Ma Peixiang, Ren Ping, Zhang Chuyue, Tang Jiaxing, Yu Zheng, Zhu Xuekai, Fan Kun, Li Guanglei, Zhu Wei, Sang Wei, Min Chenyu, Chen Wenzhang, Huang Xingxu, Yang Guang, Lerner Richard A
Shanghai Institute for Advanced Immunochemical Studies ShanghaiTech University Shanghai 201210 China.
School of Life Science and Technology ShanghaiTech University Shanghai 201210 China.
Adv Sci (Weinh). 2021 Jan 29;8(6):2003091. doi: 10.1002/advs.202003091. eCollection 2021 Mar.
Using T-cell chimeric antigen receptors (CAR-T) to activate and redirect T cells to tumors expressing the cognate antigen represents a powerful approach in cancer therapy. However, normal tissues with low expression of tumor-associated antigens (TAAs) can be mistargeted, resulting in severe side effects. An approach using a collection of T cells expressing a diverse, 10-member combinatorial cellular library of CARs, in which members can be specifically enriched based on avidity for cell membrane antigens, is reported. Using CD38 as the target antigen, an efficient and effective selection of CARs specifically recognizing CD38 tumor cells is demonstrated. These selected CAR-T's produce cytokines known to be associated with T cell activation in a CD38 expression-dependent manner. This avidity-based selection endows the engineered T cells with minimal off-tumor effects, while retaining robust antitumor efficacy both in vitro and in vivo. The described method may facilitate the application of CAR-T therapy to TAAs previously considered undruggable.
利用T细胞嵌合抗原受体（CAR-T）激活T细胞并将其重定向至表达同源抗原的肿瘤细胞，这在癌症治疗中是一种强有力的方法。然而，肿瘤相关抗原（TAA）低表达的正常组织可能会被错误靶向，从而导致严重的副作用。本文报道了一种方法，即使用表达包含10个成员的多样化CAR组合细胞文库的T细胞集合，其中的成员可基于对细胞膜抗原的亲和力进行特异性富集。以CD38作为靶抗原，证明了能高效且有效地筛选出特异性识别CD38肿瘤细胞的CAR。这些筛选出的CAR-T以CD38表达依赖的方式产生已知与T细胞激活相关的细胞因子。这种基于亲和力的筛选赋予工程化T细胞最小的非肿瘤效应，同时在体外和体内均保留强大的抗肿瘤功效。所述方法可能会促进CAR-T疗法应用于先前认为不可靶向的TAA。
