Abstract 904: Optimizing CAR T therapy via metabolic engineering for the treatment of glioblastoma

Abstract Glioblastoma represent a great challenge and current therapies are negligibly effective, with disease recurrence being inevitable. T cell therapy has emerged as a viable treatment for brain malignancies. While promising, the efficacy of this approach is often limited by a complex immunosuppressive tumor microenvironment. These complexities mean that more sophisticated T cell products are required. The brain tumor microenvironment provides local restraints via metabolic competition suppressing antitumor immunity, specifically inhibiting infiltration and effector functions of host and adoptively transferred tumor-reactive T cells. The objective of this project is to test new treatments to reverse immune dysfunction in brain cancer through the regulation of T cell metabolic signaling. We propose that modulating glucose signaling can potentiate T cell anti-tumor activity. The glucose signaling pathway of T cells was modulated through overexpression of glucose transporters and the function of metabolically modified T cells was investigated using murine and human models. We revealed a competition for glucose between T cells and tumor cells, with tumor cells imposing glucose restriction mediating T cell hyporesponsiveness. Overexpression of glucose transporters such as Glut1 and Glut3 enhanced T cell glucose utilization and provided a survival/growth advantage and greater activation, specifically in glucose-restricted conditions. We established that glucose transporter overexpression improves intratumoral infiltration and expansion of adoptively transferred CAR T cells, resulting in improved survival. Our study integrates fundamental concepts of tumor and immune metabolism in the design of immunotherapy and confirms that immunometabolism represents a viable target for new cancer therapy to treat brain tumors. Citation Format: Tanya Ghosh, Avirup Chakraborty, Linchun Jin, Diana Feier, Aryeh Silver, Maryam Rahman, Catherine Flores, Matthew Sarkisian, Jianping Huang, Duane A. Mitchell, Loic P. Deleyrolle. Optimizing CAR T therapy via metabolic engineering for the treatment of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 904.