Pule Martin A, Savoldo Barbara, Myers G Doug, Rossig Claudia, Russell Heidi V, Dotti Gianpietro, Huls M Helen, Liu Enli, Gee Adrian P, Mei Zhuyong, Yvon Eric, Weiss Heidi L, Liu Hao, Rooney Cliona M, Heslop Helen E, Brenner Malcolm K
Center for Cell and Gene Therapy, Baylor College of Medicine and The Methodist Hospital and Texas Children's Hospital, Houston, Texas 77030, USA.
Nat Med. 2008 Nov;14(11):1264-70. doi: 10.1038/nm.1882. Epub 2008 Nov 2.
Cytotoxic T lymphocytes (CTLs) directed to nonviral tumor-associated antigens do not survive long term and have limited antitumor activity in vivo, in part because such tumor cells typically lack the appropriate costimulatory molecules. We therefore engineered Epstein-Barr virus (EBV)-specific CTLs to express a chimeric antigen receptor directed to the diasialoganglioside GD2, a nonviral tumor-associated antigen expressed by human neuroblastoma cells. We reasoned that these genetically engineered lymphocytes would receive optimal costimulation after engagement of their native receptors, enhancing survival and antitumor activity mediated through their chimeric receptors. Here we show in individuals with neuroblastoma that EBV-specific CTLs expressing a chimeric GD2-specific receptor indeed survive longer than T cells activated by the CD3-specific antibody OKT3 and expressing the same chimeric receptor but lacking virus specificity. Infusion of these genetically modified cells seemed safe and was associated with tumor regression or necrosis in half of the subjects tested. Hence, virus-specific CTLs can be modified to function as tumor-directed effector cells.
针对非病毒肿瘤相关抗原的细胞毒性T淋巴细胞（CTL）不能长期存活，且在体内的抗肿瘤活性有限，部分原因是这类肿瘤细胞通常缺乏适当的共刺激分子。因此，我们对爱泼斯坦-巴尔病毒（EBV）特异性CTL进行基因工程改造，使其表达一种针对二唾液酸神经节苷脂GD2的嵌合抗原受体，GD2是一种由人类神经母细胞瘤细胞表达的非病毒肿瘤相关抗原。我们推断，这些基因工程改造的淋巴细胞在其天然受体被激活后将获得最佳共刺激，从而增强通过其嵌合受体介导的存活能力和抗肿瘤活性。在此，我们在患有神经母细胞瘤的个体中发现，表达嵌合GD2特异性受体的EBV特异性CTL确实比被CD3特异性抗体OKT3激活、表达相同嵌合受体但缺乏病毒特异性的T细胞存活时间更长。输注这些基因改造细胞似乎是安全的，并且在一半的受试对象中与肿瘤消退或坏死相关。因此，病毒特异性CTL可以被改造为发挥肿瘤定向效应细胞的功能。
