Novel mouse models using MADR-GESTALT technology to accelerate glioma research

摘要(项目) 拟议的实验利用了使用MADR-完形技术创建的新小鼠模型。这些 模型将增强从活体实验中获得的信息，并将应用于以下目标。 目的1：评价脑穿透性受体酪氨酸激酶抑制和免疫治疗的合理组合 在致癌相似的胶质母细胞瘤的新小鼠模型上进行研究。这个项目将调查机制 以免疫为基础的治疗后的免疫逃避，并开发合理的组合 克服脑瘤微环境免疫抑制环境的免疫治疗策略。 准确概括人类GBM中已知的显性致癌驱动因素的免疫活性模型 对这项工作至关重要。我们建议使用MADR-完形系统来创建EGFRvIII驱动的模型 为了测试小分子抑制剂如何有效地与活性疫苗和检查点配对 封锁免疫疗法。 目的：评价TCR基因工程细胞毒性T细胞对H3G34R/V HGG的治疗作用。上一首 研究已经确定了一小部分肿瘤相关的新抗原，它们出现在I类MHC和 在H3F3A突变型胶质母细胞瘤中被抗原特异性T细胞受体结合。H3F3A突变体和野生型 这些模型将被用来进一步深入研究这些特定突变影响肿瘤发生的机制。 在H3G34R胶质母细胞瘤中，并将用于临床前测试TCR工程过继T细胞的疗效 细胞转移作为H3F3A突变型胶质母细胞瘤的靶向治疗

ABSTRACT (Project) The proposed experiments leverage novel mouse models created using MADR-GESTALT technology. These models will enhance information derived from in vivo experiments and are being applied in the following aims. Aim 1: Evaluate rational combinations of brain penetrant receptor tyrosine kinase inhibition and immunotherapy for study in new mouse models of oncogenically similar glioblastoma. This project will investigate mechanisms of immune evasion following treatment with immune-based therapy, and develop rational combinations of immunotherapeutic strategies to overcome the immunosuppressive milieu of the brain tumor micro-environment. Immunocompetent models that accurately recapitulate the known dominant oncogenic drivers in human GBM are crucial to this work. We propose to use the MADR-GESTALT system to create models of EGFRvIII-driven GBM in order to test how small molecule inhibitors can be effectively paired with active vaccines and checkpoint blockade immunotherapy. Aim 2: Evaluate the therapeutic potential of TCR-engineered cytotoxic T cells in H3G34R/V HGG. Previous research has identified a small number of tumor-associated neoantigens that are presented on class I MHC and are bound by antigen-specific T cell receptors in H3F3A mutant glioblastoma. H3F3A mutant and wild-type models will be used to further delve into the mechanisms by which these particular mutations affect oncogenesis in H3G34R glioblastoma, and will be used for pre-clinical testing of the efficacy of TCR-engineered adoptive T cell transfer as targeted therapy for H3F3A mutant glioblastoma.