Biomarker-guided immunotherapies for primary CNS tumors

Refined immunotherapeutic modalities for the treatment of primary central nervous system (CNS) tumors - vaccines, virotherapies, immune checkpoint inhibitors, and cell therapies - are starting to show efficacy in selected patients with primary CNS tumors. Still most patients do not derive a meaningful clinical benefit, despite evidence of biological activity. While the unique immunosuppressive environment of the CNS, cellular heterogeneity and brain borders prohibiting access present substantial challenges for effective treatment, there is a need to define robust biomarkers for response to immunotherapies. As immunotherapies critically depend on multiple tumor intrinsic as well as host factors, this task is substantially more challenging than defining biomarkers for response to targeted therapies. Recent advances in biomarker identification and characterization for immunotherapies have opened new avenues for precision immunotherapy approaches. This review examines the current state of biomarker-guided immunotherapy for primary CNS tumors, focusing on key biomarkers including immunogenic antigens, HLA ligandomics, tumor immune microenvironment characteristics, cell-free DNA, tumor mutational burden, and T cell populations in tumor tissue, blood, and cerebrospinal fluid. We discuss how these biomarkers can guide the selection and optimization of immunotherapeutic strategies including cancer vaccines, T cell therapy, and immune checkpoint inhibitors particularly for glioblastoma, and highlight current challenges and future directions in the field.