# Epigenetic Programming of T Cells for Enhanced Cellular Immunotherapy

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $556,711

## Abstract

ABSTRACT
By harnessing the power of the immune system to attack cancer cells, adoptive T cell therapy (ACT) holds
tremendous potential to overcome the limitations of traditional cancer therapies and provide more effective and
personalized treatment options for patients. However, the effectiveness of ACT is hindered by T cell exhaustion
and the depletion of stem cell memory T cells (TSCM), highlighting the need to improve T cell phenotypes. In
several ACT trials, positive responses were closely linked with specific transcriptomic and epigenetic profiles of
CD8 T cell subsets in the manufactured T cell product. Epigenetic reprogramming of exhausted cells has been
widely postulated as a promising strategy to improve ACT, but we currently lack the knowledge of which genes
and epigenetic programs to manipulate. Our long-term goal is to improve cancer treatment outcomes through
epigenetic programming of immune cells. To accomplish this goal, we have assembled an experienced and
multidisciplinary team with the relevant expertise to address the critical technological challenges and develop
next-generation ACT. The overall objective of this project is to translate epigenome editing technologies to
enable next-generation ACT through the programming of critical epigenetic nodes that govern complex T cell
phenotypes. The central hypothesis is that discovery and targeted perturbation of critical epigenetic nodes can
improve T cell function and tumor control. We will accomplish our objective by 1) prioritizing lead targets via high-
throughput epigenetic perturbation of primary human T cells, 2) identifying key transcription factors and
noncoding regulatory regions driving T cell exhaustion, and 3) investigating the combined effect of master
regulatory factors in complex T cell phenotypes. This proposal is innovative because it translates recent
developments in epigenome editing technologies and high-throughput targeted epigenetic screening to develop
precision interventions that address a fundamental limitation of effective ACT. Collectively, this work will establish
a framework for epigenetic engineering in primary human T cells, providing insights into T cell regulation and
advancing the development of an enhanced ACT platform.

## Key facts

- **NIH application ID:** 10859981
- **Project number:** 1R01CA289574-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Charles A. Gersbach
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $556,711
- **Award type:** 1
- **Project period:** 2024-05-03 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10859981

## Citation

> US National Institutes of Health, RePORTER application 10859981, Epigenetic Programming of T Cells for Enhanced Cellular Immunotherapy (1R01CA289574-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10859981. Licensed CC0.

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