Jones Benjamin S, Lamb Lawrence S, Goldman Frederick, Di Stasi Antonio
Bone Marrow Transplantation and Cellular Therapy Unit, Division of Hematology-Oncology, Department of Medicine, The University of Alabama at Birmingham Birmingham, AL, USA.
Division of Hematology Oncology, Department of Pediatrics, The University of Alabama at Birmingham Birmingham, AL, USA.
Front Pharmacol. 2014 Nov 27;5:254. doi: 10.3389/fphar.2014.00254. eCollection 2014.
Adoptive T-cell therapy can involve donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation, the administration of tumor infiltrating lymphocyte expanded ex-vivo, or more recently the use of T cell receptor or chimeric antigen receptor redirected T cells. However, cellular therapies can pose significant risks, including graft-vs.-host-disease and other on and off-target effects, and therefore strategies need to be implemented to permanently reverse any sign of toxicity. A suicide gene is a genetically encoded molecule that allows selective destruction of adoptively transferred cells. Suicide gene addition to cellular therapeutic products can lead to selective ablation of gene-modified cells, preventing collateral damage to contiguous cells and/or tissues. The "ideal" suicide gene would ensure the safety of gene modified cellular applications by granting irreversible elimination of "all" and "only" the cells responsible for the unwanted toxicity. This review presents the suicide gene safety systems reported to date, with a focus on the state-of-the-art and potential applications regarding two of the most extensively validated suicide genes, including the clinical setting: herpes-simplex-thymidine-kinase and inducible-caspase-9.
过继性T细胞疗法可包括异基因造血干细胞移植后的供体淋巴细胞输注、体外扩增的肿瘤浸润淋巴细胞的给药，或最近使用的T细胞受体或嵌合抗原受体重定向T细胞。然而，细胞疗法可能带来重大风险，包括移植物抗宿主病和其他靶向及脱靶效应，因此需要实施策略来永久性逆转任何毒性迹象。自杀基因是一种基因编码分子，可选择性破坏过继转移的细胞。在细胞治疗产品中添加自杀基因可导致基因修饰细胞的选择性消融，防止对相邻细胞和/或组织造成附带损害。“理想”的自杀基因将通过不可逆地消除“所有”且“仅”造成不良毒性的细胞，确保基因修饰细胞应用的安全性。本综述介绍了迄今为止报道的自杀基因安全系统，重点关注两种最广泛验证的自杀基因的最新技术水平和潜在应用，包括临床情况：单纯疱疹胸苷激酶和诱导型半胱天冬酶-9。
