Novel multipronged Immunovirotherapy Approach for GBM Treatment

项目摘要 胶质母细胞瘤（GBM）的预后仍然令人沮丧，尽管使用了化疗，但中位生存期为16-18个月。 综合治疗免疫治疗尝试在GBM治疗中一直不成功，包括 免疫检查点抑制剂和疫苗的III期临床试验呈阴性。基于强大的临床前数据，我们 假设我们可以通过采用一种免疫治疗方法来开发一种有效的针对GBM的免疫治疗方法， 表达幽门螺杆菌嗜人免疫球蛋白激活的免疫刺激性麻疹病毒株（MV-s-NAP） 蛋白（NAP），Toll样受体2激动剂。我们还假设MV-s-NAP诱导了肿瘤的变化， 微环境，由免疫原性细胞死亡引起，可以提高疗效，并导致协同作用， 与免疫检查点抑制剂联合使用。我们建议透过以下措施，进一步提高这个方法的成效 阻断IDO上调的抑制作用。我们还建议优化胶质母细胞瘤中的病毒复制 通过阻断干扰素应答途径，一种已知的哺乳动物细胞对溶瘤药物的抗性机制， 病毒，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病毒治疗与抗体联合作用效果、最佳顺序和作用机制 在免疫活性GBM模型中阻断PD-1/PD-L1轴和IDO抑制剂，包括GL 261， CT 2A，以及自发性胶质瘤形成的基因工程模型。在具体目标2中， 评估调节干扰素刺激基因的表达对MV-s-NAP功效的影响 通过抑制干扰素应答途径进行病毒治疗和免疫病毒治疗， 降低病毒的容许性和复制。在具体目标3中，我们将测试最佳疗效的安全性 在麻疹中开展毒理学和生物分布研究， 复制许可的Ifnarko CD 46 Ge小鼠（FDA批准的麻疹病毒复制模型）， 在临床转化之前确定该组合的安全剂量。推荐的人体安全性 将在第二个灵长类动物（恒河猴）模型中进一步确认剂量。总的来说，这项工作将介绍 一种创新的多管齐下的免疫病毒治疗方法，用于治疗胶质母细胞瘤， 以克服在其他策略中观察到的功效缺乏。

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.