Immunotherapy for gliomas: from checkpoint blockade to vaccines, cellular therapy, local immune engineering and combinations

Purpose of review Immunotherapy has transformed the treatment of many malignancies but has not yet produced comparable improvements in survival for patients with gliomas. This review examines the biological rationale for immunotherapy across molecularly defined gliomas, lessons from unsuccessful immune checkpoint inhibitor trials, and emerging strategies including vaccines, adoptive cellular therapies, bispecific T-cell engagers, immunocytokines, innate immune modulators, oncolytic viruses, and approaches to improve delivery within the central nervous system. Recent findings Randomized studies have established that programmed death-1 (PD-1) blockade alone is insufficient for unselected patients with glioblastoma. Treatment resistance reflects multiple interacting barriers, including low and heterogeneous antigen expression, limited T-cell infiltration, T-cell dysfunction, immunosuppressive myeloid populations, corticosteroid exposure, and treatment-associated lymphopenia. Importantly, these features differ across glioma subtypes. Recent studies demonstrate that vaccines directed against clonal IDH1 and H3K27M mutations can generate durable antigen-specific immunity, while locoregionally delivered chimeric antigen receptor T (CAR-T) cells targeting IL13Rα2, EGFR/EGFRvIII, GD2, and B7-H3 can produce rapid and occasionally durable tumor regression. Oncolytic viruses and immunocytokines provide complementary approaches to remodeling the glioma microenvironment. Summary The principal challenge in glioma immunotherapy is no longer demonstrating that immune cells can recognize and kill glioma cells but converting immune recognition into durable tumor control. Future progress will likely depend on matching therapy to molecular subtype, targeting multiple or clonal antigens, optimizing immune-cell trafficking and persistence, modifying the suppressive microenvironment, and longitudinally monitoring tumor and immune evolution.