Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma.
Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma.
复制标题
病毒特异性的T细胞设计为共表达肿瘤特异性受体：神经母细胞瘤个体中的持久性和抗肿瘤活性。
作者：
针对非病毒肿瘤相关抗原的细胞毒性T淋巴细胞（CTLs）在体内无法长期存活，且抗肿瘤活性有限，部分原因是此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CTLs进行改造，使其表达一种针对双唾液酸神经节苷脂GD2的嵌合抗原受体，GD2是一种由人神经母细胞瘤细胞表达的非病毒肿瘤相关抗原。我们推断，这些经过基因工程改造的淋巴细胞在其天然受体结合后将获得最佳的共刺激，从而增强通过其嵌合受体介导的存活和抗肿瘤活性。在此，我们在神经母细胞瘤患者中发现，表达嵌合GD2特异性受体的EBV特异性CTLs确实比由CD3特异性抗体OKT3激活且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，并且在半数接受测试的受试者中与肿瘤消退或坏死相关。因此，病毒特异性CTLs可被改造为具有肿瘤导向效应细胞的功能。
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.