Armored chimeric antigen receptor T-cell therapy targets antigen-heterogeneous glioma

Chimeric-antigen receptor (CAR)-T cell therapy has shown early promise against glioblastoma, which lacks effective treatment options. However, two key challenges curtail efficacy: tumor-antigen heterogeneity and an immunosuppressive tumor microenvironment. CAR-T cells engineered to secrete combinations of immunomodulatory proteins can reverse immune suppression and engage endogenous immunity. Through head-to-head in vivo comparisons of potentially synergistic armor combinations, we demonstrated that T cells expressing a CAR plus IL-12 and the decoy-resistant form of IL-18 (CAR-12.DR18 T cells) show strong efficacy against antigen-heterogeneous glioma in immunocompetent mice. Robust anti-tumor efficacy with effective toxicity mitigation was achieved via combined administration of CAR-12.DR18 T cells with CAR-T cells that secrete an anti-vascular endothelial growth factor (VEGF-A) single-chain variable fragment. This combination therapy presents a clinically applicable strategy to overcome key barriers to effective treatment of glioblastoma.