# Metabolically improving the generation, function, and persistence of therapeutic T cells for the treatment of cancer

> **NIH NIH F31** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $46,752

## Abstract

Project Summary
Immunotherapy has shifted the paradigm in the understanding and treatment of cancer. Within this arsenal of
new treatment strategies, adoptive cell therapy (ACT) has shown great promise; however, several barriers to
efficacy remain. One major hurdle is the high metabolic requirements of T cell anti-tumor cytoxicity within the
nutrient-poor tumor microenvironment (TME). Current culturing strategies used to generate high numbers of T
cells in vitro exacerbate this problem by using hyperglycemic and hyperoxic culture conditions. This strategy
favors the metabolic needs of T cells during expansion but ignores their metabolic requirements for persistence
within the TME. Our preliminary data indicate that treatment with the pyruvate dehydrogenase kinase 1 (PDHK1)
inhibitor dichloroacetate (DCA) during in vitro expansion of therapeutic T cells maintains therapeutic T cell
proliferation while improving anti-tumor clearance in vivo. Intriguingly, transcriptomic analysis of DCA-treated T
cells reveals a downregulation of interferon-stimulated genes (ISGs) seen in response to mitochondrial DNA
(mtDNA) damage. We hypothesize that DCA shunts glycolysis in a manner that re-directs metabolism to
a more oxidative state and thus prevents T cell mitochondrial stress and mtDNA releases during initial
expansion allowing for more fit T cells pre-infusion. Within this study, we aim to determine how DCA’s
metabolic effects and abrogation of ISGs contribute to improved anti-tumor efficacy. Determining the mechanism
of action of DCA on therapeutic T cells will not only inform the field of the benefits of using DCA as an in vitro
culture supplement for the generation of more efficacious therapeutic T cells, but will also allow for a better
understanding of the biological requirements for T cell function overall.

## Key facts

- **NIH application ID:** 10348167
- **Project number:** 5F31CA257760-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Andrew Frisch
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 5
- **Project period:** 2021-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10348167

## Citation

> US National Institutes of Health, RePORTER application 10348167, Metabolically improving the generation, function, and persistence of therapeutic T cells for the treatment of cancer (5F31CA257760-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10348167. Licensed CC0.

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