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

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.