ENHANCING ONCOLYTIC VIROTHERAPY 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，癌症的病毒感染还引起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型干扰素（IFN）家族（IL-29、28 A、28 B;也称为IFN-γ）。 如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对免疫应答的刺激作用和增加病毒对肿瘤细胞的选择性来提高溶瘤活性。我们的初步数据显示，表达IL-28 A的VSV在培养的IL-28应答性永生化肝细胞中以及在体内鼻内递送至小鼠后减弱。使用HCC的小鼠模型，我们将检验来自VSV载体的IL-28 A的表达将增强溶瘤活性的假设。然后，我们将通过进行研究以确定对NK细胞和T细胞的免疫刺激作用的贡献、病毒对IL-28非应答性肿瘤细胞的选择性增加以及抗IL-28抗体的作用，来研究由VSV表达的IL-28增强溶瘤活性的机制。 增殖/促凋亡作用。本文提出的研究将有助于阐明VSV和IL-28的溶瘤活性的抗肿瘤机制。阐明这些机制对于更好地理解宿主免疫系统、肿瘤和病毒之间复杂的动态关系至关重要。通过结合VSV和IL-28各自已证实的抗癌活性，这些研究将为创建更有效的工程化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.