ENHANCING ONCOLYTIC VIROTHERAPY WITH TYPE III INTERFERON

使用 III 型干扰素增强溶瘤病毒治疗

基本信息

批准号：
8989222
负责人：
MICHAEL ROBEK
金额：
$ 17.18万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-15 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8989222
关键词：
Antiviral Agents Apoptotic Attenuated CD8B1 gene Cancer Model Cell Culture Techniques Cell model Cells Cessation of life Clinical Coculture Techniques Complex Cytolysis Data Disease Effectiveness Engineering Equilibrium Excision Family Gene Order Health Hepatocyte Immune Immune response Immune system Immunity In Vitro Individual Infection Inflammation Interferons Lighting Liver neoplasms Malignant Neoplasms Malignant neoplasm of liver Measures Messenger RNA Methionine Mus Mutation Natural Killer Cells Normal Cell Normal tissue morphology Oncogenic Viruses Oncolytic Oncolytic viruses Operative Surgical Procedures Positioning Attribute Primary carcinoma of the liver cells Property Recombinants Relative (related person)Role Safety T-Lymphocyte Testing Treatment Efficacy Vesicular stomatitis Indiana virus Vesicular stomatitis virus M protein Viral Viral Genome Viral Proteins Viral Vector Virotherapy Virus Virus Diseases anticancer activity base cancer cell cytokine effective therapy improved in vivo innovation liver transplantation mRNA Export mouse model neoplastic cell novel therapeutic intervention novel therapeutics oncolysis oncolytic Vesicular Stomatitis Virus overexpression receptor response stable cell line tumor tumor progression vector

项目摘要

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.

描述（由申请人提供）：肝细胞癌 (HCC) 每年导致全球超过 500,000 人死亡。这种疾病缺乏有效的治疗方法，因此需要新的治疗方法，例如基于水泡性口炎病毒的治疗方法。 VSV）是一种有前景的 HCC 新型抗癌平台，虽然 VSV 的溶瘤作用已明确，但其背后的机制。除了直接细胞溶解作用外，病毒感染癌细胞还会引发特异性和非特异性免疫反应，从而克服抗病毒细胞因子的 III 型干扰素 (IFN) 家族的免疫耐受。 28B；也已知由于 IFN-λ1、2 和 3）具有抗病毒和免疫调节特性，并且在小鼠癌症模型中抑制肿瘤进展，我们发现 VSV 中这些细胞因子的表达将通过对免疫反应的刺激作用和增加来提高溶瘤活性。我们的初步数据表明，表达 IL-28A 的 VSV 在培养的 IL-28 反应性永生化肝细胞中以及鼻内递送至体内后减弱。使用 HCC 小鼠模型，我们将检验 VSV 载体表达的 IL-28A 将增强溶瘤活性的假设，然后我们将研究 VSV 表达的 IL-28 通过以下方式增强溶瘤活性的机制。进行研究以确定免疫刺激作用对 NK 细胞和 T 细胞的贡献、病毒对 IL-28 无反应性肿瘤细胞的选择性增加以及抗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，对于更好地理解宿主免疫系统、免疫系统之间的复杂和动态关系至关重要。通过将 VSV 和 IL-28 各自经过验证的抗癌活性结合起来，这些研究将为创建更有效的工程溶瘤病毒载体提供信息。