# Vaccine therapy for pediatric high-grade glioma: current landscape, challenges, and future directions

## TL;DR

This review explores vaccine-based immunotherapy as a potential treatment for aggressive childhood brain tumors called high-grade gliomas, highlighting current strategies, challenges, and future directions.

## Contribution

The paper provides a comprehensive overview of vaccine therapy for pediatric high-grade gliomas, emphasizing novel antigen targets and clinical platforms.

## Key findings

- Vaccine therapies targeting glioma-associated antigens and neoantigens show safety and immunogenicity in early-phase trials.
- Challenges include the immunosuppressive tumor environment, low mutational burden, and logistical issues in vaccine production.
- Future directions involve optimizing antigen selection, combining therapies, and improving delivery systems for pediatric use.

## Abstract

Pediatric high-grade gliomas (pHGG) are among the most aggressive childhood brain tumors, with limited treatment options and poor prognosis. Vaccine-based immunotherapy offers a promising strategy by leveraging tumor-specific or associated antigens to stimulate durable anti-tumor immune responses with minimal toxicity.

This review outlines the scientific rationale for vaccine therapies in pHGG, detailing key targets such as glioma-associated antigens (EphA2, IL-13Rα2, survivin), driver mutation–derived neoantigens (H3.3K27M, TP53, IDH1), and viral antigens (CMV pp65). We evaluate current vaccine platforms, including peptide vaccines, dendritic cell vaccines, mRNA-based vaccines, and neoantigen-personalized approaches, highlighting early-phase clinical trial results that demonstrate safety and immunogenicity. Despite encouraging preliminary data, several challenges hinder clinical translation, including the distinct immune environment in the central nervous system, intratumoral heterogeneity, low mutational burden, immunosuppressive microenvironments, steroid use, and logistical hurdles in vaccine production and trial design. Future research must address these barriers through optimized antigen selection, combinatorial therapies, novel delivery systems, and pediatric-specific immune profiling.

With continued multidisciplinary collaboration, vaccine therapies may emerge as a meaningful addition to the therapeutic arsenal for children with pHGG.