Project 4: Immunovirotherapy

项目4 -项目概要 肝细胞癌（HCC）是癌症死亡的第二大最常见原因， 有效的治疗选择导致5年生存率低于12%。我们的团队进行了广泛的 工程化水泡性口炎病毒（VSV）作为溶瘤平台的临床前表征， 证明它是一种治疗癌症的高效免疫抑制剂。我们有 建立了小鼠模型，其证明全身性检查点阻断的组合， 与肿瘤内递送的溶瘤病毒结合可以显著改善生存结果， 或者单独使用。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 一种疫苗载体，其能够破坏几种小鼠中对肿瘤相关抗原（TAA）的耐受性 肿瘤模型在目前的提案中，我们将建立在正在进行的HCC I期临床试验的基础上， 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的组合疗法的临床前数据 战略目前项目的总体假设是溶瘤VSV提供了一种互补的 免疫检查点抑制的作用机制。VSV-IFN-β与durvalumab（抗-IFN-β）的组合可抑制VSV-IFN-β的表达。 PD-L1）将在晚期HCC患者的IB期临床研究中进行测试（目的1）。使用两种鼠 肝癌模型，我们将进一步完善合理的，基于机制的， 多重检查点阻断抗体与VSV-IFN-β（Aim 2）。使用小鼠HCC模型，将鉴定和 验证我们将用VSV免疫疗法靶向的新型HCC TAA（目标3）。总的来说，这些研究将 为优化联合治疗的设计提供见解，并导致一系列新的临床试验， 治疗这种疾病，目前几乎没有有效的常规疗法。

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.