Grewal Eric P, Nahed Brian V, Carter Bob S, Gerstner Elizabeth R, Curry William T, Maus Marcela V, Choi Bryan D
Brain Tumor Immunotherapy Laboratory, Massachusetts General Hospital, Boston, MA, USA.
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
J Neurooncol. 2025 Feb;171(3):571-579. doi: 10.1007/s11060-024-04909-7. Epub 2024 Dec 18.
Chimeric antigen receptor (CAR) T cell therapy is an exciting modality of immunotherapy that has revolutionized the treatment of hematologic malignancies. However, translating this success to malignant gliomas such as glioblastoma (GBM) and diffuse midline glioma (DMG) remains a formidable challenge due to multiple biologic, anatomic, and immunologic factors. Despite these hurdles, a number of clinical trials deployed over the last decade have increased optimism for the potential of CAR T cell therapy in glioma treatment.
We highlight historical and ongoing clinical trials of CAR T cell therapy in glioma, with a focus on key tumor-associated antigens such as IL-13Rα2, HER2, EGFR, EGFRvIII, EphA2, GD2, and B7-H3. Early studies established proof-of-concept for antigen-specific CAR T cell targeting, yet immune evasion mechanisms such as antigen downregulation and limited CAR T cell persistence remain significant obstacles. Recent approaches, including multiantigen targeting, alternative cell sources, and innovations in delivery routes offer promising strategies to overcome these challenges.
The rapid evolution of investigational CAR T cell therapies portends great potential for the future of glioma treatment. Future studies will need to refine antigen targeting strategies, optimize CAR T cell persistence, and integrate combinatorial approaches to fully harness the therapeutic potential of this modality and improve the therapeutic window against brain tumors.
嵌合抗原受体（CAR）T细胞疗法是一种令人兴奋的免疫疗法，它彻底改变了血液系统恶性肿瘤的治疗方式。然而，由于多种生物学、解剖学和免疫学因素，将这种成功应用于恶性胶质瘤，如胶质母细胞瘤（GBM）和弥漫性中线胶质瘤（DMG），仍然是一项艰巨的挑战。尽管存在这些障碍，但在过去十年中开展的多项临床试验增加了人们对CAR T细胞疗法治疗胶质瘤潜力的乐观态度。
我们重点介绍了CAR T细胞疗法在胶质瘤方面的历史和正在进行的临床试验，重点关注关键的肿瘤相关抗原，如IL-13Rα2、HER2、表皮生长因子受体（EGFR）、EGFRvIII、 EphA2、GD2和B7-H3。早期研究确立了抗原特异性CAR T细胞靶向治疗的概念验证，但免疫逃逸机制，如抗原下调和CAR T细胞持久性有限，仍然是重大障碍。最近的方法，包括多抗原靶向、替代细胞来源和递送途径的创新，为克服这些挑战提供了有前景的策略。
研究性CAR T细胞疗法的快速发展预示着胶质瘤治疗的未来具有巨大潜力。未来的研究需要完善抗原靶向策略，优化CAR T细胞的持久性，并整合联合治疗方法，以充分发挥这种治疗方式的治疗潜力，改善针对脑肿瘤的治疗窗口。
