Systemic versus intracranial immunotherapy delivery in pediatric malignant brain tumors: a systematic review,...

Immunotherapy has emerged as a promising strategy for pediatric high-grade gliomas and diffuse midline gliomas, yet the clinical impact of delivery route remains uncertain. This study evaluated whether intracranial or systemic administration influences survival and toxicity outcomes. A systematic review and meta-analysis were conducted according to PRISMA guidelines. Clinical studies reporting survival or toxicity outcomes of immunotherapy in pediatric brain tumors were identified. Random-effects models were used to pool hazard ratios (HRs) for overall survival (OS) and 12-month survival (OS12), and odds ratios (ORs) for grade ≥ 3 neurotoxicity. Meta-regression assessed the influence of delivery route. Twenty-two studies were included in the quantitative synthesis. Intracranial delivery showed a pooled HR for OS of 1.12 (95% CI 0.88-1.42) with moderate heterogeneity (I² = 27.3%), whereas systemic delivery showed HR 1.21 (95% CI 0.99-1.47) with minimal heterogeneity (I² = 1.1%). No significant difference between delivery routes was observed (ratio of HRs 0.93, 95% CI 0.67-1.29). For grade ≥ 3 neurotoxicity, intracranial administration demonstrated markedly higher risk (OR 73.80, 95% CI 41.50-131.20) compared with systemic therapy (OR 6.20, 95% CI 1.80-20.90). Meta-regression confirmed that delivery route was not associated with OS or OS12 but was significantly associated with increased neurotoxicity (β = 3.064, p < 0.001).

Immunotherapy delivery route does not appear to influence survival outcomes. Although intracranial administration was associated with higher reported rates of severe neurotoxicity, this finding should be interpreted cautiously given the heterogeneity of immunotherapy platforms and the potential confounding effect of treatment modality. Future studies should prioritize biologically guided therapeutic strategies while carefully balancing locoregional exposure and safety.

• Locoregional (intracranial) immunotherapy has been proposed to improve CNS drug delivery in pediatric high-grade and diffuse midline gliomas, but its benefit over systemic administration is unproven. • Early-phase trials show biological activity with heterogeneous survival and toxicity, leaving the clinical impact of delivery route uncertain.

• Across 22 studies, immunotherapy delivery route was not associated with overall or 12-month survival (rHR 0.93 and 0.87, both non-significant). • Intracranial delivery carried markedly higher severe neurotoxicity, but meta-regression showed this was largely driven by treatment platform (CAR-T/oncolytic) rather than route itself.