A cross-talk established by tumor-targeted cytokines rescues CAR T cell activity and engages host T cells against glioblastoma in mice

Chimeric antigen receptor (CAR) T cells have shown limited efficacy against solid tumors because of poor tissue penetration, constrained activity, and early exhaustion due to the immunosuppressive tumor microenvironment (TME). Although stimulatory cytokines can counteract immune suppression, their systemic administration entails risk of toxicities and counter-regulatory responses. Here, we leveraged a population of tumor-associated TIE2-expressing macrophages (TEMs) to release interferon-α (IFN-α) and/or orthogonal interleukin-2 (oIL2) at the tumor site. Targeted cytokine delivery rescued CAR T cell functionality against the clinically relevant tumor antigen B7-homolog 3 (B7-H3) in an orthotopic, CAR T cell–refractory, immunocompetent mouse model of glioblastoma (GBM) named mGB2 that recapitulates pathological features of the human disease. Immunophenotypic and transcriptomic analyses revealed that inhibition of premature terminal exhaustion and induction of effector and memory states featuring activation of signaling pathways and transcriptional networks putatively boosted CAR T cell antitumor activity. Furthermore, IFN-α, especially when combined with private oIL2 signaling to CAR T cells, elicited potent endogenous T cell responses against multiple tumor-associated antigens, leading to delayed GBM growth and prolonged mouse survival even with tumors expressing B7-H3 in only a fraction of cells. These data suggest that the combination of TEM-based cytokine delivery and CAR T cells may have synergistic effects and support the further study of this approach for the treatment of patients with GBM.