Gene Therapy Laboratory, Liver Unit, School of Medicine, Austral University, Buenos Aires, Argentina.
Clin Cancer Res. 2009 Dec 1;15(23):7256-65. doi: 10.1158/1078-0432.CCR-09-1861. Epub 2009 Nov 17.
Interleukin-12 (IL-12) is an immunostimulatory cytokine with potent antitumor effects in several animal models. However, serious toxicity has been associated with its systemic application in humans. Gene transfer has emerged as a tool to specifically express therapeutic genes into the tumor/peritumoral milieu, thus avoiding systemic toxicity. The aim of this study was to analyze whether subtherapeutic doses of an adenovirus encoding IL-12 (AdIL-12) might synergize with low immunopotentiating doses of cyclophosphamide in the treatment of colorectal carcinoma.
The antitumor effect of combining a single low dose of cyclophosphamide with an intratumoral injection of AdIL-12 was evaluated in an in vivo murine colorectal carcinoma model. The immune responses achieved with different treatments were monitored, comparing the effect of combining both therapies with individual treatments.
The combined therapy induced a complete tumor regression in >50% of mice in a synergistic fashion, and it significantly prolonged their survival. This strategy was superior to each single treatment in reducing both peripheral and splenic CD4+CD25+Foxp3+ regulatory T cells, increasing the number of activated dendritic cells, and inducing IFN-gamma-secreting CD4-positive T lymphocytes. Importantly, the combined treatment generated a powerful tumor-specific CTL response. Consistently, a significant reduction in IL-10 levels was found. Our data suggest that the combination of nontoxic doses of cyclophosphamide with AdIL-12 allows the generation of good antitumoral responses, thus avoiding undesired side effects of both agents.
Our data strongly support the use of a combination of cyclophosphamide and AdIL-12 as a novel therapeutic strategy against colorectal carcinoma.
白细胞介素-12（IL-12）是一种免疫刺激细胞因子，在几种动物模型中具有强大的抗肿瘤作用。然而，其全身应用于人类时会产生严重的毒性。基因转移已成为一种将治疗性基因特异性表达到肿瘤/肿瘤周围环境中的工具，从而避免全身毒性。本研究旨在分析亚治疗剂量的编码白细胞介素-12 的腺病毒（AdIL-12）是否与低免疫增强剂量的环磷酰胺联合治疗结直肠癌具有协同作用。
在体内结直肠癌小鼠模型中评估单次低剂量环磷酰胺联合肿瘤内注射 AdIL-12 的抗肿瘤作用。监测不同治疗方法所获得的免疫反应，比较联合两种治疗方法与单独治疗方法的效果。
联合治疗以协同方式诱导>50%的小鼠完全肿瘤消退，并显著延长其生存期。与单独治疗相比，这种策略在减少外周和脾脏 CD4+CD25+Foxp3+调节性 T 细胞、增加活化树突状细胞数量和诱导 IFN-γ分泌的 CD4+阳性 T 淋巴细胞方面更具优势。重要的是，联合治疗产生了强大的肿瘤特异性 CTL 反应。相应地，发现 IL-10 水平显著降低。我们的数据表明，非毒性剂量的环磷酰胺与 AdIL-12 的联合使用可以产生良好的抗肿瘤反应，从而避免两种药物的不良副作用。
我们的数据强烈支持将环磷酰胺和 AdIL-12 联合使用作为一种针对结直肠癌的新治疗策略。
