Efficacy and safety of immunotherapy in pediatric malignant brain tumors: a systematic review and exploratory meta-analysis.
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BACKGROUND: Immunotherapy for pediatric brain tumors has expanded rapidly, yet its effects on survival and neurologic safety remain unclear. A systematic review and meta-analysis was conducted to quantify efficacy and toxicity across immunotherapy modalities. METHODS: Following PRISMA 2020 guidelines, prospective pediatric immunotherapy studies were identified. Random-effects meta-analyses were performed using vaccine-based immunotherapy as the reference. Primary endpoints were overall survival (OS) and 12-month overall survival (OS12); grade ≥3 neurotoxicity was the primary safety outcome. Meta-regression and sensitivity analyses explored modality-specific effects. RESULTS: Twenty studies were included. Median OS ranged from 3.6 months in heavily pretreated recurrent cohorts to 17.8 months in selected intratumoral oncolytic virus trials, while OS12 ranged from 8-13% to 75%. Compared with vaccines, non-vaccine immunotherapy did not improve OS (pooled HR 1.14, 95% CI 0.99-1.31; I² 43%) or OS12 (HR 1.13, 95% CI 0.95-1.34; I² 65%). Subgroup analyses showed comparable OS for CAR-T therapies (OS HR 1.09, 95% CI 0.89-1.34) and checkpoint/systemic therapies (OS HR 1.14, 95% CI 0.96-1.36), or oncolytic/viral therapies (OS HR 1.51, 95% CI 0.81-2.84). Severe neurotoxicity differed substantially by modality. No grade ≥3 neurotoxicity occurred in vaccine studies. In contrast, pooled non-vaccine therapies showed a markedly increased risk (OR 19.66, 95% CI 6.78-57.02; I² 60%). CAR-T therapies (OR 57.95, 95% CI 16.15-207.98) and oncolytic/viral approaches (OR 69.41, 95% CI 17.00-283.33) had the highest risk, whereas checkpoint/systemic therapy showed a lower, non-significant increase (OR 2.26, 95% CI 0.77-6.60). CONCLUSIONS: Across pediatric immunotherapy trials, survival outcomes were comparable to vaccine-based approaches, but neurotoxicity varied markedly by modality. Cellular and oncolytic therapies carry a substantial neurologic risk that must be balanced against uncertain survival benefit in future trial designs.