Previously, we described an oncolytic vesicular stomatitis virus variant pseudotyped with the nonneurotropic glycoprotein of the lymphocytic choriomeningitis virus, VSV-GP, which was highly effective in glioblastoma. Here, we tested its potency for the treatment of ovarian cancer, a leading cause of death from gynecological malignancies. Effective oncolytic activity of VSV-GP could be demonstrated in ovarian cancer cell lines and xenografts in mice; however, remission was temporary in most mice. Analysis of the innate immune response revealed that ovarian cancer cell lines were able to respond to and produce type I interferon, inducing an antiviral state upon virus infection. This is in stark contrast to published data for other cancer cell lines, which were mostly found to be interferon incompetent. We showed that in vitro this antiviral state could be reverted by combining VSV-GP with the JAK1/2-inhibitor ruxolitinib. In addition, for the first time, we report the in vivo enhancement of oncolytic virus treatment by ruxolitinib, both in subcutaneous as well as in orthotopic xenograft mouse models, without causing significant additional toxicity. In conclusion, VSV-GP has the potential to be a potent and safe oncolytic virus to treat ovarian cancer, especially when combined with an inhibitor of the interferon response.

中文翻译：

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干扰素调节剂在克服人类卵巢癌对VSV-GP溶瘤病毒治疗的部分耐药性中的应用。

以前，我们描述了一种溶细胞性水疱性口炎病毒变异体，该变异体以淋巴细胞性脉络膜脑膜炎病毒VSV-GP的非神经营养糖蛋白为假型，在胶质母细胞瘤中非常有效。在这里，我们测试了其治疗卵巢癌的功效，卵巢癌是妇科恶性肿瘤致死的主要原因。VSV-GP的有效溶瘤活性可以在小鼠的卵巢癌细胞系和异种移植物中得到证实。但是，大多数小鼠的缓解是暂时的。对先天免疫应答的分析表明，卵巢癌细胞系能够对I型干扰素产生反应，并在感染病毒后诱导产生抗病毒状态。这与其他癌细胞系的公开数据形成了鲜明对比，其他癌细胞系大多被发现是干扰素缺乏能力的。我们表明，在体外，通过将VSV-GP与JAK1 / 2抑制剂鲁索替尼联合使用可以逆转这种抗病毒状态。此外，我们首次报道了鲁索替尼在皮下以及原位异种移植小鼠模型中体内增强溶瘤病毒治疗的效果，而没有引起明显的其他毒性。总之，VSV-GP有潜力成为治疗卵巢癌的有效且安全的溶瘤病毒，尤其是与干扰素应答抑制剂联合使用时。