Abstract 583: Improving anti-tumor response by increasing mitochondrial respiration of T-cell

Abstract

Abstract Chimeric antigen receptor (CAR)-T cell therapy is revolutionary as a promising approach of cancer immunotherapy against lymphoblastic leukemia and lymphoma. While initially effective in up to 90% of patients with B-cell lymphoblastic leukemia, over 40% of patients will relapse, with sub-optimal persistence of functional CAR-T cells underlying many of these relapses. The major challenges of CAR-T cell to effectively eliminate cancer cells are extending persistence of CAR-T cells and retaining the effector function of CAR-T cells in vivo after prolonged in vitro expansion. To overcome such limitations, enhancing mitochondrial metabolism is emerging as an appealing approach to regulate CAR-T cell function, however, increasing mitochondrial respiration and ATP production is a challenging strategy. We have previously identified MCJ/DnaJC15 as an endogenous negative regulator of Complex I of electron transport chain. The absence of MCJ in CD8 cells (MCJ KO CD8 cells) increases Complex I activity, mitochondrial membrane potential, and mitochondrial respiration without affecting glycolysis. Lack of MCJ enhances cytokine secretion and cytotoxicity (two processes dependent on mitochondrial ATP) in CD8 cells in vitro and in vivo. Using the B16 melanoma cell model, we have shown that antigen-specific MCJ KO CD8 cells are superior in killing melanoma cells in vitro and in vivo. We have generated WT and MCJ KO CD19-41BB CAR-T cells and tested their anti-tumor activity against B-cell leukemia. The results reveal that MCJ-deficient CAR-T cells exhibit superior killing capacity against leukemia B cells and prolong survival of the leukemia-bearing mice. Together, these data demonstrate MCJ as an attractive target to enhance CAR-T cell therapy efficacy. Citation Format: Meng-Han Wu, Emily Giddlings, Catherine Danis, Megan McCalab, Mark Eric Kohler, Mercedes Rincon. Improving anti-tumor response by increasing mitochondrial respiration of T-cell [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 583.