R01CA279135

Ltbr Cars as Next-Generation Therapies for R/R Lymphoma - Project Summary

Up to 50% of patients with diffuse large B-cell lymphoma (DLBCL) relapse after first-line treatment. Chimeric antigen receptor (CAR) T-cells have recently emerged as a curative therapy for relapsed or refractory (R/R) DLBCL. However, only 35% of R/R DLBCL patients treated with CAR T-cells have a durable response, and survival is measured in months for patients who fail to benefit.

Improvements in CAR T-cells are urgently required to improve outcomes. Recently, we identified the cell surface lymphotoxin beta receptor (LTBR) as a positive T-cell regulator that enhances CD19 CAR T-cell efficacy in vitro and in vivo. LTBR is typically expressed in a subset of myeloid cells but absent in lymphocytes; however, when expressed in T-cells, LTBR induces proinflammatory cytokine release and improves antigen-specific CAR T- and D T-cell responses with no appreciable off-target toxicity.

Based on these observations, we hypothesize that LTBR can effectively potentiate anti-tumor activity in R/R lymphoma T-cells, reducing markers of T cell exhaustion and outperforming current FDA-approved CAR-Ts across R/R DLBCL subtypes.

In Aim 1, we characterize differences in expression of T-cell differentiation, activation, and exhaustion markers and myeloid populations in 25 treatment-naive and 25 R/R DLBCL patient samples. To understand if LTBR can similarly improve CAR-T response in the R/R context, we will use single-cell profiling and functional assays to test autologous CD19+ cell killing, with and without LTBR.

In Aim 2, we will evaluate the impact of DLBCL subtype on CAR T-cell activity by introducing LTBR and CAR T-cells into mice xenotransplanted with multiple germinal center B-cell (GCB) and activated B-cell (ABC) cell lines. Since T-cell activation and kinetics are further influenced by patient tumor burden, we will also investigate the efficacy of LTBR-CAR T-cell therapy in a high tumor burden context and test for durable immune memory after complete tumor regression.

Recently, by fusing the intracellular signaling domain of LBTR directly to existing (CD28 and 4-1BB) CARs, we have developed a novel CAR construct with more potent antitumor response. In Aim 3, using comprehensive scanning mutagenesis of the LTBR domain, we will create a library of CAR variants and test their ability to improve tumor killing, resistance to exhaustion, and cytokine secretion. We will also measure changes in T-to-B cell immune synapses and resistance to immunosuppression by myeloid-derived suppressor cells (MDSCs) in the most promising LTBR-CARs.

This project is the first to comprehensively characterize T cell states in treatment-naive and R/R DLBCL and evaluate LTBR as a T-cell activating strategy to maximize intrinsic anti-tumor activity in R/R DLBCL. There is substantial potential for our work to serve as a bridge from laboratory studies to clinical trials and to help the 40,000 patients per year with R/R DLBCL and other B-cell NHLs.

New York Genome Center

TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH. RESEARCH IS SUPPORTED IN THE DISCOVERY, DEVELOPMENT, AND CLINICAL TESTING OF ALL MODES OF THERAPY INCLUDING: SURGERY, RADIOTHERAPY, CHEMOTHERAPY, AND BIOLOGICAL THERAPY INCLUDING MOLECULARLY TARGETED THERAPIES, BOTH INDIVIDUALLY AND IN COMBINATION. IN ADDITION, RESEARCH IS CARRIED OUT IN AREAS OF NUTRITIONAL SUPPORT, STEM CELL AND BONE MARROW TRANSPLANTATION, IMAGE GUIDED THERAPIES AND STUDIES TO REDUCE TOXICITY OF CYTOTOXIC THERAPIES, AND OTHER METHODS OF SUPPORTIVE CARE THAT MAY SUPPLEMENT AND ENHANCE PRIMARY TREATMENT. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM; TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.395 - Cancer Treatment Research

National Cancer Institute (NCI) [HHS - NIH]

New York, New York 100131933 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 288% from $831,692 to $3,223,949.