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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 -项目总结