Inhibition of glycogen synthase kinase 3 beta promotes long term cytokine-free survival of chimeric antigen receptor-expressing T cells (VAC11P.1008)

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 (TCR), is a novel and alternative strategy to bypass the failure of cytotoxic immune response induction by most tumor cells. The resulting CAR+ T cells are redirected by the neo-specificity to attack tumors expressing the surface antigen or receptors recog¬nized by the gene-modified TCRs. Although CARs have shown impressive preclinical efficacy, translational success is restricted due to the limited viability of the T cells in absence of IL2 consequent to preconditioning 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. In this study we have identified that inhibition of glycogen synthase kinase 3 beta (GSK3β) maintained increased survival of the CAR+ T cells in the absence of IL2, upon activation with target-specific tumor cells. Increased CAR+ T cell proliferation was observed upon GSK3β-inhibition in comparison to non-treated CAR+ T cells. GSK3β-inhibited CAR+ T cells also showed increased CD127 (IL7R) expression compared to the bystanders as well as non-treated CAR+ T cells indicating a possible development of memory population. This is a fundamental progress towards the development of a cancer immunotherapy strategy that will avoid the complications arising from IL2-toxicity.