Miller P W, Sharma S, Stolina M, Chen K, Zhu L, Paul R W, Dubinett S M
Department of Medicine, Jonsson Comprehensive Cancer Center, UCLA School of Medicine and the West Los Angeles Veterans Affairs Medical Center, California 90073, USA.
Cancer Gene Ther. 1998 Nov-Dec;5(6):380-9.
Lung cancer, the leading cause of cancer death in the United States, is resistant to most currently available therapies. To evaluate a multicomponent gene therapy approach that replaces tumor-bearing host immune deficits, we genetically modified Line 1 (L1C2), a weakly immunogenic alveolar cell carcinoma cell line. L1C2 was transduced ex vivo with a retroviral construct that contained two components: a cytokine gene (granulocyte-macrophage colony-stimulating factor) and a drug sensitivity gene (herpes simplex virus thymidine kinase). The third component of this therapy, in vitro-activated syngeneic bone marrow-derived dendritic cells, was included to augment antigen presentation. The addition of ganciclovir (GCV) caused the lysis of transduced tumor cells, resulting in the release of potential tumor antigens. Ex vivo-transduced tumor cells regressed in vivo following GCV therapy but were not effective in the treatment of established parental tumors. To treat established tumors, dendritic cells were administered in combination with transduced tumor cells and GCV. A total of 50% of these mice rejected the 5-day-old established tumors and were immune to rechallenge with parental L1C2 cells. Thus, this multicomponent gene therapy system leads to both the regression of established tumors and enhanced immunogenicity in this weakly immunogenic murine lung cancer model.
肺癌是美国癌症死亡的主要原因，对目前大多数可用疗法具有抗性。为了评估一种替代荷瘤宿主免疫缺陷的多组分基因治疗方法，我们对1号线（L1C2）进行了基因改造，这是一种免疫原性较弱的肺泡细胞癌细胞系。L1C2在体外被一种逆转录病毒构建体转导，该构建体包含两个组分：一个细胞因子基因（粒细胞-巨噬细胞集落刺激因子）和一个药物敏感性基因（单纯疱疹病毒胸苷激酶）。这种治疗的第三个组分，即体外激活的同基因骨髓来源的树突状细胞，被纳入以增强抗原呈递。加入更昔洛韦（GCV）导致转导的肿瘤细胞裂解，从而释放潜在的肿瘤抗原。体外转导的肿瘤细胞在GCV治疗后在体内消退，但对已建立的亲本肿瘤治疗无效。为了治疗已建立的肿瘤，将树突状细胞与转导的肿瘤细胞和GCV联合给药。这些小鼠中有50%排斥5天大的已建立肿瘤，并且对亲本L1C2细胞的再次攻击具有免疫力。因此，在这个免疫原性较弱的小鼠肺癌模型中，这种多组分基因治疗系统导致已建立肿瘤的消退和免疫原性增强。
