Development and validation of an autologous mouse model for the study of immune interactions with glioblastoma

Project Summary An adaptive immunosuppressive microenvironment is a major barrier to immune-based therapies for solid tumors, including glioblastoma (GBM). Current model systems for preclinical development either lack substantial components of the immune system or rely upon different species’ immune systems, which display significant differences when compared to human immune systems. These deficiencies lead to the disconnect between preclinical and clinical research. Here we propose to develop a humanized mouse system for the study of immune system interactions with GBM. By taking hematopoietic stem cells from a GBM patient, we will engraft a human immune system in mice. From the same patient, we will obtain tumor tissue and T cells. This will allow creation of an autologous mouse system, where the components, immune system, tumor, and cell-based therapy, all come from the same source. In doing so, we aim to avoid any complications that would arise from cells coming from multiple individuals. We will validate the autologous mouse system by generating chimeric antigen receptor (CAR) T cells from the patients’ own T cells. These redirected T cells will allow for evaluation of the model system, both in terms of how the tumors respond to immunotherapy and how the existing immune system responds to immunotherapy. Results in the animal model will be compared to patients receiving the same treatment, in clinical trials at the University of Pennsylvania. Initial work for will focus on demonstrating the fidelity of the system to the originating tumor and immune microenvironment, in terms of both tumor characteristics and immune system response. Thorough characterization of immune cell subpopulations and anti-tumor activity will help identify discrepancies in the current models as well as areas in which the new, autologous models are preferable. At the conclusion of this project, we will have demonstrated the feasibility of using autologous materials for glioblastoma modeling and elucidated the aspects of tumor-immune interaction that these models are most suited for use in.