Project 4: Immunovirotherapy

项目4：免疫病毒疗法

• 批准号: 10251135
• 负责人: Richard G. Vile
• 金额: $ 29.86万
• 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/10251135
• 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 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 Protocols; Tumor Antigens; 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 situ vaccination; in vivo Model; insight; melanoma; mouse model; next generation; novel; oncolytic Vesicular Stomatitis Virus; pre-clinical; research clinical testing; response; survival outcome; therapeutically effective; 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）是癌症第二大死亡原因，缺乏 有效的治疗选择导致5年生存率低于12％。我们的小组进行了广泛的 工程囊泡口腔炎病毒（VSV）作为溶瘤平台的临床前表征，具有 证明它是用于治疗癌症的高效免疫治疗剂。我们有 已建立的鼠模型，表明系统检查点封锁的组合 与肿瘤内传递的溶瘤病毒的结合可以显着改善生存结果 一个单独的方式。除了VSV的溶瘤效应外，我们还开发了这个平台作为有效的 能够破坏几只小鼠中与肿瘤相关抗原（TAA）耐受性的疫苗载体 肿瘤模型。在当前的提案中，我们将在HCC的I期临床试验中建立 表达免疫刺激基因干扰素β（IFN-β）的溶瘤VSV直接注入肝脏 癌症，以及我们的临床前数据支持组合疗法，并具有免疫检查点抑制 战略。当前项目的总体假设是溶瘤VSV提供了完整性 免疫抑制作用的作用机理。 VSV- IFN-β与杜瓦卢马布的组合（抗 PD-L1）将在IB期临床研究中进行晚期HCC患者的测试（AIM 1）。使用两种鼠 HCC模型，我们将进一步完善理性，基于机制的剂量方案 带有VSV-IFN-β的多个检查点阻断抗体（AIM2）。使用Murine HCC模型，将识别并 验证我们将使用VSV免疫疗法靶向的新型HCC TAA（AIM 3）。总体而言，这些研究将 提供有关优化组合疗法的设计的见解，并导致一系列新的临床试验 这种疾病的治疗方法目前很少有有效的常规疗法。