Rubinstein M P, Salem M L, Kadima A N, Nguyen C L, Gillanders W E, Nishimura M I, Cole D J
Department of Biological Sciences, The University of California San Diego, La Jolla, CA 92093, USA.
Cancer Gene Ther. 2009 Feb;16(2):171-83. doi: 10.1038/cgt.2008.63. Epub 2008 Aug 8.
Adoptive T-cell therapy is clinically efficacious in the treatment of select cancers. However, it is often difficult to obtain adequate numbers of tumor-specific T cells for therapy. One method for overcoming this limitation is to generate tumor-specific T cells by retrovirally mediated T-cell-receptor (TCR) gene transfer. However, despite instances of therapeutic success, major obstacles remain, including attaining the survival of retrovirally modified T cells in vivo as well as inducing long-term and multi-gene retroviral expression. Using a murine model of adoptively transferred retrovirally modified CD8(+) T cells, where antitumor immunity was dependent on sustained, multigene expression, we found that in vitro assays are poor indicators of in vivo efficacy. Despite persisting for over 9 months in a nonlymphopenic environment, genetically modified T cells exhibited discordant retrovirally mediated gene expression in vivo not readily evident from initial in vitro assays. In particular, one of the two TCR subunit genes necessary for antigen specificity was selectively lost in vivo. As this discordant gene expression was associated with the loss of antitumor immunity, consideration of these findings may provide guidance in the design, evaluation and application of retroviral vectors for use in the treatment of cancer and other human disease.
过继性T细胞疗法在治疗某些癌症方面具有临床疗效。然而，通常很难获得足够数量的肿瘤特异性T细胞用于治疗。克服这一限制的一种方法是通过逆转录病毒介导的T细胞受体（TCR）基因转移来产生肿瘤特异性T细胞。然而，尽管有治疗成功的案例，但主要障碍仍然存在，包括实现逆转录病毒修饰的T细胞在体内的存活以及诱导长期和多基因逆转录病毒表达。使用过继性转移逆转录病毒修饰的CD8(+) T细胞的小鼠模型，其中抗肿瘤免疫依赖于持续的多基因表达，我们发现体外试验不能很好地指示体内疗效。尽管在非淋巴细胞减少的环境中持续存在超过9个月，但基因修饰的T细胞在体内表现出不一致的逆转录病毒介导的基因表达，这在最初的体外试验中并不明显。特别是，抗原特异性所需的两个TCR亚基基因之一在体内选择性丢失。由于这种不一致的基因表达与抗肿瘤免疫的丧失有关，考虑这些发现可能为用于治疗癌症和其他人类疾病的逆转录病毒载体的设计、评估和应用提供指导。
