Project 4: Immunovirotherapy

项目4：免疫病毒疗法

基本信息

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
项目类别：
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

项目摘要

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，缺乏足够的我们的小组进行了广泛的有效治疗选择，使 5 年生存率低于 12%。工程化水泡性口炎病毒（VSV）作为溶瘤平台的临床前表征，并具有我们已经证明它是一种治疗癌症的高效免疫治疗剂。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除了 VSV 的溶瘤作用之外，我们还开发了该平台作为一种有效的平台。能够打破几只小鼠对肿瘤相关抗原（TAA）耐受性的疫苗载体在当前的提案中，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当前项目的总体假设是溶瘤 VSV 提供了补充。 VSV-IFN-β 与 durvalumab（抗-）组合的作用机制。 PD-L1）将在晚期 HCC 患者中进行 IB 期临床研究（目标 1）。针对HCC模型，我们将进一步完善合理、机制、组合的给药方案使用 VSV-IFN-β (Aim2) 的多重检查点阻断抗体将使用鼠 HCC 模型进行识别和鉴定。验证我们将用 VSV 免疫疗法靶向的新型 HCC TAA（目标 3）。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。