Novel multipronged Immunovirotherapy Approach for GBM Treatment

GBM 治疗的新型多管齐下免疫病毒治疗方法

基本信息

批准号：
10173067
负责人：
Evanthia Galanis
金额：
$ 35.4万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10173067
关键词：
Address Agonist Algorithms Animal Model Antibodies Antigens Biodistribution CD46 Antigen CD8B1 gene Cancer Patient Cell Death Cells Clinical Clinical Data Combined Modality Therapy Data Dendritic Cells Dose Engineering FDA approved Gene Expression Genes Genetic Engineering Glioblastoma Gliomagenesis Helicobacter pylori Human ITGAX gene Immune checkpoint inhibitor Immune response Immunocompetent Immunologic Markers Immunologics Immunooncology Immunophenotyping Immunosuppression Immunotherapeutic agent Immunotherapy Interferons Lead Macaca mulatta Malignant Neoplasms Mammalian Cell Measles Measles virus Modeling Molecular Mus Mutation Natural Killer Cells Oncolytic Oncolytic viruses Outcome PD-1 blockade PD-1 inhibitors PD-1/PD-L1 Pathway interactions Patients Pattern Penetration Phase Population Primates Prognosis Proteins Recurrence Regulatory T-Lymphocyte Resistance Safety Signal Transduction Spleen TLR2 gene Testing Therapeutic Toxicology Transgenes Treatment Efficacy Tryptophan 2,3 Dioxygenase Tumor Antigens Tumor Tissue Tumor-infiltrating immune cells Up-Regulation Vaccines Viral Virotherapy Virus Diseases Virus Replication Work anti-tumor immune response base circulating biomarkers clinical translation combinatorial conventional therapy cytokine efficacy evaluation experience imaging study immunogenic cell death immunogenicity immunotherapeutic virotherapy immunotherapy trials improved inhibitor/antagonist innovation neoantigens neutrophil novel oncolytic virotherapy patient derived xenograft model permissiveness phase I trial phase III trial pre-clinical resistance mechanism response safety testing synergism tumor tumor microenvironment

项目摘要

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.

项目摘要胶质母细胞瘤（GBM）预后仍然令人沮丧，尽管使用了16-18个月的中位生存期多模式处理。免疫疗法尝试在GBM治疗中没有成功，包括免疫检查点抑制剂和疫苗的阴性III期试验。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刺激性麻疹病毒菌株（MV-S-NAP）表达幽门螺杆菌嗜中性粒细胞激活蛋白质（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死亡引起的微环境可以提高功效，并在协同作用中引起协同作用。结合免疫检查点抑制剂。我们建议通过阻止IDO上调的抑制作用。我们还建议在胶质母细胞瘤中优化病毒复制通过阻止干扰素响应途径，这是一种已知的哺乳动物细胞抗性的机理病毒，带有JAK抑制剂。该项目具有三个特定的目标：在特定目标1中，我们计划评估 MV-S-NAP病毒疗法的功效，最佳序列和作用机理与抗体结合免疫能力GBM模型中PD-1/PD-L1轴和IDO抑制剂的阻断，包括GL261， CT2A以及自发神经胶质作用的基因工程模型。在特定目标2中，我们将评估调节干扰素刺激基因表达对MV-S-NAP功效的影响通过抑制干扰素反应途径，病毒疗法和免疫疗法减少病毒允许和复制。在特定目标3中，我们将测试最佳功效的安全性特定目标1和2中通过在麻疹中进行毒理学和生物分布研究确定的方法复制允许的IFNARKO CD46 GE小鼠（FDA认可的麻疹病毒复制模型），以便为了在临床翻译之前确定组合的安全剂量。推荐人的安全剂量将在第二个灵长类动物（恒河猕猴）模型中进一步确认。总的来说，这项工作将介绍一种具有创新的多收益免疫治疗方法，用于治疗具有潜力的胶质母细胞瘤克服缺乏其他策略观察到的疗效。