Chimeric Antigen Receptor (CAR) T cell therapy represents a groundbreaking advancement in immunotherapy, initially gaining FDA approval for treating hematological malignancies. This therapy has shown promising results in solid tumors, particularly in pediatric brain tumors, which are the leading cause of cancer-related death in children. CAR T cells are engineered to target specific antigens on tumor cells, thereby reducing off-target effects and increasing the cytotoxic impact on cancer cells. Over the years, CAR T cell technology has evolved through five generations, each enhancing the structure, functionality, and safety of these cells. Despite these advancements, the application of CAR T cells in solid tumors, especially within the central nervous system (CNS), faces significant challenges. These include the physical barrier posed by the blood-brain barrier (BBB), the immunosuppressive tumor microenvironment (TME), and the heterogeneity of tumor antigens. The review discusses several promising antigenic targets for CAR T cells in pediatric brain tumors, such as HER2, EphA2, IL-13Rα2, and Survivin, which have been explored in recent clinical trials. These trials have shown early promise in improving patient outcomes, though the risks of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) remain concerns. The future of CAR T cell therapy lies in overcoming these barriers through innovative approaches like “Armored CARs” or TRUCKs, designed to modulate the TME and improve CAR T cell efficacy in solid tumors. Additionally, combination therapies and safety switches in next-generation CAR T cells are being explored to enhance therapeutic potential while minimizing adverse effects.
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