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.

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.

We will test the first fully oral, chemotherapy-free drug combination that simultaneously blocks two different key survival mechanisms in hairy cell leukemia. First, it blocks the genetic cause of the disease, i.e. the BRAF mutant gene, using the BRAF inhibitor drug vemurafenib. Second, it deprives leukemic cells of their intrinsic ability of resisting natural cell death (apoptosis) by blocking the apoptosis inhibitor BCL2 with the drug venetoclax. We have already tested in patients either drug alone, and found that both have some efficacy and each one has its distinct limitations. By combining them for a short period of time, we aim to develop an overall more effective treatment. Importantly, this approach is designed with patients in mind to also preserve their quality of life and lessen treatment-related social disruption.