Department of Cancer Biology, Lerner Research Institute, Cleveland, Ohio, USA.
Mol Ther. 2013 Sep;21(9):1749-57. doi: 10.1038/mt.2013.112. Epub 2013 Jun 4.
The use of lytic viruses to preferentially infect and eliminate cancer cells while sparing normal cells is a promising experimental therapeutic approach for treating cancer. However, the efficacy of oncolytic virotherapy is often limited by two innate immunity pathways, the protein kinase PKR and the 2'-5'-oligoadenylate (OAS)/RNase L systems, which are widely present in many but not all tumor cell types. Previously, we reported that the anticancer drug, sunitinib, an inhibitor of VEGF-R and PDGF-R, has off-target effects against both PKR and RNase L. Here we show that combining sunitinib treatments with infection by an oncolytic virus, vesicular stomatitis virus (VSV), led to the elimination of prostate, breast, and kidney malignant tumors in mice. In contrast, either virus or sunitinib alone slowed tumor progression but did not eliminate tumors. In prostate tumors excised from treated mice, sunitinib decreased levels of the phosphorylated form of translation initiation factor, eIF2-α, a substrate of PKR, by 10-fold while increasing median viral titers by 23-fold. The sunitinib/VSV regimen caused complete and sustained tumor regression in both immunodeficient and immunocompetent animals. Results indicate that transient inhibition of innate immunity with sunitinib enhances oncolytic virotherapy allowing the recovery of tumor-bearing animals.
溶瘤病毒选择性感染和消除癌细胞而不影响正常细胞，是一种很有前途的癌症治疗实验治疗方法。然而，溶瘤病毒疗法的疗效往往受到两种固有免疫途径的限制，即蛋白激酶 PKR 和 2'-5'-寡腺苷酸（OAS）/核糖核酸酶 L 系统，这两种途径广泛存在于许多（但不是所有）肿瘤细胞类型中。此前，我们报道称，抗癌药物舒尼替尼（一种 VEGF-R 和 PDGF-R 的抑制剂）对 PKR 和 RNase L 具有非靶向作用。在这里，我们表明舒尼替尼治疗与溶瘤病毒水疱性口炎病毒（VSV）感染相结合，导致小鼠前列腺癌、乳腺癌和肾癌的消除。相比之下，单独使用病毒或舒尼替尼虽然会减缓肿瘤的进展，但不能消除肿瘤。在接受治疗的小鼠切除的前列腺肿瘤中，舒尼替尼使翻译起始因子 eIF2-α的磷酸化形式的水平降低了 10 倍，而病毒的中位数滴度增加了 23 倍。舒尼替尼/VSV 方案使免疫缺陷和免疫功能正常的动物完全和持续地消退肿瘤。结果表明，用舒尼替尼短暂抑制固有免疫可增强溶瘤病毒疗法，使携带肿瘤的动物得到恢复。
