Tahara H, Zitvogel L, Storkus W J, Robbins P D, Lotze M T
Department of Surgery, University of Pittsburgh School of Medicine, Pennsylvania, USA.
Ann N Y Acad Sci. 1996 Oct 31;795:275-83. doi: 10.1111/j.1749-6632.1996.tb52677.x.
Cytokine gene therapy, in particular IL-12 gene therapy, is one of the more novel and promising approaches in cancer therapy based on significant preclinical data derived mainly from murine tumor models. IL-12 is a heterodimeric cytokine that requires the simultaneous expression of both the p35 and p40 chains from the same cell for production of biologically active IL-12. A variety of biological functions have been attributed to IL-12 including the induction of IFN-gamma production and the promotion of predominantly Th1-type immune responses to antigens. Our previous studies using systemic administration of recombinant murine IL-12 have demonstrated profound antitumor efficacy against all tumors tested with the concomitant long-lived specific antitumor immunity in some cases. To determine whether the local secretion of IL-12 achieved by gene transduction has significant antitumor effects, fibroblast cell lines or murine tumor cell lines were transduced with expression plasmids or the retroviral vector TFG-mIL-12-Neo and inoculated intradermally (i.d.). Our first study using IL-12-transfected NIH3T3 cells admixed with the murine melanoma, BL-6, showed that local IL-12 expression suppresses tumor growth and promotes the acquisition of specific antitumor immunity. Subsequent studies showed that IL-12 gene therapy is also effective in treating established day 3 tumors. CD4+ and CD8+ T cells, as well as NK cells, appear to play important roles in the observed antitumor effects resulting from IL-12 paracrine secretion. Administration of neutralizing antibody specific for IFN-gamma also abrogated some of the IL-12-associated antitumor effects. Finally, this IL-12 gene therapy strategy to elicit an antitumor immune response was more effective when used in combination with the transduction of tumor cells with B7.1. Based on these promising results, a clinical protocol for the treating patients with cancer using genetically engineered fibroblasts to express IL-12 has been initiated at our institution.
细胞因子基因疗法，尤其是白细胞介素-12（IL-12）基因疗法，是癌症治疗中较新且有前景的方法之一，这基于主要来自小鼠肿瘤模型的大量临床前数据。IL-12是一种异源二聚体细胞因子，需要同一细胞同时表达p35和p40链才能产生具有生物活性的IL-12。IL-12具有多种生物学功能，包括诱导γ干扰素（IFN-γ）产生以及促进针对抗原的主要为Th1型免疫反应。我们之前使用重组小鼠IL-12全身给药的研究表明，对所有测试肿瘤都有显著的抗肿瘤效果，在某些情况下还伴有持久的特异性抗肿瘤免疫。为了确定通过基因转导实现的IL-12局部分泌是否具有显著的抗肿瘤作用，用表达质粒或逆转录病毒载体TFG-mIL-12-Neo转导成纤维细胞系或小鼠肿瘤细胞系，并进行皮内接种。我们第一项使用与小鼠黑色素瘤BL-6混合的IL-12转染NIH3T3细胞的研究表明，局部IL-12表达可抑制肿瘤生长并促进获得特异性抗肿瘤免疫。随后的研究表明，IL-12基因疗法对治疗已形成3天的肿瘤也有效。CD4+和CD8+ T细胞以及自然杀伤（NK）细胞似乎在IL-12旁分泌产生的抗肿瘤作用中发挥重要作用。给予针对IFN-γ的中和抗体也消除了一些与IL-12相关的抗肿瘤作用。最后与用B7.1转导肿瘤细胞联合使用时，这种引发抗肿瘤免疫反应的IL-12基因疗法策略更有效。基于这些有前景的结果，我们机构已启动一项使用基因工程改造的成纤维细胞表达IL-12治疗癌症患者的临床方案。
