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

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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 and CDK4/6-driven GBM in order to test how small molecule inhibitors can be effectively paired with active vaccines and checkpoint blockade immunotherapy. Aim 2: Establish a moderate-throughput, high-fidelity, patient-specific in vivo modeling platform using MADR in order to understand pathogenicity of novel germline variants, their effects on gene expression, and their contribution to pHGG susceptibility. This project seeks to determine the role of novel germline mutations in pediatric glioma. The MADR technology will be used to develop mouse models to determine the potential of these germline mutations to contribute to tumorigenesis. The mice will be analyzed for time to tumor development, progression, and survival. Aim 3: 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.