为实现 CAR-T 疗法的精确性而制定的合成控制策略取得突破性进展。

3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology
Wang Tik Tang, Ryohichi Sugimura
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引用次数: 0

摘要

嵌合抗原受体(CAR)是针对用户定义的抗原而设计的合成受体。它们由用于识别目标的胞外单链可变片段和通常来自免疫细胞的胞内信号结构域组成。事实证明,CAR-T 细胞可成功治疗某些癌症。CAR-T 细胞通过抗原刺激和随后的细胞内信号传导被激活。然而,CAR-T 细胞中的强直信号仍是开发高效 CAR-T 疗法的一个挑战,因为它会导致 T 细胞早期衰竭,从而限制治疗的持续性。此外,靶抗原选择不当会导致脱靶细胞毒性,往往会妨碍宿主的生存。此外,传递 CAR 基因回路的传统方法利用慢病毒和逆转录病毒等病毒载体,将 CAR 基因回路插入基因组中转录活跃的位点。由于基因组整合不当,这增加了恶性转化的风险。要确保CAR-T疗法的高效性、持久性和精确性,就必须优化CAR-T工程,从CAR基因回路的架构到CAR的结构以及CAR-T细胞的行为。本综述通过重点介绍最近开发的优化 CAR 功能和效率的关键策略,深入探讨如何通过 CAR-T 细胞工程实现癌症治疗的精准性。将讨论 CAR 基因回路的传递方法、CAR 的回路和结构改造、T 细胞表型操作和 T 细胞武装,以强调它们在调节 CAR-T 疗法的安全性、精确性和有效性方面的相互作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Breakthroughs in synthetic controlling strategies for precision in CAR-T therapy.

Chimeric antigen receptors (CAR) are synthetic receptors engineered to target a user-defined antigen. They comprise an extracellular single-chain variable fragment for target recognition and intracellular signalling domains commonly derived from immune cells. CAR-T cells have proven to be successful in therapy of some cancers. CAR-T cells are activated upon antigen-priming and subsequent intracellular signalling. However, tonic signalling in CAR-T cells remains a challenge in developing CAR-T therapeutics of high efficacy as it causes early T-cell exhaustion, limiting therapeutic persistence. Moreover, a poor choice of target antigen leads to off-target cytotoxicity, often hampering the host's survival. In addition, conventional methods of delivering CAR gene circuits utilise viral vectors, such as lentiviruses and retroviruses, which insert the CAR gene circuits into transcriptionally active sites in the genome. This increases the risks of malignant transformation due to improper genome integration. Optimisation in CAR-T engineering, from the architecture of CAR gene circuits to the structure of CAR and the behaviour of CAR-T cells, is paramount to ensure high efficacy, persistence, and precision in CAR-T therapy. This review provides insights into engineering CAR-T cells for precision in cancer therapy by highlighting the key strategies recently developed to optimise the function and efficiency of CARs. The delivery method of CAR gene circuits, circuit and structural modification of CAR, T-cell phenotype manipulation and T-cell arming will be discussed to accentuate their interplay in regulating CAR-T therapy's safety, precision, and efficacy.

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来源期刊
CiteScore
6.90
自引率
0.00%
发文量
0
审稿时长
>12 weeks
期刊介绍: Progress in Molecular Biology and Translational Science (PMBTS) provides in-depth reviews on topics of exceptional scientific importance. If today you read an Article or Letter in Nature or a Research Article or Report in Science reporting findings of exceptional importance, you likely will find comprehensive coverage of that research area in a future PMBTS volume.
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