Oncolytic vesicular stomatitis virus expressing interferon-γ has enhanced therapeutic activity
Oncolytic vesicular stomatitis virus expressing interferon-γ has enhanced therapeutic activity
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DOI：
10.1038/mto.2016.1
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发表时间：
2016-02-17
影响因子：
5.7
通讯作者：
Bell, John Cameron
中科院分区：
文献类型：
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作者：
Bourgeois-Daigneault, Marie-Claude;Roy, Dominic Guy;Bell, John Cameron
已知溶瘤病毒通过在肿瘤细胞中特异性复制来刺激抗肿瘤免疫反应。这被认为是在一些患者中观察到的持久反应的一个重要方面，并且该领域正在迅速转向免疫治疗。作为参与免疫系统的进一步手段，我们设计了一种病毒，即水泡性口炎病毒（VSV），来编码促炎细胞因子干扰素-γ。我们使用 4T1 乳腺癌以及其他小鼠肿瘤模型来表征荷瘤动物通过我们的病毒治疗产生的免疫反应。与亲本病毒相比，编码干扰素γ的病毒表现出更强的树突状细胞活化作用，并驱动促炎细胞因子的更深层分泌。从治疗的角度来看，干扰素-γ病毒在几种小鼠肿瘤模型中减缓了肿瘤生长，最大限度地减少了肺部肿瘤，并延长了生存期。在免疫功能低下的动物中，改善的功效消失了；因此，该机制似乎是 T 细胞介导的。总而言之，这些结果证明了溶瘤病毒作为免疫刺激剂驱动抗肿瘤免疫的能力以及它们进行靶向基因治疗的潜力。
Oncolytic viruses are known to stimulate the antitumor immune response by specifically replicating in tumor cells. This is believed to be an important aspect of the durable responses observed in some patients and the field is rapidly moving toward immunotherapy. As a further means to engage the immune system, we engineered a virus, vesicular stomatitis virus (VSV), to encode the proinflammatory cytokine interferon-gamma. We used the 4T1 mammary adenocarcinoma as well as other murine tumor models to characterize immune responses in tumor-bearing animals generated by treatment with our viruses. The interferon-gamma-encoding virus demonstrated greater activation of dendritic cells and drove a more profound secretion of proinflammatory cytokines compared to the parental virus. From a therapeutic point of view, the interferon-gamma virus slowed tumor growth, minimized lung tumors, and prolonged survival in several murine tumor models. The improved efficacy was lost in immunocompromized animals; hence the mechanism appears to be T-cell-mediated. Taken together, these results demonstrate the ability of oncolytic viruses to act as immune stimulators to drive antitumor immunity as well as their potential for targeted gene therapy.