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通用嵌合抗原受体(CARs)、通用 T 细胞和通用 CAR T 细胞。

Universal CARs, universal T cells, and universal CAR T cells.

机构信息

The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, 127 Dongming Road, Zhengzhou, 450008, China.

出版信息

J Hematol Oncol. 2018 Nov 27;11(1):132. doi: 10.1186/s13045-018-0677-2.

Abstract

Currently, the two approved T cell products with chimeric antigen receptors (CAR) are from autologous T cells. These CAR T cells approved for clinical use must be generated on a custom-made basis. This case-by-case autologous T cell production platform remains a significant limiting factor for large-scale clinical application due to the costly and lengthy production process. There is also an inherent risk of production failure. The individualized, custom-made autologous CAR T cell production process also posts constriction on the wide application on diverse tumor types. Therefore, universal allogeneic T cells are needed for the preparation of universal CAR T cells that can serve as the "off-the-shelf" ready-to-use therapeutic agents for large-scale clinical applications. Genome-editing technologies including ZFN (zinc finger nuclease), TALEN (transcription activator-like effector nuclease), and CRISPR-Cas9 are being used to generate the universal third-party T cells. In addition, split, universal, and programmable (SUPRA) CARs are being developed to enhance the flexibility and controllability of CAR T cells. The engineered universal T cells and universal CARs are paving the road for a totally new generation of CAR T cells capable of targeting multiple antigens and/ or being delivered to multiple recipients without re-editing of T cells. This may escalate to a new wave of revolution in cancer immunotherapy. This review summarized the latest advances on designs and development of universal CARs, universal T cells, and clinical application of universal CAR T cells.

摘要

目前,两种获准的嵌合抗原受体(CAR)T 细胞产品均来自自体 T 细胞。这些获准用于临床的 CAR-T 细胞必须基于定制化生产。由于生产成本高、生产过程漫长,这种个体化、定制化的自体 T 细胞生产平台仍然是大规模临床应用的一个重大限制因素。此外,生产失败的固有风险也存在。个体化、定制化的自体 CAR-T 细胞生产过程也限制了其在多种肿瘤类型中的广泛应用。因此,需要制备通用的异体 T 细胞,以制备可作为“现货”即用型治疗剂的通用 CAR-T 细胞,从而实现大规模临床应用。基因组编辑技术包括 ZFN(锌指核酸酶)、TALEN(转录激活因子样效应核酸酶)和 CRISPR-Cas9,正在被用于生成通用的第三方 T 细胞。此外,正在开发分裂型、通用型和可编程型(SUPRA)CAR 以增强 CAR-T 细胞的灵活性和可控性。工程化的通用 T 细胞和通用 CAR 正在为新一代能够靶向多种抗原和/或无需再次编辑 T 细胞即可递送给多个受体的 CAR-T 细胞铺平道路。这可能会引发癌症免疫治疗的新浪潮。本综述总结了通用 CAR、通用 T 细胞的设计和开发以及通用 CAR-T 细胞的临床应用的最新进展。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7537/6257951/bbaf3ca9cd4f/13045_2018_677_Fig1_HTML.jpg

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