文章：

开关式CAR-T细胞：一个重定向T细胞靶向AML原始细胞的新型模块化平台

Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts

原文发布日期：2016-08-12

DOI: 10.1038/bcj.2016.61

类型: Original Article

开放获取: 是

英文摘要：

The adoptive transfer of CD19-specific chimeric antigen receptor engineered T cells (CAR T cells) resulted in encouraging clinical trials in indolent B-cell malignancies. However, they also show the limitations of this fascinating technology: CAR T cells can lead to even life-threatening off-tumor, on-target side effects if CAR T cells crossreact with healthy tissues. Here, we describe a novel modular universal CAR platform technology termed UniCAR that reduces the risk of on-target side effects by a rapid and reversible control of CAR T-cell reactivity. The UniCAR system consists of two components: (1) a CAR for an inert manipulation of T cells and (2) specific targeting modules (TMs) for redirecting UniCAR T cells in an individualized time- and target-dependent manner. UniCAR T cells can be armed against different tumor targets simply by replacement of the respective TM for (1) targeting more than one antigen simultaneously or subsequently to enhance efficacy and (2) reducing the risk for development of antigen-loss tumor variants under treatment. Here we provide ‘proof of concept’ for retargeting of UniCAR T cells to CD33- and/or CD123-positive acute myeloid leukemia blasts in vitro and in vivo.

摘要翻译： 

CD19特异性嵌合抗原受体工程化T细胞（CAR T细胞）的过继性转移在惰性B细胞恶性肿瘤中取得了令人鼓舞的临床试验结果。然而，这些试验也揭示了这项引人注目技术的局限性：若CAR T细胞与健康组织发生交叉反应，可能导致甚至危及生命的脱瘤on-target副作用。本文介绍了一种新型模块化通用CAR平台技术——UniCAR，该技术通过快速可逆的CAR T细胞活性控制来降低on-target副作用风险。UniCAR系统包含两个组成部分：（1）用于T细胞惰性化操作的CAR；（2）用于以个体化时间及靶点依赖性方式重定向UniCAR T细胞的特异性靶向模块。通过简单更换相应靶向模块，UniCAR T细胞即可针对不同肿瘤靶点进行武装，实现（1）同时或序贯靶向多个抗原以增强疗效，（2）降低治疗中抗原缺失肿瘤变异体产生的风险。本研究通过体外和体内实验为UniCAR T细胞重定向至CD33和/或CD123阳性急性髓系白血病原始细胞提供了概念验证。

原文链接：

Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts