# Enhancing CAR T cell fitness using novel epigenetic reprogramming factors

> **NIH NIH DP2** · CHILDREN'S HOSP OF PHILADELPHIA · 2024 · $1,602,000

## Abstract

PROJECT SUMMARY/ABSTRACT
 Chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable clinical responses in
patients with B cell malignancies. However, approximately 50% of treated patients do not exhibit durable
responses and CAR T cells for solid tumors have been largely ineffective. Poor T cell fitness, whereby T cells
lose the ability to expand, persist, and mediate antitumor responses, is a major barrier to progress for the
development improved CAR T cell therapies. Emerging research suggests poor fitness is associated with
epigenetic changes that lock T cells into a dysfunctional state, and further, that epigenetic reprogramming is
mechanistically important for overcoming poor fitness. This presents a unique challenge since existing
epigenome engineering approaches 1) are associated with technical hurdles that limit feasibility and
translatability, and 2) are either non-specific (e.g., epigenetic drugs that induce global chromatin remodeling) or
exceedingly specific (e.g., dCas9-based methods that target 1 or a few genes) and are therefore suboptimal for
inducing the extensive but pathway-specific epigenetic changes associated with changes in fitness. The goal of
this proposal is to develop and optimize a new class of epigenetic reprogramming factors (ERFs) which can
target hundreds, thousands, or tens of thousands of DNA regions in a pathway-specific manner. The ERF
platform is modular and fully programmable, thereby enabling fine-tuning of the specificity, strength, and
durability of epigenetic marks. We will leverage this technology to target T cell exhaustion and aging-associated
dysfunction, which are characterized by stable epigenetic marks that limit T cell responsiveness. ERFs will be
designed to prevent or reverse epigenetic signatures that manifest during exhaustion and aging, thereby
augmenting CAR T cell fitness and antitumor function. The proposed work will advance the state-of-the-art in T
cell reprogramming and provide a powerful approach to enhance CAR T cell potency for liquid and solid tumors.
In addition to their translational potential, ERFs can also function as molecular tools to interrogate transcription
factor biology, gene expression programs, and epigenetics, and therefore have important implications for basic
human T cell biology. Ultimately, we envision an ERF toolkit whereby combinations of ERFs can be tailored to
enhance T cell fitness in a patient- or disease-specific manner. Since chromatin remodeling underpins cellular
reprogramming in other cell types and disease settings, we predict that ERFs will be broadly applicable to other
therapeutic modalities and represent a paradigm shift in the growing field of epigenome engineering.

## Key facts

- **NIH application ID:** 10910386
- **Project number:** 1DP2CA301078-01
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Evan William Weber
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,602,000
- **Award type:** 1
- **Project period:** 2024-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10910386

## Citation

> US National Institutes of Health, RePORTER application 10910386, Enhancing CAR T cell fitness using novel epigenetic reprogramming factors (1DP2CA301078-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10910386. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*