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

使用 MADR-GESTALT 技术加速神经胶质瘤研究的新型小鼠模型

基本信息

批准号：
10709379
负责人：
Linda M Liau
金额：
$ 23.56万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-11 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10709379
关键词：
Acceleration Affect Alleles Alternative Splicing Antigen Presentation Bar Codes Basic Science Brain Brain Neoplasms Cancer Patient Childhood Glioblastoma Chromatin Clinical Cytotoxic T-Lymphocytes Engineering Epidermal Growth Factor Receptor Epigenetic Process Evolution Genetic Glioblastoma Glioma Goals Heterogeneity Human Immune Evasion Immunocompetent Immunophenotyping Immunotherapeutic agent Immunotherapy Laboratories MHC Class I Genes Malignant neoplasm of brain Modeling Morbidity - disease rate Mus Mutation Oncogenic PDGFRA gene Pathology Patients Plasmids Pre-Clinical Model Preclinical Testing Proteins Radiation Recurrence Research Research Project Grants Scientist Series Site Structure System T cell therapy T-Cell Receptor TP53 gene Technology Testing Therapeutic Transgenes Translating Translational Research Tyrosine Kinase Receptor Inhibition Vaccines Work Yeasts antigen binding antigen-specific T cells chemotherapy clinical care driver mutation efficacy testing epidermal growth factor receptor VIII experimental study fascinate genome editing immune checkpoint blockade improved in vivo life history mosaic analysis mouse model mutant neoantigens novel novel strategies novel therapeutic intervention recombinase response small molecule inhibitor standard of care targeted treatment transcriptome treatment response tumor tumor microenvironment tumorigenesis

项目摘要

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.

摘要（项目）提出的实验利用了使用MADR-GESTALT技术创建的新型鼠标模型。这些模型将增强从体内实验中得出的信息，并在以下目标中应用。目标1：评估脑穿透受体酪氨酸激酶抑制和免疫疗法的合理组合用于在新的小鼠模型中进行肿瘤上相似的胶质母细胞瘤模型。该项目将调查机制通过免疫治疗治疗后的免疫逃避，并形成合理组合克服脑肿瘤微环境的免疫抑制环境的免疫治疗策略。免疫能力模型准确地概括了人类GBM中已知的显性致癌驱动器对于这项工作至关重要。我们建议使用MADR-GESTALT系统来创建EGFRVIII-DRIEN的模型 GBM为了测试如何有效地将小分子抑制剂与活性疫苗配对封锁免疫疗法。 AIM 2：评估H3G34R/V HGG中TCR工程细胞毒性T细胞的治疗潜力。以前的研究已经确定了I类MHC和由H3F3A突变胶质母细胞瘤中的抗原特异性T细胞受体结合。 H3F3A突变体和野生型模型将用于进一步研究这些特定突变影响肿瘤的机制在H3G34R胶质母细胞瘤中，将用于临床前测试TCR工程的收养T的功效细胞转移作为H3F3A突变胶质母细胞瘤的靶向治疗。