Function and evolution of the prototypic CD28ζ and 4-1BBζ chimeric antigen receptors.
Function and evolution of the prototypic CD28ζ and 4-1BBζ chimeric antigen receptors.
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DOI：
10.1016/j.iotech.2020.09.001
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Sadelain, M
中科院分区：
文献类型：
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作者：
Feucht, J;Sadelain, M
经工程改造以表达对CD 19特异性的嵌合抗原受体（汽车）的T细胞在患有难治性B细胞恶性肿瘤的患者中产生了显著的临床结果。美国食品和药物管理局和欧洲药品管理局批准的第一批汽车是包含CD 28/CD 3 β或4-1BB/CD 3 β双信号传导结构域的CD 19汽车。虽然它们在B细胞恶性肿瘤患者中的疗效和安全性总体上相当，但这两种CAR设计赋予工程化T细胞的功能特性显著不同。值得注意的是，迄今为止，替代共刺激结构域还没有取代这些基础设计。相反，最近的CAR进展集中在通过校准激活强度，预先阻止T细胞耗尽和增加CAR T细胞的功能持久性来完善原始的基于CD 28和4- 1BB的CD 19汽车。本文综述了这些一流原型的基本生物学特性及其最近的演变。CD 19嵌合抗原受体（CAR）疗法已经显示出针对B细胞恶性肿瘤的显著成功。原型⑶ 19汽车包含⑶ 28/⑶ 3 β或4-1BB/⑶ 3 β信号传导结构域。两种CD 19汽车产生相似的功效，但赋予不同的T细胞功能。新的CAR设计旨在增强T细胞的持久性或效应效力。基因组编辑避免了多样化的CAR表达并维持了T细胞功能。
T cells engineered to express chimeric antigen receptors (CARs) specific for CD19 have yielded remarkable clinical outcomes in patients with refractory B-cell malignancies. The first CARs to be approved by the US Food and Drug Administration and the European Medicines Agency are CD19 CARs that comprise either CD28/CD3ζ or 4-1BB/CD3ζ dual-signalling domains. While their efficacy and safety profiles in patients with B-cell malignancies are comparable overall, the functional properties these two CAR designs impart upon engineered T cells differ significantly. Remarkably, alternative costimulatory domains have not, to date, superseded these foundational designs. Rather, recent CAR advances have focused on perfecting the original CD28- and 4-1BB-based CD19 CARs by calibrating strength of activation, pre-empting T-cell exhaustion and increasing the functional persistence of CAR T cells. This article reviews the essential biological properties of these first-in-class prototypes and their recent evolution. CD19 chimeric antigen receptor (CAR) therapy has shown remarkable success against B-cell malignancies. The prototypic CD19 CARs comprise either CD28/CD3ζ or 4-1BB/CD3ζ signalling domains. Both CD19 CARs yield similar efficacy but impart distinct T-cell functionalities. Novel CAR designs aim to enhance the persistence or effector potency of T cells. Genome editing averts variegated CAR expression and sustains T-cell function.