Enhancing Oncolytic Virus Function with Type III Interferon

描述(由申请者提供)：每年全球约有500,000人死于肝细胞癌。这种疾病缺乏有效的治疗方法，因此需要新的治疗方法。溶瘤病毒载体，如基于水泡性口炎病毒(VSV)的溶瘤病毒载体，是一种很有前途的新型肝癌抗癌平台。虽然VSV的溶瘤作用已被明确定义，但其抗肿瘤活性的机制尚不完全清楚。除了直接的细胞溶解，病毒感染癌细胞已经被证明可以引起特异性和非特异性的免疫反应，从而克服对肿瘤的免疫耐受。III型干扰素家族抗病毒细胞因子(IL-29、28A、28B；也称为干扰素-λ1、2和3)具有抗病毒和免疫调节特性，并在小鼠癌症模型中抑制肿瘤进展。我们推测，VSV的这些细胞因子的表达将通过免疫刺激效应和增加病毒对肿瘤细胞的选择性来改善VSV的溶瘤活性。我们的初步数据显示，在培养的对IL-28敏感的永生化肝细胞中，表达IL-28A的VSV在体内和经鼻给药后均减弱。使用小鼠肝细胞癌模型，我们将检验从VSV载体表达IL-28将增强溶瘤活性的假设。然后，我们将通过机制研究来研究VSV表达的IL-28增强VSV的溶瘤活性的机制，以确定刺激作用对NK细胞和T细胞的贡献，增加病毒对IL-28耐药肿瘤细胞的选择性，以及抗增殖/促凋亡作用。总的来说，这项研究中提出的研究将增加对溶瘤病毒抗肿瘤机制的理解，以应用于肝癌和其他癌症的替代治疗。我们的研究还将更好地了解宿主免疫系统、肿瘤和病毒之间复杂而动态的关系，并深入了解癌细胞为逃避免疫系统消除而操纵的调节机制。

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is responsible for more than 500,000 estimated deaths worldwide each year. The lack of effective therapies for this disease necessitates novel therapeutic approaches. Oncolytic viral vectors, such as those based on vesicular stomatitis virus (VSV), are a promising new anticancer platform for HCC. While the oncolytic effects of VSV are clearly defined, the mechanisms underlying this antitumor activity are incompletely understood. In addition to direct cytolysis, viral infection of cancer cels has been shown to elicit specific and nonspecific immune responses, thus overcoming immunological tolerance to the tumor. The type III IFN family of antiviral cytokines (IL-29, 28A, 28B; also known as IFN-λ1, 2, and 3) have antiviral and immunomodulatory properties, and inhibit tumor progression in mouse models of cancer. We hypothesize that expression of these cytokines from VSV will improve oncolytic VSV activity by both immunostimulatory effects and through increased selectivity of the virus for tumor cells. Our preliminary data show that VSV expressing IL-28A is attenuated in cultured IL-28-sensitive immortalized hepatocytes and after intranasal delivery to mice in vivo. Using a mouse model of HCC, we will examine the hypothesis that expression of IL-28 from a VSV vector will augment oncolytic activity. We will then investigate the mechanisms by which IL-28 expressed from VSV enhances the oncolytic activity of VSV by performing mechanistic studies to determine the contribution of stimulatory effects on NK cells and T cells, increased selectivity of the virus for IL-28-resistant tumor cells and anti-proliferative/pro-apoptotic actions. Broadly, the studies proposed in this investigation will increase the understanding of antitumor mechanisms of oncolytic viruses for application as alternative therapies for HCC and other cancers. Our studies will also provide a better understanding of the complex and dynamic relationship between the host immune system, the tumor, and the virus, and provide insight into the regulatory mechanisms manipulated by cancer cells to evade elimination by the immune system.