteristics of the individual cancer cells and their interaction with surrounding cells in the tumor environment with the goal of identifying new drugs that we can validate in preclinical models and move into more efficient treatments for lymphoma patients.

Interrogating T-cell apoptotic priming to improve CAR-T persistence in treatment of lymphoid malignancies

CAR-T cells are made from a patient’s own immune cells, altered so that they specifically recognize and kill the patient’s cancer cells. They are effective in many but not all cases of B-acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL), among other blood cancers. In this proposal we seek to better understand ways to select T cells that will make better CAR-T cells as well as to treat CAR T cells them in ways to make them work better in the cancer patient.

Epigenetic Mechanisms and Targeting in Hematological Malignancy

Blood cancers can be caused by aberrant regulation of genes that control cell growth and development. The root cause of this problem may be the presence of mutant regulator proteins in the cell and abnormal switching on or off of target genes. Our SCOR studies the molecular basis of this gene deregulation using cell cultured in the laboratory, in human specimen and animal models.

Melnick will study the complex of proteins evolve in looping DNA segments to put gene regulatory sequences in proximity of genes critical for the development of antibody producing B cells. Abnormalities of this apparatus lead to lymphoma. Roeder will study multi-protein complexes involved in “bookmarking” chromatin (the complex of DNA and histones found in the cell nucleus) by chemical modification. He studies the proteins that initiate transcription of DNA into RNA and that assure the passage of the polymerase that creates messenger RNA across genes. Soto-Feliciano studies TRIM28, a protein essential for growth of acute leukemia will identify its mechanisms and target genes. Licht will study the role of chromatin regulators in the response of the immune system to multiple myeloma and how inhibitors of chromatin regulator inhibitors affect the tumor immune response. Patel will study in explore the three-dimensional structures of these protein complexes critical for gene regulation in blood malignancies to understand their mechanisms and develop new small molecules to modulate their action.

Impact of State Health Insurance Mandates on Affordability and Utilization of Fertility Preservation in Adolescent and Young Adults with Blood Cancers

Fertility preservation (FP) treatments can prevent infertility caused by blood cancer. However, FP costs are high, and these services are typically not covered by insurance, contributing to low utilization. New state laws require insurers to cover FP, but it is unknown if they improve access to care. Using national insurance data, this study will examine how much out-of-pocket costs remain, whether patients’ share of costs is like that of other cancer services, and whether and which types of laws increase use and affordability.

Insurance Inequities in Hodgkin Lymphoma Treatment and Survivorship in the Southeast

Black and Hispanic individuals diagnosed with Hodgkin lymphoma (HL) face worse survival rates across all ages. Using an innovative data source, this study will examine differences by insurance status in the receipt and quality of HL treatment in Aim 1 and care engagement and support after treatment (survivorship care) in Aim 2. Using diverse patient voices, this study will characterize and understand how patients make decisions about treatment and survivorship care by insurance type in Aim 3.

RECONNECT: Overcoming Racial and Ethnic Inequity in Clinical Trial Enrollment via Clinical Trial Nurse Navigation and Provider Communication Training​

This study will implement a skill-based didactic course for providers to improve the quality of communication around structural racism, mistrust, implicit biases, and clinical trial counseling. This study will also implement a culturally competent, specialized clinical trials nurse navigation program that connects patients to educational resources around clinical trials and standardizes pre-screening for new patients prior to the initial clinic visit.​

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

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

Lower Dose Mitoxantrone for Venetoclax Resistant Acute Myeloid Leukemia

Venetoclax-based regimens are the standard of care for many patients with acute myeloid leukemia (AML) and are highly active therapeutic strategies for this challenging disease. However, some patients do not respond, and most patients who do respond will relapse. We have discovered that resistance to venetoclax may be mediated by the movement patterns of calcium throughout a cell. Furthermore, we have found that mitoxantrone, a conventional chemotherapy agent, can interrupt these calcium fluctuations at very low doses. Therefore we have proposed a clinical trial using lower-dose mitoxantrone for AML patients whose disease has resistance to venetoclax-based regimens.

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

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

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

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

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

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

Targeting SF3B1 splicing factor mutant myeloid malignancies through dependency on GPATCH8

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

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

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

Towards Risk-Adapted Therapeutic Strategies in CNS Lymphoma

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

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

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

Targeting Leukemia Stem Cells with the Novel Antibody Drug Conjugate

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

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

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

Targeting the Osteogenic Lineage as a Therapeutic Strategy in Multiple Myeloma

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

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

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

BAFF-ligand CAR T-cells and pre-apheresis B cell lymphodepletion for relapsed / refractory CLL

Most CLL patients treated with CAR T-cells that target the CD19 antigen on the cell do not achieve a complete remission. CLL cells express other molecules on their surface; one of them is the receptor for BAFF (BAFF-R), which is highly expressed. We propose a phase I trial investigating LMY-920 for treatment of CLL. LMY-920 is a different type of CAR T-cell because it does not rely on an antibody structure to identify BAFF-R, but uses the structure of the ligand BAFF itself, and this may help avoid resistance to CAR T-cells.

