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

> **NIH NIH R01** · NEW YORK GENOME CENTER · 2024 · $762,975

## Abstract

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.

## Key facts

- **NIH application ID:** 10825597
- **Project number:** 5R01CA279135-02
- **Recipient organization:** NEW YORK GENOME CENTER
- **Principal Investigator:** Catherine Sibyl Diefenbach
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $762,975
- **Award type:** 5
- **Project period:** 2023-04-10 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10825597

## Citation

> US National Institutes of Health, RePORTER application 10825597, LTBR CARs as next-generation therapies for R/R lymphoma (5R01CA279135-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10825597. Licensed CC0.

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