| Summary: | The metabolic milieu of solid tumors provides a barrier to chimeric antigen receptor (CAR) T-cell therapies. Excessive lactate or hypoxia suppresses T-cell growth, through mechanisms including NADH buildup and the depletion of oxidized metabolites. NADH is converted into NAD<sup>+</sup> by the enzyme <i>Lactobacillus brevis</i> NADH Oxidase (<i>LbNOX</i>), which mimics the oxidative function of the electron transport chain without generating ATP. Here we determine if <i>LbNOX</i> promotes human CAR T-cell metabolic activity and antitumor efficacy. CAR T-cells expressing <i>LbNOX</i> have enhanced oxygen as well as lactate consumption and increased pyruvate production. <i>LbNOX</i> renders CAR T-cells resilient to lactate dehydrogenase inhibition. But in vivo in a model of mesothelioma, CAR T-cell’s expressing <i>LbNOX</i> showed no increased antitumor efficacy over control CAR T-cells. We hypothesize that T cells in hostile environments face dual metabolic stressors of excessive NADH and insufficient ATP production. Accordingly, futile T-cell NADH oxidation by <i>LbNOX</i> is insufficient to promote tumor clearance.
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