Immune checkpoint inhibitors in children with replication-repair-deficient high-grade gliomas. The South London Paediatric & TYA Neuro-Oncology Network experience

Purpose High-grade gliomas (HGG) are the most common intracranial tumors in children with replication repair deficiency (RRD) syndromes. Defective DNA repair leads to a high mutational burden, providing biological rationale for immune checkpoint inhibitors (ICI). However, responses to ICI are heterogeneous, and resistance mechanisms remain poorly understood. We report on the experience of the Paediatric & TYA Neuro-Oncology South London Network (SLN) and collaborators on the safety and efficacy of ICI in RRD-HGG. Methods Clinical, histopathological, molecular, and survival data were collected from children with molecularly confirmed RRD-HGG treated with ICI at SLN between 2019–2023. Descriptive statistics were used for demographics. Survival outcomes were analyzed using Kaplan-Meier estimates and univariable Cox proportional hazards models. Results Six patients were identified (Lynch syndrome n = 4,constitutional mismatch repair deficiency n = 2). Median age 9.6 years (range 2.74–11.02). ICI was administered upfront, at relapse, or at both stages (n = 2 each). No grade 4–5 toxicities were observed. Two patients treated upfront achieved sustained responses of 14 and 26.5 months, with one remaining in complete remission at last follow-up. Median progression-free survival from first ICI exposure was 4.1 months (95% CI 0.13–8.06; range 0.6–26.5), and median overall survival was 11.1 months (95% CI 10.06–12.14; range 10.2–35.3). Conclusions ICI use in RRD-HGG is biologically justified, but optimal agents, combinations, and predictive biomarkers need yet to be fully determined. Given the rarity of RRD-HGG, international collaborations, such as the International Replication Repair Deficiency Consortium (IRRDC), are essential to advance treatment strategies for these patients.