Making Better Chimeric Antigen Receptors for Adoptive T-cell Therapy.
Making Better Chimeric Antigen Receptors for Adoptive T-cell Therapy.
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DOI：
10.1158/1078-0432.ccr-15-1433
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发表时间：
2016-04-15
期刊：
影响因子：
--
通讯作者：
June CH
中科院分区：
文献类型：
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作者：
Maus MV;June CH
嵌合抗原受体（CAR）是由抗原识别、信号传导和共刺激结构域构建的工程化融合蛋白，其可以在细胞毒性T细胞中表达，目的是重编程T细胞以特异性靶向肿瘤细胞。CAR T细胞疗法使用基因转移技术重新编程患者自身的T细胞以稳定表达CAR，从而将抗体的特异性与T细胞的强效细胞毒性和记忆功能相结合。在早期临床试验中，靶向CD19的CAR T细胞在其他难治性B细胞恶性肿瘤患者群体中产生了持续的完全缓解，更具体地说，在复发性或难治性急性淋巴细胞白血病患者中显示出90%的完全缓解率。鉴于这种临床疗效，CAR T细胞疗法用于许多癌症适应症的临床前开发已得到积极研究，CAR T细胞领域的未来是广泛和动态的。目前正在探索几种提高CAR T细胞可行性和安全性的方法，包括研究调节CAR T细胞持久性的机制。此外，许多早期临床试验正在研究CAR T细胞疗法，而不仅仅是靶向CD19，特别是在实体瘤中。研究CAR T细胞与免疫检查点阻断疗法组合的试验现在已经开始，人们热切期待结果。本文综述了CAR T细胞治疗的几个正在进行和未来的方向。
Chimeric antigen receptors (CARs) are engineered fusion proteins constructed from antigen recognition, signaling, and costimulatory domains that can be expressed in cytotoxic T cells with the purpose of reprograming the T cells to specifically target tumor cells. CAR T-cell therapy uses gene transfer technology to reprogram a patient's own T cells to stably express CARs, thereby combining the specificity of an antibody with the potent cytotoxic and memory functions of a T cell. In early phase clinical trials, CAR T cells targeting CD19 have resulted in sustained complete responses within a population of otherwise refractory patients with B-cell malignancies and, more specifically, have shown complete response rates of ≈90% in patients with relapsed or refractory acute lymphoblastic leukemia. Given this clinical efficacy, preclinical development of CAR T-cell therapy for a number of cancer indications has been actively investigated, and the future of the CAR T-cell field is extensive and dynamic. Several approaches to increase the feasibility and safety of CAR T cells are currently being explored, including investigation into mechanisms regulating the persistence of CAR T cells. Additionally, numerous early-phase clinical trials are now investigating CAR T-cell therapy beyond targeting CD19, especially in solid tumors. Trials investigating combinations of CAR T cells with immune checkpoint blockade therapies are now beginning and results are eagerly awaited. This review evaluates several of the ongoing and future directions of CAR T-cell therapy.