Mitochondrial Metabolism in CAR T-Cells​

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Elad Jacoby, Sheba Medical Center

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The need to improve CAR T-cells is essential in current products, and even more when targeting solid tumors or tumors in the CNS, in which the metabolic environment is different. We and others have previously shown that CD19 CAR-T cell products with high mitochondrial activity are associated with improved outcome. There are several options to enhance mitochondrial function, of which we will discuss three. Initially, through the change of the carbon source in the media we show a shift of cellular metabolism toward the mitochondria, as demonstrated in mitochondrial functional studies, metabolomics and transcriptomics. This results in improved in vitro and in vivo tumor killing, independently of memory and exhaustion profiles. Next we show an interplay between signaling domains and mitochondrial function in CAR T-cells. Finally, we use unique murine models which have a joint nuclear background but different mtDNA sequence and subsequent mitochondrial function. Preliminary data show that these changes lead to difference in T-cell function and anti tumor effects. Altogether, mitochondrial manipulation is an opportunity to impact CAR T-cell function for future clinical use.