Project 4: Immunovirotherapy

项目4：免疫病毒疗法

• 批准号: 10006086
• 负责人: Richard G. Vile
• 金额: $ 31.58万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-10 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006086
• 关键词: Antibodies; Autoantigens; BAY 54-9085; Back; Cause of Death; Clinic; Clinical; Clinical Data; Clinical Research; Clinical Treatment; Clinical Trials; Combined Modality Therapy; Data; Development; Diagnosis; Disease; Dose; Engineering; Genes; Glioma; Hepatobiliary; Human; Immune; Immune checkpoint inhibitor; Immunotherapeutic agent; Immunotherapy; In Situ; In Vitro; Interferon-beta; Interferons; Lead; Malignant Neoplasms; Malignant neoplasm of liver; Memory; Modality; Modeling; Mus; Oncolytic; Oncolytic viruses; Patients; Phase; Phase I Clinical Trials; Primary carcinoma of the liver cells; Prostate; Refractory; Regimen; Research Project Grants; Series; Survival Rate; Testing; Treatment Efficacy; Treatment Protocols; Tumor Antigens; Vaccination; Vesicular stomatitis Indiana virus; Viral; Virus; anti-PD-L1; anti-PD-L1 antibodies; antibody inhibitor; base; bench to bedside; cancer therapy; checkpoint inhibition; cohort; combinatorial; conventional therapy; design; early phase clinical trial; first-in-human; human study; immune checkpoint blockade; immunotherapeutic virotherapy; improved; in vivo Model; insight; melanoma; mouse model; next generation; novel; oncolytic Vesicular Stomatitis Virus; pre-clinical; research clinical testing; response; survival outcome; treatment optimization; tumor; vector vaccine

PROJECT 4 – PROJECT SUMMARY Hepatocellular carcinoma (HCC) is the second most frequent cause of death from cancer and a lack of effective therapeutic options has led to a 5-year survival rate below 12%. Our group has conducted extensive preclinical characterization of engineered Vesicular Stomatitis Virus (VSV) as an oncolytic platform and has demonstrated it to be a highly effective immunotherapeutic agent for the treatment of cancer. We have established murine models which demonstrate that the combination of systemic checkpoint blockade in conjunction with an intratumorally delivered oncolytic virus can significantly improve survival outcome over either modality alone. In addition to the oncolytic effects of VSV, we developed this platform as a potent vaccine vector that is capable of breaking tolerance to tumor-associated antigens (TAAs) in several mouse tumor models. In the current proposal, we will build on an ongoing Phase I clinical trial for HCC in which oncolytic VSV expressing the immune stimulatory gene Interferon-β (IFN-β) is injected directly into liver cancers, and on our pre-clinical data supporting combinatorial therapy with an immune checkpoint inhibition strategy. The overall hypothesis of the current project is that oncolytic VSV provides a complementary mechanism of action to immune checkpoint inhibition. The combination of VSV- IFN-β with durvalumab (anti- PD-L1) will be tested in a Phase IB clinical study in patients with advanced HCC (Aim 1). Using both murine models of HCC, we we will further refine dosing regimens of rational, mechanism-based, combinations of multiple checkpoint blockade antibodies with VSV-IFN-β (Aim2). Using murine HCC models, will identify and validate novel HCC TAAs that we will target with VSV immunotherapy (Aim 3). Overall, these studies will provide insight into the design of optimized combination therapy and lead to a series of new clinical trials for the treatment this disease for which few effective conventional therapies currently exist.

项目 4 – 项目摘要 肝细胞癌 (HCC) 是癌症死亡的第二常见原因，缺乏足够的 有效的治疗选择导致 5 年生存率低于 12%。我们组进行了广泛的 工程化水泡性口炎病毒（VSV）作为溶瘤平台的临床前表征，并具有 证明它是一种治疗癌症的高效免疫治疗剂。我们有 建立的小鼠模型表明，全身检查点阻断的组合 与瘤内递送的溶瘤病毒相结合可以显着改善生存结果 单独使用任一方式。除了 VSV 的溶瘤作用外，我们还开发了该平台作为有效的 能够打破几种小鼠对肿瘤相关抗原（TAA）耐受性的疫苗载体 肿瘤模型。在当前的提案中，我们将以正在进行的 HCC 一期临床试验为基础，其中 将表达免疫刺激基因干扰素-β (IFN-β) 的溶瘤 VSV 直接注射到肝脏中 癌症，以及我们支持免疫检查点抑制联合治疗的临床前数据 战略。当前项目的总体假设是溶瘤 VSV 提供了一种补充 免疫检查点抑制的作用机制。 VSV-IFN-β 与 durvalumab（抗 PD-L1）将在晚期 HCC 患者的 IB 期临床研究中进行测试（目标 1）。使用小鼠 针对HCC模型，我们将进一步完善合理的、基于机制的、组合的给药方案 含有 VSV-IFN-β 的多重检查点阻断抗体 (Aim2)。使用小鼠 HCC 模型，将识别和 验证我们将用 VSV 免疫疗法靶向的新型 HCC TAA（目标 3）。总体而言，这些研究将 提供对优化联合疗法设计的见解，并引发一系列新的临床试验 目前尚无有效的常规疗法来治疗这种疾病。