Research we fund

This collaborative program investigates why Hairy Cell Leukemia (HCL) and its variant often relapse despite effective therapies and why bone-marrow fibrosis frequently persists after treatment. This proposal examines fibrosis as both a biomarker and a biological driver of disease. Project 1 determines whether persistent scarring predicts relapse and uses human bone-marrow organoid cultures to test how leukemia and stromal cells interact. Together, these studies connect patient data and experimental systems to reveal how fibrosis contributes to disease persistence in HCL and HCL-v.

Hairy Cell Leukemia (HCL) is a rare blood cancer that affects white blood cells. The usual first treatment is with drugs called purine analogs (PAs). While PAs work well initially, their efficacy decreases with each treatment round, they cause long-lasting immune suppression and increase the likelihood of developing serious infections.

Therefore, safer treatments that can control or even eliminate the disease, and allow the immune system to recover are urgently needed. New targeted oral therapies offer a promising alternative to chemotherapy, and those that induce apoptosis (BCL2 inhibitors) or inhibit B-cell receptor signaling (BTK inhibitors) have shown single-agent activity and excellent tolerability in HCL patients. However, alone, they often result in incomplete responses and require long-term administration. We will test if combining a BTK inhibitor (zanubrutinib) with a BCL2 inhibitor (sonrotoclax) can achieve deeper, longer-lasting remissions and allow treatment to stop after a fixed period rather than continuing indefinitely.

We will examine responses after 6, 12, and 18 cycles (a cycle is 28 days) to assess how quickly the disease resolves and how deep the response is. We will monitor immune recovery using blood tests and advanced techniques to investigate how the treatment affects any remaining leukemia cells.

The ultimate goal is to determine if this drug combination can eliminate HCL and how long treatment needs to continue to achieve this result.

Over the past year, we explored whether there is a biological basis that helps explain why African and African American patients typically present with more aggressive forms of lymphoma, which tend to be less responsive to treatments. Our findings revealed that, in addition to having slightly different mutations in the lymphoma cells, the tissue microenvironment surrounding these cells is rich in cells that suppress the immune response. We were the first to describe this type of cell, which is also commonly observed in other patients with less responsive tumors. We discovered that these mutations might make lymphoma cells more likely to respond to novel targeted therapies that are not yet available in clinical settings. Furthermore, we developed innovative therapeutic strategies aimed at targeting the microenvironment cells to enhance the immune response against these tumors. These studies were conducted using pre-clinical models as a precursor to clinical trials. We anticipate that these studies will benefit patients with high-risk diffuse large B cell lymphoma, regardless of their ethnicity. To help identify patients more likely to respond to these treatments, we are developing minimally invasive biomarkers that use a drop of blood to analyze specific characteristics in both lymphoma and microenvironment cells. This approach is crucial for reducing reliance on biopsies and tissue analysis, which can be challenging or cumbersome to obtain from patients. Over the past year, we have continued to investigate how epigenetic drugs can be used in combination with immune therapies to increase the likelihood of curing lymphoma patients. We have several ongoing clinical trials exploring the concept that administering epigenetic drugs can make tumors more susceptible to being destroyed by immune cells, either naturally present in the body or administered via blood transfusion. In these patients, we also apply biomarkers to determine which individuals can benefit most from epigenetic therapy and to understand how and when the drugs modify the microenvironment, allowing us to decide the optimal timing for immune cell transfusion.

T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive leukemia in adults with 5-year survival rate of only about 10% in patients with relapsed/refractory (R/R) disease, but LCK and BCL2 are novel therapeutic targets. In this project, we aim to conduct a Phase II clinical trial evaluating LCK inhibitor, ponatinib and BCL2 antagonist, venetoclax combination therapy in R/R T-ALL, with correlative biology studies to define biological mechanisms of drug response and resistance.

Patients with B cell malignancies who do not fall into a distinct pathological disease category pose a challenge for patient care, and patient classification has been exacerbated by the recent emergence of two separate classification systems. Genome-wide DNA methylation is a stable and information-rich biomarker that has been successfully used to classify other cancer types, however remains understudied in hairy cell leukemia and related splenic B cell lymphoma and leukemia. In this proposal we will investigate the utility of DNA methylation to establish a novel, unbiased, biologically-based classification paradigm for hairy cell leukemia, with a focus on the variant subtype, and investigate novel mechanisms and etiology underlying these rare leukemia patients.

The overall objective of this project is to identify novel pathways that may be targeted for therapeutic benefit in CMML. We have identified abnormal inflammation mediated by RSK1 in CMML patient cells, and we hypothesize that RSK1 drives CMML disease development. We thus propose studies to determine how RSK1 contributes to CMML pathogenesis, and to evaluate the therapeutic potential of RSK1 inhibition for CMML patients.

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.

This proposal examines the use of CD19-directed chimeric antigen receptor (CD19-CAR) T cell immunotherapy to treat adults aged 55 years or older who have acute lymphoblastic leukemia (ALL) that is in remission following induction therapy (i.e., “first remission”). In this clinical trial, we will infuse the CD19-CAR T cells early in the treatment sequence, which may prevent the leukemia from returning without additional therapy. This clinical trial aims to give us a better understanding of CD19-CAR T cell safety and activity when given during first remission, with the goal of improving the very poor outcomes of older adults with ALL.

On the basis that T-cell acute lymphoblastic leukemia (T-ALL) cells overexpress IL-7 receptor (IL7R), which promotes chemotherapy resistance and relapse, we developed IL7R-targeted chimeric antigen receptor (CAR) T cells with low- and high-affinity single-chain variable fragments (scFvs). Following extensive investigation, we established the antitumor efficacy of low-affinity IL7R CAR against T-ALL cells in vitro, in vivo and against patients’ T-ALL blasts using their own T cells transduced with IL7R CAR. With data establishing tumor specificity and antitumor efficacy, and a novel manufacturing method of ‘natural selection’ to seamlessly manufacture a large number of IL7R CAR T cells from patients with T-ALL, we are now proceeding with Investigational New Drug studies to initiate a phase I clinical trial in 2025 Q4.

We aim to determine if rigorous assessment of quality of life (QOL) can help with treatment decisions for hairy cell leukemia (HCL). We will first analyze a robust HCL patient database to understand QOL trajectories among patients before they need initial treatment or relapse, as well as among specific subgroups such as those who are younger (75), and those who or working. We will then then utilize a patient-driven consensus process to determine which QOL instruments most accurately reflect experiences when facing treatment or re-treatment. Finally, we will engage 30 HCL patients nearing treatment or re-treatment, measure QOL, and provide results for discussion with providers, measuring feasibility and preliminary impact of this approach.