成胶质细胞瘤CAR-T免疫治疗的研究进展

Research progress on chimeric antigen receptor-engineered T cells for immunotherapy of glioblastoma

成胶质细胞瘤是发病率高、侵袭性强、预后差的中枢神经系恶性肿瘤。自2005年FDA批准的替莫唑胺后,再无明显改善疗效的新策略。随着多形性成胶质细胞瘤(glioblastoma multiforme,GBM)分子生物学、肿瘤免疫学与免疫治疗技术的发展,以及分子靶点的发现、中枢免疫"豁免"理论的突破和基因转导与细胞技术的进步,GBM治疗迎来了免疫治疗的新跨越。以嵌合抗原受体修饰T细胞(chimeric antigen receptor-modified T cell,CAR-T)为代表的细胞免疫治疗,在靶向EGFRvⅢ、IL-13Rα2、HER2、促红细胞生成素产生肝细胞受体A2(erythropoietin-producing hepatocellular carcinoma A2,Eph A2)的GBM体外实验、动物模型及临床试验中都展示了良好的应用前景。然而,GBM的分子异质性、免疫抑制微环境、血脑屏障等为CAR-T进入一线治疗提出了挑战。研究者们正在探索肿瘤恶性表型所必需的新靶点、防止免疫逃逸的最优靶抗原组合,致力于提高CAR-T血脑屏障穿越和肿瘤组织侵润的能力,寻找最佳注射途径和治疗方案,同时逐步完善中枢神经肿瘤免疫治疗评估体系。相信CAR-T免疫治疗的突破终将为GBM患者向往美好生活圆梦。

Glioblastoma multiforme（GBM）is a malignant tumor of central nervous system with high incidence, aggressive and poor prognosis. Since temozolomide was approved by FDA in 2005, there is no new curative strategy with obvious improvement in therapeutic effect. With the developments in molecular biology, tumor immunology and immunotherapy technology, the discovery of new molecular targets, breakthrough in central immunization exemption theory, and advance in gene transduction and cell technology, GBM immunotherapy ushered in a new breakthrough in immunotherapy. Cellular immunotherapy, presented by chimeric antigen receptor-modified T cell（CAR-T） therapy, has exhibited its prominent application prospect in GBM in vitro experiments targeting EGFRv III, IL-13 Rα2,HER2, erythropoietin-producing hepatocellular carcinoma A2（Eph A2）, animal models and early clinical trials. However, the GBM molecular heterogeneity, immunosuppressive microenvironment and blood-brain barrier have presented challenge for CAR-T going into the first-line clinical treatment. Researchers are now exploring key antigens of oncogenic phenotype, designing optimal combination of target antigens to prevent the immune escape, improving CAR-T passing through blood-brain barrier and invading tumor tissue, finding the best route for cell deliver, and optimizing evaluation system for central nervous system（CNS） immunotherapy. It is believed that the breakthrough of CAR-T cell immunotherapy will finally help GBM patients pursuing a beautiful life.