Tuesday, November 4, 2025 11/4/2025

LTBR CARs as next-generation therapies for R/R lymphoma

Award Number: R01CA279135
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/10/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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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 γδ 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 section. 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 cells 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $810,022 )
2025	2025	NEW YORK GENOME CENTER, INC.	101 AVENUE OF THE AMERICAS FL 7	NEW YORK	NY	10013	NEW YORK	USA	Cancer Treatment Research	000	3	4/3/2025	NON-COMPETING CONTINUATION	$729,020
2025	2025	NEW YORK GENOME CENTER, INC.	101 AVENUE OF THE AMERICAS FL 7	NEW YORK	NY	10013	NEW YORK	USA	Cancer Treatment Research	001	3	5/22/2025	NON-COMPETING CONTINUATION	$81,002
														Subtotal = $810,022

Issue Date FY: 2024 ( Subtotal = $762,975 )
2024	2024	NEW YORK GENOME CENTER, INC.	101 AVENUE OF THE AMERICAS FL 7	NEW YORK	NY	10013	NEW YORK	USA	Cancer Treatment Research	000	2	2/28/2024	NON-COMPETING CONTINUATION	$722,819
2024	2024	NEW YORK GENOME CENTER, INC.	101 AVENUE OF THE AMERICAS FL 7	NEW YORK	NY	10013	NEW YORK	USA	Cancer Treatment Research	001	2	4/18/2024	NON-COMPETING CONTINUATION	$40,156
														Subtotal = $762,975

Issue Date FY: 2023 ( Subtotal = $831,692 )
2023	2023	NEW YORK GENOME CENTER, INC.	101 AVE OF THE AMERICAS FL 7	NEW YORK	NY	10013	NEW YORK	USA	Cancer Treatment Research	001	1	8/15/2023	NEW	$0
2023	2023	NEW YORK GENOME CENTER, INC.	101 AVE OF THE AMERICAS FL 7	NEW YORK	NY	10013	NEW YORK	USA	Cancer Treatment Research	000	1	4/10/2023	NEW	$831,692
														Subtotal = $831,692

Grand Total All Awards = $2,404,689

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LTBR CARs as next-generation therapies for R/R lymphoma

Award Number: R01CA279135

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/10/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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