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Research Article

通过内在白细胞介素-15Rα信号功能改善嵌合抗原受体

卷 19, 期 1, 2019

页: [40 - 53] 页: 14

弟呕挨: 10.2174/1566523218666181116093857

摘要

简介：最近对CD19特异性嵌合抗原受体（CAR）修饰的T细胞（CART）的研究已经证明在治疗难治性和复发性B细胞恶性肿瘤方面取得了前所未有的成功。最新CART治疗进展的关键可归因于CAR设计中改进的共刺激信号。 方法：在此，我们通过将CD28的T细胞信号传导结构域与4-1BB，CD27，OX40，ICOS和IL-15Rα的细胞内信号传导基序结合，建立了几种新型CAR。基于简单的靶细胞杀伤测定，对这些新型CAR进行功能评估。 结果：结果显示CD28 / IL-15Rα共信号传导（153z）CAR表现出最快的T细胞扩增潜能和细胞毒活性。 IL-15是介导免疫效应活性的关键细胞因子。 153z CART在重复一轮靶细胞接合后维持了长时间的杀伤活动。与增强的靶杀伤功能一致，153z CART在与靶细胞相互作用时产生增加量的效应细胞因子，包括IFN-γ，TNFα和IL-2。 结论：在一项随访临床研究中，一名急性淋巴细胞白血病（ALL）患者，经历了多次中枢神经系统白血病复发（CNSL）并且未通过所有常规治疗，参加了CD19特异性153z CART治疗。在153z CART细胞输注后，患者达到完全缓解。翻译结果支持进一步研究IL-15Rα修饰的CART细胞在癌症患者中的安全性和增强的治疗功效。

关键词: IL-15受体，嵌合抗原受体，免疫疗法，急性B淋巴细胞白血病，慢病毒载体，CNS白血病。

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