Chimeric Antigen Receptor-T Cell Therapy for Pediatric and Young Adult Primary Central Nervous System Tumors: A Systematic Review of Early Phase Clinical Trials with a Focus on Diffuse Midline Glioma.
This systematic review of eight early-phase trials reports that 63 treated pediatric and young adult patients with recurrent or refractory primary CNS tumors received CAR-T cells targeting several antigens, with feasible delivery, reversible immune toxicities, infrequent objective responses, frequent disease stabilization, and evidence of CNS trafficking and immune activation.
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This systematic review of eight early-phase trials reports that 63 treated pediatric and young adult patients with recurrent or refractory primary CNS tumors received CAR-T cells targeting several antigens, with feasible delivery, reversible immune toxicities, infrequent objective responses, frequent disease stabilization, and evidence of CNS trafficking and immune activation.
Research significance
The reviewed clinical evidence supports that CNS-directed CAR-T cells can reach or activate within the CNS and may stabilize disease in some heavily pretreated patients; it remains an inference requiring prospective confirmation that optimizing antigen targets, administration routes, dosing, and toxicity management will produce durable survival benefit, particularly in diffuse midline glioma.
Source abstract
BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapy has demonstrated substantial efficacy in hematologic malignancies; however, its application in pediatric and young adult primary central nervous system (CNS) tumors, particularly pediatric diffuse midline glioma (DMG), remains investigational. Several early phase trials have recently reported clinical experiences with CNS-directed CAR-T cell therapies, necessitating a systematic distillation to better understand the state of the field. OBJECTIVE: The aim of the study was to systematically review early phase clinical evidence evaluating the safety, feasibility, and preliminary efficacy of CAR-T cell therapy in pediatric and young adult patients with primary CNS tumors. PATIENTS AND METHODS: A systematic review was conducted on early phase clinical studies assessing CAR-T cell therapies in pediatric and young adult patients diagnosed with primary brain tumors. Data collected included information on antigen targets, route of administration, dosing strategies, patient characteristics, prior therapies, toxicity profiles, anti-inflammatory management, radiographic and clinical outcomes, biologic correlates, and survival. RESULTS: The search identified eight early phase trials involving 74 pediatric and young adult patients. Of the cohort, 63 received CAR-T cell infusion, targeting B7-H3, GD2, HER2, EGFR806, and PSMA-GD2 via intraventricular, intravenous, or combined routes. All patients had heavily pretreated, recurrent, or refractory disease, with all DMG cohorts receiving prior radiation. CAR-T cell therapy was feasible, with no treatment-related mortality. Immune toxicities, including cytokine release syndrome and CNS neurotoxicity, were common but reversible with corticosteroids and cytokine therapies. Among response-evaluable patients, 65% achieved disease control (stable disease or partial response), while 35% had progressive disease. Objective responses were rare, but many had disease stabilization, especially in DMG cohorts. Post-infusion, immune activation was evident, with CAR-T cell trafficking to CNS and increased cytokines in cerebrospinal fluid and plasma. Median survival ranged from 13 to over 30 months, with some patients exceeding expectations. CONCLUSIONS: Preliminary clinical experience indicates that CAR-T cell therapy for pediatric and young adult CNS tumors is biologically active and clinically feasible, exhibiting a distinct yet manageable toxicity profile. Although durable objective responses are currently limited, the frequent occurrence of disease stabilization and extended survival in certain patients substantiate ongoing research and the refinement of CAR-T cell strategies for CNS malignancies.