Modulating T Cell Metabolism to Improve CAR-T Cell Therapy success

Abstract Chimeric antigen receptor (CAR)-T cell therapy is a promising treatment for lymphoblastic leukemia and lymphoma. Despite initial response to CAR-T therapy, about 40% of patients relapse. Modulating metabolism (immunometabolism) being considering as novel approach improve efficacy. We have identified MCJ (DnaJC15) target enhance mitochondrial metabolism. an endogenous negative regulator Complex I electron transport chain. The absence in KO CD8 cells increases activity, membrane potential, respiration without affecting glycolysis or ROS production. Lack also enhances ATP-dependent effector functions cells, including cytokine secretion cytotoxicity. Using the B16 melanoma model, we shown that antigen-specific are superior eliminating through enhanced function vitro vivo. Importantly, generated MCJ-deficient against CD19+ B they exhibit killing capacity their increase cytotoxicity activity vitro. higher maximal spare respiratory capacity. Furthermore, vivo efficacy than WT overall survival leukemia-bearing mice. Together, these data demonstrate To show translational relevance our studies moving forward clinic, currently investigating whether silencing human R21 AI110016 AI149187 R56 AI148434 R01 CA260909 CA223389