Pediatric high-grade glioma: moving toward subtype-specific multimodal therapy

Pediatric high-grade gliomas (pHGG) comprise a deadly, heterogenous category of pediatric gliomas with a clear need for more effective treatment options. Advances in high-throughput molecular techniques have enhanced molecular understanding of these tumors, but outcomes are still poor, and treatments beyond resection and radiation have not yet been clearly established as standard of care. In this review, we first discuss the history of treatment approaches to pHGG to this point. We then review four distinct categories of pHGG, including histone 3-mutant, IDH-mutant, histone 3/IDH-wildtype, and radiation-induced pHGG. We discuss the molecular understanding of each subgroup and targeted treatment options in development. Finally, we look at the development and current status of two novel approaches to pHGG as a whole: localized convection-enhanced chemotherapy delivery and immunotherapy, including checkpoint inhibitors, vaccine therapy, and CAR-T cells. Through this review, we demonstrate the potential for rational, molecularly driven, subtype-specific therapy to be used with other novel approaches in combinations that could meaningfully improve the prognosis in pHGG.