Seattle Children's Research Institute, University of Washington, Seattle, WA, USA.
Immunol Rev. 2014 Jan;257(1):127-44. doi: 10.1111/imr.12139.
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.
过继性 T 细胞疗法（ACT）的一个主要进展是通过稳定或调节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，从而有效地使患者的 T 细胞对肿瘤抗原产生反应。使用 TCR 或 CAR 修饰的 T 细胞治疗的病例报告和小系列患者表明，在一部分患者中，特别是用靶向 CD19 分子的 CAR 修饰的 T 细胞治疗 B 细胞恶性肿瘤的患者中，可获得持久的反应。然而，许多患者对治疗没有反应，并且已经观察到 TCR 和 CAR 修饰的 T 细胞存在严重的脱靶毒性。因此，仍然存在挑战，需要使基因修饰的 T 细胞的 ACT 成为一种可重复有效且安全的治疗方法，并扩大可以治疗的患者范围，包括那些常见的上皮恶性肿瘤患者。本文综述了我们实验室在 CAR 修饰的 T 细胞的 ACT 设计和实施方面的研究课题。这些课题包括不同 T 细胞亚群的内在特性，这些特性可能有助于制备具有明确组成的治疗性 T 细胞产品，以实现可重复的疗效和安全性；设计肿瘤靶向受体，优化 T 细胞效应功能的信号转导，并促进 CAR 修饰的 T 细胞在体内的迁移追踪；以及具有替代配体结合结构域或赋予转导的 T 细胞调节功能和/或存活的新型 CAR 设计。
