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《工程(英文)》 >> 2019年 第5卷 第1期 doi: 10.1016/j.eng.2018.11.010

从药物开发的角度看工程化T细胞疗法

a Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
b Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA
c Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA 19104, USA
d Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA
e Department of Immunology, Peking University, Beijing 100871, China

收稿日期: 2018-07-03 修回日期: 2018-10-19 录用日期: 2018-11-15 发布日期: 2018-12-13

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摘要

癌症是全世界人口死亡的主要原因之一。细胞治疗的最新进展表明,其有可能为某些癌症患者带来第二次生命的机会。与化合物和蛋白质不同,细胞是活的、可自我复制的药物,具有精准的特异性。例如,经基因修饰后,T 细胞可表达嵌合抗原受体(chimeric antigen receptor,CAR),使其能够识别并杀死肿瘤细胞,并形成一个记忆库,准备回击持续存在的恶性细胞。抗CD19 嵌合抗原受体T 细胞(CAR T cells,CART19)对某些恶性肿瘤具有显著的临床疗效。CART19 的开发过程基本上遵循了“一个基因,一种药物,一种疾病”的传统模式,该模式源于Paul Ehrlich 提出的“魔法子弹”理念。随着制药行业的主要参与者联手使这种新型“活药物”商业化,以CART19 为例,与传统药物相比,研究其开发过程中的相似性和差异性非常有用。这样,我们可以将现有的知识融会贯通,找出推进类似策略最有效的方法。本文综述了基于生物标志物的分析方法在优化CAR结构、临床前研究和临床疗效评价、不良反应(AE)和CART19 细胞动力学方面的应用。同时还探讨了能够发现最佳靶标、新型CAR 结合结构域以及预测临床反应和不良反应的生物标志物的先进技术和计算工具。我们相信,就像胂凡纳明的发现开创了合成药物时代一样,CART19 的成功能够带来其他工程化T 细胞疗法的发展。

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