Design and implementation of adoptive therapy with chimeric antigen receptor-modified T cells.
Design and implementation of adoptive therapy with chimeric antigen receptor-modified T cells.
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DOI：
10.1111/imr.12139
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发表时间：
2014-01
影响因子：
8.7
通讯作者：
Riddell SR
中科院分区：
文献类型：
--
作者：
Jensen MC;Riddell SR
过继性 T 细胞疗法 (ACT) 的一个重大进步是能够通过稳定或受调控地引入编码高亲和力肿瘤靶向 T 细胞受体 (TCR) 或合成嵌合抗原受体 (CAR) 的基因，有效地赋予患者 T 细胞对肿瘤抗原的反应性。病例报告和小系列患者接受 TCR 或 CAR 修饰的 T 细胞治疗后，部分患者显示出持久的反应，特别是使用经过修饰的 T 细胞治疗的 B 细胞恶性肿瘤，以表达靶向 CD19 分子的 CAR。然而，许多患者对治疗没有反应，并且 TCR 和 CAR 修饰的 T 细胞观察到严重的靶向和脱靶毒性。因此，如何使基因修饰 T 细胞的 ACT 成为一种可重复有效且安全的疗法，并扩大可治疗的患者范围以包括患有常见上皮恶性肿瘤的患者，仍然面临着挑战。本综述讨论了我们实验室的研究主题，重点是使用 CAR 修饰的 T 细胞设计和实施 ACT。其中包括不同T细胞亚群的细胞内在特性，这些特性可能有助于制备具有确定成分的治疗性T细胞产品，以实现可重复的功效和安全性；肿瘤靶向受体的设计，可以优化T细胞效应器功能的信号传导并促进体内CAR修饰的T细胞的迁移跟踪；以及具有替代配体结合域或赋予转导T细胞的调节功能和/或存活的新型CAR设计。
A major advance in adoptive T-cell therapy (ACT) is the ability to efficiently endow patient’s T cells with reactivity for tumor antigens through the stable or regulated introduction of genes that encode high affinity tumor-targeting T-cell receptors (TCRs) or synthetic chimeric antigen receptors (CARs). Case reports and small series of patients treated with TCR- or CAR-modified T cells have shown durable responses in a subset of patients, particularly with B-cell malignancies treated with T cells modified to express a CAR that targets the CD19 molecule. However, many patients do not respond to therapy and serious on and off-target toxicities have been observed with TCR- and CAR-modified T cells. Thus, challenges remain to make ACT with gene-modified T cells a reproducibly effective and safe therapy and to expand the breadth of patients that can be treated to include those with common epithelial malignancies. This review discusses research topics in our laboratories that focus on the design and implementation of ACT with CAR-modified T cells. These include cell intrinsic properties of distinct T-cell subsets that may facilitate preparing therapeutic T-cell products of defined composition for reproducible efficacy and safety, the design of tumor targeting receptors that optimize signaling of T-cell effector functions and facilitate tracking of migration of CAR-modified T cells in vivo, and novel CAR designs that have alternative ligand binding domains or confer regulated function and/or survival of transduced T cells.