{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T05:02:08Z","timestamp":1784869328759,"version":"3.55.0"},"reference-count":20,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Pediatric brain tumors are the leading cause of cancer-related mortality in children, and current standard therapies like surgery, radiotherapy, and chemotherapy offer limited survival benefits and significant long-term morbidity. Chimeric antigen receptor (CAR) T-cell therapy is a transformative treatment for hematologic malignancies and is now being explored for pediatric brain tumors. This review summarizes the latest advances, preclinical and clinical findings, challenges of CAR T-cell therapy, and future directions in pediatric neuro-oncology. 18 studies that met the eligibility criteria were selected, consisting of preclinical models, early-phase clinical trials, and translational studies. A registry search of central nervous system (CNS) tumor trials from Clinicaltrials.gov, ISRCTN, and ANZCTR identified 12 active or completed interventional trials of CAR T-cell therapy in patients with CNS tumors, their eligibility criteria and parameters were compared. Preclinical studies consistently demonstrate that CAR T-cells targeting antigens such as B7-H3, GD2, HER2, IL13R\u03b12, and EphA2 can induce robust and specific tumor regression in models of medulloblastoma, diffuse intrinsic pontine glioma (DIPG), ependymoma, and high-grade gliomas. On the other hand, B7-H3 is a pan-pediatric target due to its high expression in multiple CNS tumors, including medulloblastoma, ependymoma, and glioma, whereas GD2 is highly relevant for H3K27M-mutant diffuse midline gliomas. Early-phase clinical trials confirm that CAR T-cells can traffic to CNS tumors, infiltrate tumor tissue, and mediate tumor regression. The ICV B7-H3 phase 1 trial in DIPG achieved noteworthy results, with a median survival of 19.8 months across 21 patients and 3 patients surviving more than 40 months. GD2-CAR T-cell therapy in H3K27 M-mutant gliomas showed partial clinical responses, with neurotoxicity and encephalopathy observed, whereas the HER2-targeted locoregional therapy showed no dose-limiting toxicities. Future interventions such as multi-antigen targeting, combinatorial CAR designs, and enhanced cytokine signaling are being developed to improve efficacy and safety. A comparison of 12 registered pediatric CAR T-cell trials showed heterogeneity in eligibility criteria, including age ranges, performance status thresholds, H3K27M mutation requirements, and geographic concentration bias. CAR T-cell therapy holds significant promise for improving outcomes in pediatric brain tumors, but its clinical translation is challenged by tumor heterogeneity, antigen escape, neurotoxicity, and the immunosuppressive tumor microenvironment.<\/jats:p>","DOI":"10.3389\/fonc.2026.1869826","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T04:23:00Z","timestamp":1784866980000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["CAR T-cell therapy in pediatric brain tumors: a narrative review with comparative analysis of clinical trial eligibility criteria"],"prefix":"10.3389","volume":"16","author":[{"given":"Akshaya","family":"Srinivasan","sequence":"first","affiliation":[{"name":"Tbilisi State Medical University","place":["Tbilisi, 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