Enhancing Oncolytic Virus Function with Type III Interferon

描述（由申请人提供）：肝细胞癌（HCC）每年在全世界造成超过50万人死亡。由于缺乏有效的治疗方法，这种疾病需要新的治疗方法。溶瘤病毒载体，如基于水泡性口炎病毒（VSV）的那些，是用于HCC的有前途的新抗癌平台。虽然VSV的溶瘤作用已被明确定义，但这种抗肿瘤活性的机制尚不完全清楚。除了直接的细胞溶解外，癌细胞的病毒感染已显示出引发特异性和非特异性免疫应答，从而克服对肿瘤的免疫耐受。抗病毒细胞因子的III型IFN家族（IL-29、28 A、28 B;也称为IFN-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。我们假设VSV表达这些细胞因子将通过免疫刺激作用和增加病毒对肿瘤细胞的选择性来提高VSV的溶瘤活性。我们的初步数据显示，表达IL-28 A的VSV在培养的IL-28敏感的永生化肝细胞中以及在体内鼻内递送至小鼠后被减弱。使用HCC的小鼠模型，我们将检验来自VSV载体的IL-28的表达将增强溶瘤活性的假设。然后，我们将研究VSV表达的IL-28增强VSV溶瘤活性的机制，方法是进行机制研究，以确定对NK细胞和T细胞的刺激作用、病毒对IL-28抗性肿瘤细胞的选择性增加以及抗增殖/促凋亡作用的贡献。广泛地说，本研究中提出的研究将增加对溶瘤病毒作为HCC和其他癌症的替代疗法的抗肿瘤机制的理解。我们的研究还将更好地了解宿主免疫系统，肿瘤和病毒之间的复杂和动态关系，并深入了解癌细胞操纵的调节机制，以逃避免疫系统的消除。

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.