Project 4: Immunovirotherapy

项目4：免疫病毒疗法

• 批准号: 10468832
• 负责人: Richard G. Vile
• 金额: $ 25.32万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468832
• 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; Persons; 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; liver cancer model; 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--项目总结 肝细胞癌(肝细胞癌)是第二常见的癌症死亡原因，缺乏 有效的治疗方案使5年存活率低于12%。我们小组已经进行了广泛的 工程水疱性口炎病毒(VSV)作为溶瘤平台的临床前特征 证明它是一种治疗癌症的高效免疫治疗剂。我们有 已建立的小鼠模型表明，全身检查点封锁联合 联合瘤内注射溶瘤病毒可显著改善患者的生存结果。 两种方式都不能单独使用。除了VSV的溶瘤作用外，我们还开发了这个平台作为一种有效的 一种能够在几只小鼠中打破对肿瘤相关抗原(TAA)耐受的疫苗载体 肿瘤模型。在目前的提案中，我们将建立在正在进行的肝细胞癌第一阶段临床试验的基础上 表达免疫刺激基因干扰素-β(干扰素-β)的溶瘤病毒直接注射到肝脏 癌症，以及我们的临床前数据支持免疫检查点抑制的联合治疗 策略。目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-干扰素-β与杜瓦单抗(抗-抗)联合应用 PD-L1)将在晚期肝癌患者的IB期临床研究中进行测试(AIM 1)。用这两只小鼠 在建立肝细胞癌模型的基础上，我们将进一步细化合理的、以机制为基础的、以 用VSv-干扰素-β(AIM2)阻断多个检查点抗体。使用小鼠肝细胞癌模型，将识别和 验证我们将以VSV免疫疗法为靶点的新型肝癌TAAs(目标3)。总体而言，这些研究将 为优化组合疗法的设计提供洞察力，并导致一系列新的临床试验 这种疾病的治疗目前几乎没有有效的传统疗法。