Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS Ospedale San Raffaele Scientific Institute, Milan, Italy.
Program in Immunology, Division of Translational Sciences and Therapeutics, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
Hum Gene Ther. 2023 Sep;34(17-18):853-869. doi: 10.1089/hum.2023.128.
Advanced gene transfer technologies and profound immunological insights have enabled substantial increases in the efficacy of anticancer adoptive cellular therapy (ACT). In recent years, the U.S. Food and Drug Administration and European Medicines Agency have approved six engineered T cell therapeutic products, all chimeric antigen receptor-engineered T cells directed against B cell malignancies. Despite encouraging clinical results, engineered T cell therapy is still constrained by challenges, which could be addressed by genome editing. As RNA-guided Clustered Regularly Interspaced Short Palindromic Repeats technology passes its 10-year anniversary, we review emerging applications of genome editing approaches designed to (1) overcome resistance to therapy, including cancer immune evasion mechanisms; (2) avoid unwanted immune reactions related to allogeneic T cell products; (3) increase fitness, expansion capacity, persistence, and potency of engineered T cells, while preserving their safety profile; and (4) improve the ability of therapeutic cells to resist immunosuppressive signals active in the tumor microenvironment. Overall, these innovative approaches should widen the safe and effective use of ACT to larger number of patients affected by cancer.
先进的基因转移技术和深刻的免疫学见解使抗癌过继细胞疗法（ACT）的疗效有了实质性的提高。近年来，美国食品和药物管理局和欧洲药品管理局已经批准了六种基因工程 T 细胞治疗产品，这些产品均为针对 B 细胞恶性肿瘤的嵌合抗原受体基因工程 T 细胞。尽管临床结果令人鼓舞，但基因工程 T 细胞疗法仍然受到挑战的限制，基因组编辑可以解决这些问题。随着 RNA 引导的簇状规律间隔短回文重复技术迎来十周年，我们回顾了基因组编辑方法的新应用，这些方法旨在（1）克服对治疗的耐药性，包括癌症免疫逃逸机制；（2）避免与同种异体 T 细胞产品相关的不必要的免疫反应；（3）提高基因工程 T 细胞的适应性、扩增能力、持久性和效力，同时保持其安全性；（4）提高治疗细胞抵抗肿瘤微环境中免疫抑制信号的能力。总的来说，这些创新方法应该扩大 ACT 的安全有效使用范围，使更多的癌症患者受益。