We also aim to improve the quality of the CAR T-cell product by removing the circulating B cells with a monoclonal antibody prior to collecting lymphocytes for manufacture.

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

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

Novel Immunotherapy Combinations in Relapsed, Refractory Mantle Cell Lymphoma

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

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

Mechanisms of oncogenic transcription in NPM1-mutant myeloid leukemia

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

Patient-Reported Outcomes and Survivorship in Histiocytic Neoplasms

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

Role of ID2 in mature T-cell lymphoma

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

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

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

Novel targeted therapies for acute myeloid leukaemia and multiple myeloma

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

Limited-duration bispecific antibody therapy for multiple myeloma

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

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

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

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

In August 2017, LLS TAP partnered with Ryvu Therapeutics (formerly known as Selvita) to support "A Phase 1b Study of SEL120 in Patients With Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome."

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

RVU120 (SEL120) is a highly selective first-in-class CDK8/CDK19 small molecule inhibitor. Ryvu is currently enrolling several Phase 2 clinical trials: RVU120 as monotherapy in genetically defined cohorts of patients with relapsed/refractory AML and high-risk myelodysplastic syndromes (RIVER-52, NCT06268574), RVU120 in combination with venetoclax for patients with relapsed/refractory AML (RIVER-81, NCT06191263), RVU120 as monotherapy for patients with low-risk myelodysplastic syndromes (REMARK, NCT06243458) and RVU120 as monotherapy and in combination with ruxolitinib for patients with myelofibrosis (POTAMI-61, NCT06397313).

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

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

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

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

Targeting the inflammatory GM-CSF pathway in high risk CMML

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

Advancing the therapeutic landscape for Chronic Myelomonocytic Leukemia (CMML)

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

Targeting the inflammasome in CMML

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

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

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

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

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

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

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

Therapeutic targeting of AML stem cells 2023

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

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

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

Targeting metabolic reprogramming in MDS and AML stem/progenitor cells

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

Understanding Resistance Mechanism to Enhance CAR-T Immunotherapy for MCL

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

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

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

New Targeted Therapies for Pediatric Acute Myeloid Leukemia

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Towards clinical testing of epitope editing to enable novel adoptive immunotherapies

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

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

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

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

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

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

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

Identifying novel regulators of leukemic progression in GATA2-deficiency syndrome

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

Molecular basis and new therapeutic strategies in lineage ambiguous leukemia

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

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

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

Development of novel BTK-MALT1 dual inhibitors to treat MCL

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

Epigenetic Mechanisms in Acute Myeloid Leukemia

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

Modeling and targeting leukemic transformation of human hematopoietic stem cells

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

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

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

Clinical and molecular determinants of CLL eradication with targeted combination therapy

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

Supporting development of RNA-targeting molecules for blood cancers

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

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

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

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

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

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

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

A phase 1/2 study of DR-01, an anti-CD94 monoclonal antibody, in patients with large granular lymphocytic leukemia or cytotoxic lymphomas

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

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

DR-01 is a novel antibody targeting CD94 which is known to be upregulated on LGLL cells. DR-01 functions through depletion of target cells via ADCC by means of fratricide, a method in which the same cell type induces ADCC on each other. A Phase 1/2 trial is ongoing to assess the safety and efficacy of DR-01 in previously treated LGLL patients and cytotoxic lymphomas (NCT05475925).

DR-0201 is a first-in-class bispecific antibody capable of engaging tissue-resident and trafficking myeloid cells to induce deep B cell depletion via targeted phagocytosis. DR-0201 is currently being evaluated in a Phase 1 study in B-NHL patients (NCT06392477).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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

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

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.

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.

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.

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.

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

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

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

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

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.

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

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

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

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

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

In August 2017, LLS TAP partnered with Ryvu Therapeutics (formerly known as Selvita) to support "A Phase 1b Study of SEL120 in Patients With Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome."

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

RVU120 (SEL120) is a highly selective first-in-class CDK8/CDK19 small molecule inhibitor. Ryvu is currently enrolling several Phase 2 clinical trials: RVU120 as monotherapy in genetically defined cohorts of patients with relapsed/refractory AML and high-risk myelodysplastic syndromes (RIVER-52, NCT06268574), RVU120 in combination with venetoclax for patients with relapsed/refractory AML (RIVER-81, NCT06191263), RVU120 as monotherapy for patients with low-risk myelodysplastic syndromes (REMARK, NCT06243458) and RVU120 as monotherapy and in combination with ruxolitinib for patients with myelofibrosis (POTAMI-61, NCT06397313).

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

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

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

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

Supporting in vivo CAR development for blood cancers

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

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Therapeutic targeting of AML stem cells 2018

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

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.

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.

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

Coming soon.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.