Department of Pathology, NYU Cancer Institute, NYU Gene Therapy Center, NYU School of Medicine, New York, USA.
Cancer Gene Ther. 2012 Aug;19(8):588-91. doi: 10.1038/cgt.2012.33. Epub 2012 Jun 8.
Oncolytic viruses (OVs) have shown great anti-cancer potential in animal models, but only modest success in early clinical trials. A better understanding of the mechanisms underlining OV efficacy is needed to resolve this discrepancy. In the clinic, OV therapy will likely be combined with traditional chemotherapy, underscoring the need to also evaluate the interactions between these therapeutic modalities. Here we show that combining Sindbis viral vector therapy with the topoisomerase inhibitor irinotecan (CPT-11) results in the long-term survival of about 35% of SCID mice bearing aggressively growing ES2 human ovarian cancer. Single-agent treatments did not result in long-term survival. Flow cytometry analysis, bioluminescent imaging and survival experiments revealed that Sindbis and CPT-11 utilize non-overlapping natural killer (NK)-cell-dependent and -independent anti-cancer mechanisms, respectively. Notably, the combinatorial therapy was only effective in the presence of NK cells. These results highlight the hidden role of immune cell activation in combinatorial cancer therapy involving OVs and provide a potential method for tackling tumor cell resistance to cancer therapy while limiting treatment-related side effects.
溶瘤病毒（OVs）在动物模型中显示出了巨大的抗癌潜力，但在早期临床试验中仅取得了适度的成功。为了解决这一差异，需要更好地了解OV 疗效背后的机制。在临床上，OV 治疗可能与传统化疗联合使用，这突显了评估这些治疗方式之间相互作用的必要性。在这里，我们表明，用辛德比斯病毒载体治疗联合拓扑异构酶抑制剂伊立替康（CPT-11）可使携带生长迅速的 ES2 人卵巢癌细胞的 SCID 小鼠的长期存活率达到约 35%。单一药物治疗不会导致长期存活。流式细胞术分析、生物发光成像和生存实验表明，辛德比斯和 CPT-11 分别利用非重叠的自然杀伤（NK）细胞依赖和非依赖的抗癌机制。值得注意的是，组合疗法仅在存在 NK 细胞的情况下才有效。这些结果强调了免疫细胞激活在涉及 OV 的组合癌症治疗中的隐藏作用，并为解决肿瘤细胞对癌症治疗的耐药性提供了一种潜在方法，同时限制了治疗相关的副作用。
