NIH grant: Targeting TOX-Imposed Epigenetic and Transcriptional Circuits to Restore T Cell Function in Cancer (1K08CA312446-01)

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NIH grant 1K08CA312446-01: Targeting TOX-Imposed Epigenetic and Transcriptional Circuits to Restore T Cell Function in Cancer
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Omar  Khan. Award: $237546.
Start: 2026-07-03T00:00:00.
PROJECT SUMMARY/ABSTRACT
T cell exhaustion remains a major barrier to effective cancer immunotherapy, particularly in solid tumors. Exhausted T cells acquire fixed transcriptional and epigenetic states that impair their ability to proliferate, persist, and eliminate tumor cells. Transcription factors, including TOX, are central enforcers of the transcriptional and epigenetic programs that define exhausted T cells, reshaping immune cell fitness under chronic antigen exposure. However, the molecular basis of TOX-driven exhaustion remains poorly defined, and there are no scalable tools to reprogram this cell state therapeutically.
The goal of this proposal is to overcome T cell exhaustion by combining mechanistic dissection of TOX-dependent regulatory networks with the design of programmable synthetic transcription factors (synTFs). The central hypothesis is that (1) TOX domains function through interactions with chromatin modulators that enforce exhaustion, and (2) synthetic transcription factors can be designed to rewire this circuitry and restore durable effector function in T cells.
Aim 1 will dissect the regulatory architecture of TOX-driven exhaustion using chromatin profiling and CRISPR-based perturbation to define TOX-bound cofactors in syngeneic models of chronic antigen exposure. Targeted domain mutagenesis of TOX will identify regions critical for protein-protein interactions, and selective disruption of these interfaces will be evaluated for their impact on T cell persistence and function in vivo. Murine tumor and infection models are essential for these studies, as they enable evaluation of exhausted T cell function within an intact immune system and microenvironment that cannot be replicated in vitro. 
Aim 2 will establish a synthetic biology framework to reprogram exhausted T cells using modular synTFs composed of DNA-binding domains fused to epigenetic effectors. We will validate lead synTFs in primary T cells and tumor models, and perform a pooled screen of 750 constructs to discover new synthetic regulators that enhance T cell resilience under chronic stimulation.
These studies will provide foundational mechanistic insights into TOX function and a new synthetic biology toolkit for rewiring T cell fate, and may inform next-generation adoptive T cell therapies for solid tumors resistant to checkpoint blockade or CAR-T treatment. To accomplish these goals, I have assembled a multidisciplinary mentorship team including Dr. Alex Marson (primary mentor), Dr. Matthew Krummel (co-mentor), and advisory members Drs. John Wherry, Brian Shy, Kole Roybal, and Arun Wiita. This training plan will prepare me to lead an independent research program that unites mechanistic immunology with synthetic biology, leveraging my clinical expertise to translate programmable transcriptional tools into T cell therapeutics.

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