Enhancing Oncolytic Virotherapy with Type III Interferon

描述(由申请者提供)：据估计，全世界每年有超过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作用外，病毒感染肿瘤细胞还能引起特异性和非特异性免疫反应，从而克服对肿瘤的免疫耐受。III型干扰素(IFN)家族的抗病毒细胞因子(IL-29、28A、28B；也称为 由于干扰素-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。我们假设，VSV的这些细胞因子的表达将通过刺激免疫反应和增加病毒对肿瘤细胞的选择性来改善溶瘤活性。我们的初步数据显示，表达IL-28A的VSV在培养的IL-28反应的永生化肝细胞中以及经鼻给药后在体内均减弱。使用小鼠肝细胞癌模型，我们将检验从VSV载体表达IL-28A将增强溶瘤活性的假设。然后，我们将通过研究确定免疫刺激效应对NK细胞和T细胞的作用，增加病毒对IL-28无反应性肿瘤细胞的选择性，以及抗IL-28抗体，来研究VSV表达的IL-28增强肿瘤溶解活性的机制。 增殖/促凋亡作用。这些研究将有助于阐明VSV和IL-28的抗肿瘤作用机制。阐明这些机制对于更好地理解宿主免疫系统、肿瘤和病毒之间的复杂和动态关系至关重要。通过联合单独证实的VSV和IL-28的抗癌活性，这些研究将因此为创建更有效的工程溶瘤病毒载体提供信息。

DESCRIPTION (provided by applicant): Hepatocellular arcinoma (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 elicits specific and nonspecific immune responses, thus overcoming immunological tolerance to the tumor. The type III interferon (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 activity through both stimulatory effects on the immune response and by increasing selectivity of the virus for tumor cells. Our preliminary data show that VSV expressing IL-28A is attenuated in cultured IL-28-responsive 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-28A 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 by performing studies to determine the contribution of immunostimulatory effects on NK cells and T cells, increased selectivity of the virus for IL-28-nonresponsive tumor cells, and anti proliferative/pro-apoptotic actions. The studies proposed here will help elucidate the antitumor mechanisms responsible for the oncolytic activity of VSV and IL-28. Illumination of these mechanisms is crucial for better understanding the complex and dynamic relationship between the host immune system, the tumor, and the virus. By uniting the individually proven anticancer activities of VSV and IL-28, these studies will thereby inform the creation of more potent engineered oncolytic viral vectors.