Inhibition of GSK3beta leads to increased survival, proliferation and memory phenotype generation of GBM-specific CAR T cells (VAC5P.1125)

Abstract

Abstract Application of chimeric antigen receptors (CAR), where an antibody or ligand-binding domain is fused with the zeta signaling chain of the T cell receptor, is a novel and alternative strategy to bypass the failure of cytotoxic immune response induction by most tumor cells. Although CARs have shown impressive preclinical efficacy, translational success in solid tumors like glioblastoma (GBM) is often restricted by the limited viability of the T cells either due to the absence of IL2 in the central nervous system and/or because of mandated chemotherapy. Although multiple doses of T cell transfer and systemic administration of IL2 are effective for short time periods, unregulated overdose of T cells and IL2 result in immune toxicity. Inhibition of glycogen synthase kinase 3 beta (GSK3β) in GBM-specific IL13CAR T cells increased IL2-independent survival and proliferation of the CAR-positive T cells upon activation with IL13Rα2-expressing GBM tumor cells or soluble target antigen, when compared to bystander CAR-negative T cells or untreated IL13CAR T cells. GSK3β-inhibited IL13CAR T cells also showed increased IL7R and CD45RO expression compared to the bystanders as well as untreated IL13CAR T cells indicating a possible development of memory population. Exposure to target antigen increased cytotoxic efficacy and tumor-killing ability specifically in GSK3β-inhibited IL13CAR T cells. These observations suggest an innovative advancement in anti-GBM CAR T cell-mediated immunotherapy.