Novel multipronged Immunovirotherapy Approach for GBM Treatment

项目摘要 胶质母细胞瘤(GBM)的预后仍然很差，中位生存期为16-18个月 综合治疗。免疫治疗尝试在GBM治疗中未获成功，包括 免疫检查点抑制剂和疫苗的第三阶段试验呈阴性。基于强大的临床前数据，我们 假设我们可以开发一种有效的针对GBM的免疫治疗方法 表达幽门螺杆菌中性粒细胞激活的免疫刺激麻疹病毒株(MV-S-NAP) 蛋白质(NAP)，一种Toll样受体2激动剂。我们还假设MV-S-NAP诱导了肿瘤的变化 由免疫原性细胞死亡引起的微环境在以下情况下可以提高疗效并产生协同作用 与免疫检查点抑制剂结合使用。我们建议通过以下方式进一步提高这一方法的有效性 阻断IDO上调的抑制作用。我们还建议优化胶质母细胞瘤的病毒复制 通过阻断干扰素反应途径，哺乳动物细胞对溶瘤的已知抵抗机制 病毒，使用JAK抑制剂。该项目有三个具体目标：在具体目标1中，我们计划评估 MV-S-NAP病毒联合抗体的疗效、最佳治疗顺序及作用机制 阻断免疫活性GBM模型中PD-1/PD-L1轴和IDO抑制剂，包括GL261， CT2a，以及自发胶质瘤发生的基因工程模型。在具体目标2中，我们将 干扰素刺激基因表达调控对MV-S-NAP疗效的影响 病毒疗法和免疫病毒疗法通过抑制干扰素反应途径，这已被证明 减少病毒的传播和复制。在具体目标3中，我们将测试最优疗效的安全性 在特定目标1和2中确定的方法，通过在麻疹中进行毒理学和生物分布研究 允许复制的Ifnarko CD46 GE小鼠(FDA批准的麻疹病毒复制模型)，以便 在临床转译前确定联合用药的安全剂量。推荐人的安全 剂量将在第二个灵长类动物(恒河猴)模型中进一步确认。总体而言，这项工作将介绍 一种创新的多管齐下的免疫病毒疗法治疗有潜力的胶质母细胞瘤 以克服其他策略所观察到的疗效不足。

Project Summary Glioblastoma (GBM) prognosis remains dismal with a median survival of 16-18 months despite the use of multimodality treatment. Immunotherapy attempts have been unsuccessful in GBM treatment, including negative phase III trials of immune checkpoint inhibitors and vaccines. Based on strong preclinical data, we hypothesize that we can develop an effective immunotherapy approach against GBM by employing an immunostimulatory measles virus strain (MV-s-NAP) expressing the Helicobacter Pylori neutrophil-activating protein (NAP), a toll-like receptor 2 agonist. We also hypothesize that MV-s-NAP induced changes in the tumor microenvironment, resulting from immunogenic cell death, can increase efficacy and lead in synergy when combined with immune checkpoint inhibitors. We propose to further enhance the efficacy of this approach by blocking the inhibitory effect of IDO upregulation. We also propose to optimize viral replication in glioblastoma by blocking the interferon response pathway, a known mechanism of mammalian cell resistance to oncolytic viruses, with JAK inhibitors. This project has three specific aims: In specific aim 1, we plan to evaluate the efficacy, optimal sequence and mechanism of action of MV-s-NAP virotherapy in conjunction with antibody blockade of the PD-1/PD-L1 axis and IDO inhibitors in immunocompetent GBM models, including GL261, CT2A, as well as genetically engineered models of spontaneous gliomagenesis. In specific aim 2 we will evaluate the impact of modulating expression of interferon stimulated genes on the efficacy of MV-s-NAP virotherapy and immunovirotherapy by inhibiting the interferon response pathway, which has been shown to decrease viral permissiveness and replication. In specific aim 3 we will test the safety of the optimal efficacy approach identified in specific aims 1 and 2 by conducting toxicology and biodistribution studies in measles replication permissive Ifnarko CD46 Ge mice (an FDA approved model of measles virus replication) in order to determine the safe dose of the combination prior to clinical translation. Safety of the recommended human dose will be further confirmed in a second primate (Rhesus macaques) model. Overall, this work will introduce an innovative multipronged immunovirotherapy approach in the treatment of glioblastoma that has the potential to overcome the lack of efficacy observed with other strategies.