CAR-T cell therapy for pediatric high grade gliomas: Opportunities, challenges, and future directions

Abstract

Pediatric gliomas account for approximately 30% of primary CNS tumors in children and range from low-grade pilocytic astrocytoma to aggressive diffuse midline gliomas. High-grade gliomas carry a 5-year survival below 20% despite maximal multimodal therapy, underscoring the need for innovative options. Chimeric antigen receptor T-cell (CAR-T) therapy enables tumor-specific targeting with potential for reduced systemic toxicity and increased survival. Preclinical studies targeting B7-H3, GD2, and HER2 have shown potent cytotoxicity and survival benefits in pediatric glioma models. Early-phase clinical trials of HER2-and GD2-CAR-T in children and adolescents demonstrate feasibility, manageable safety, and occasional radiographic responses, though durable remissions remain rare. Key barriers include antigen heterogeneity, immunosuppressive tumor microenvironment, blood brain barrier, therapy-related toxicities, and limited CAR-T persistence. Emerging strategies such as multi-antigen CAR designs, resistance engineering, locoregional or BBB-penetrant delivery, cytokine armoring, and rapid toxicity mitigation offer promise for overcoming these obstacles. Integrating these innovations into biomarker-driven, multicenter pediatric trials with robust correlative studies will be essential to validate efficacy and ensure safety in this vulnerable population.