Research we fund

I focus on developing bispecific antibodies (BsAb) for the treatment of B-cell non-Hodgkin lymphoma (B-NHL). We are testing chemo-free epcoritamab or mosunetuzumab combinations in follicular lymphoma, incorporating glofitamab or epcoritamab in the treatment of aggressive lymphomas, studying resistance mechanisms in patient samples from our trials, analyzing our experience to increase BsAb safety. Our goal is to leverage BsAb to improve upon current standards and shift B-NHL treatment paradigms.

The overall focus of my research is improving outcomes with immunotherapy in multiple myeloma.  I will accomplish this through 1) novel clinical trials of bispecific antibodies and CAR-T therapy; 2) outcomes research including real world evidence and patient reported outcomes to understand the safety, efficacy and areas of unmet need with standard of care immunotherapy; and 3) correlative studies focused on understanding factors impacting the efficacy and toxicity of these therapies.

My group studies the mechanisms of relapse and toxicity after chimeric antigen receptor T cell (CART) immunotherapy to rationally design innovative next-generation immunotherapies for relapsed/refractory lymphomas. To achieve this goal, we use patient-derived samples, cutting-edge technologies, and translational models. The ultimate objective of my research is to establish novel clinical strategies to overcome relapses and improve the safety of our patients.

We investigate the biology, genetics and treatment of myeloid malignancies, including CHIP, MDS and AML. Our goal is to improve our understanding of the effect of chromatin organization on hematopoietic stem cell transformation in the context of mutations in cohesin genes and other recurrently mutated epigenetic modulators. We employ a combination of genomic, mouse modeling, biochemistry and molecular biology approaches to answer disease relevant questions to identify novel therapeutic targets.

Hematopoiesis is tightly regulated by intrinsic and extrinsic signals, alterations of which can affect hematopoietic stem cell (HSC) function and lead to leukemia. We will employ novel preclinical mouse models to investigate the mechanisms that promote leukemogenesis, with the focus on interplay between DNA damage and immune response; stem cell-niche interaction; aging; oncogenic stress-induced complex formation; thereby develop new approaches to improve HSC function and for leukemia therapy.

AML recurrence is a devastating event after allo-HCT. I hypothesize that it could be counteracted through targeting of leukemia-restricted mHAgs via TCR-like CARs. I will identify scFVs recognizing mHAg:HLA complexes using a cell-free nanobody screening platform, and test the anti-leukemia activity and safety of CAR-Ts bearing such scFVs in vitro and in vivo. Through this approach, I will build a library of CAR constructs able to provide population-scale coverage for at-risk allo-HCT patients.

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.

Richter’s syndrome (RS) is a critical complication of chronic lymphocytic leukemia. RS patients are refractory to most existing therapies and show a median survival of ~12 months. I aim to dissect the function of a frequently mutated gene in RS (i.e., MGA) through cutting-edge single-cell analyses of patient samples and mouse models. The objective of these studies is to understand transformation biology, unravel novel therapeutic vulnerabilities, and provide the basis for personalized therapy.

Based on our preliminary data, we hypothesize that IRAK4 inhibition leads to LSPC reprogramming in MDS and AML. Aim 1 will evaluate the mechanism by which IRAK4 inhibition leads to LSPC reprogramming in cell lines, mice, and PDX samples. Aim 2 will concentrate on understanding of how IRAK4 inhibition creates synthetic lethal dependencies with the CELMoD CC-885 and how neosubstrates of CC-885 mediate the synergy upon IRAK4 inhibition in leukemic cells.

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.