Immunotherapy in central nervous system tumors

Immunotherapy has revolutionized cancer treatment across multiple solid and hematological malignancies, yet its impact on central nervous system (CNS) tumors remains limited. The biological characteristics of these tumors, including low immunogenicity, highly immunosuppressive tumor microenvironment, and blood-brain barrier, hinder the efficacy of immunotherapeutic strategies. In glioblastoma, the most common malignant primary CNS tumor, immune checkpoint inhibitors have failed to demonstrate survival benefit in phase III trials (CheckMate-498, CheckMate-548, CheckMate-143, NRG BN007). Neoadjuvant anti-PD-1 administration initially showed promising signals, though recent studies did not confirm these findings. CAR-T therapies targeting IL-13Rα2, EGFRvIII, and HER2 have demonstrated safety and transient radiographic responses, limited by antigenic escape and tumor heterogeneity. Therapeutic vaccines, including DCVax-L and personalized neoantigen vaccines, have shown signals of biological activity without definitive phase III benefit. Oncolytic viruses such as G47Δ (conditionally approved in Japan) and PVSRIPO have demonstrated prolonged survival in patient subsets. In IDH-mutant gliomas 2-hydroxyglutarate-mediated immunosuppression limits checkpoint inhibitor efficacy, although vaccines targeting IDH1-R132H have shown 89% immunogenicity. In primary CNS lymphoma, anti-CD19 CAR-T cells achieve 56% complete response rates. In medulloblastoma and ependymoma, research remains in preclinical phases. The future requires combinatorial strategies, patient selection through molecular and immunological biomarkers, and innovative delivery approaches to overcome current barriers and translate experimental advances into meaningful clinical benefits for patients with CNS malignancies.