IMMU-21. OVEREXPRESSING CAR T-CELL GLUCOSE TRANSPORTER TO ENHANCE ANTI-TUMOR ACTIVITY IN GLIOBLASTOMA

Abstract INTRODUCTION Despite aggressive interventions, Glioblastoma (GBM) remains as a challenge for neuro-oncologists. Standard treatments are often followed by disease recurrence. Adoptive cell therapies have emerged as a viable therapeutic for brain malignancies. CAR-T cell therapy has generated substantial interest because of its efficacy and specificity in treating various cancers. Despite these efficacies, studies reveal limitations of CAR-T therapy due to the altered metabolic environment in GBM. GBM tumors shift towards aerobic glycolysis, regardless of oxygen availability leading to massive glucose consumption. This results in impeding T-cell glycolysis and activation. OBJECTIVE The GBM microenvironment provides local restraints via metabolic competition suppressing antitumor immunity, specifically inhibiting infiltration and tumoricidal functions of host and adoptively transferred tumor-reactive T-cells. In our study, we manipulated the metabolic fitness of the therapeutic T-cells to enhance their tumoricidal activity, by overexpressing glucose transporter GLUT1 and GLUT3. We show that this manipulation can enhance their anti-tumor activity. METHODS The T-cell glucose metabolic pathway was modulated via glucose transporter overexpression. The functionality of metabolically modified T-cells was investigated in murine and human models. RESULTS We demonstrated that tumor cells impose glucose restriction when competing for glucose with T-cells leading to T-cell hypo responsiveness. Overexpression of glucose transporters such as Glut1 and Glut3 increased T-cell glucose utilization and provide survival advantage leading to enhanced T-cell activation in glucose-restricted conditions. The metabolic modifications regulate T-cell efficacy by enhancing intra-tumoral trafficking. We tested this approach in the context of CD70CAR T cell therapy. It was established that glucose transporter overexpression in CD70 CAR T-cells not only improves intracranial tumor invasion but also elicit functional anti-tumor cell response thus improving survival. CONCLUSIONS This 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.