Sunday, December 22, 2024
12/22/2024
PROJECT SUMMARY/ABSTRACT This project will develop a new mouse model to improve chimeric antigen receptor (CAR) T cell cancer immunotherapy for malignant brain tumors. CAR T cells are patient derived T cells that are genetically modified with a CAR to allow them to recognize and destroy malignant target cells. CAR T therapy has shown impressive results against leukemia and lymphoma, but has not yet been as successful in clinical trials for brain tumors. Although CAR T cells can kill brain tumor cells successfully in vitro and in mouse models, they have much more limited ability to find the tumor and survive in the hostile tumor microenvironment when given to patients either intravenously or into the cerebrospinal fluid that surrounds the brain. Our mouse model allows the following innovations which we believe are key to approaching the situation in real patients: an immunocompetent mouse model which receives CAR T cells made from the same species, and which develops tumors that are intrinsic to the brain, as opposed to being implanted. We will focus on high grade gliomas, which continue to be the brain tumors killing the largest number of children and adults. We will optimize the tumor growth parameters to allow us to image the tumor and infiltrating CAR T and other immune cells through a skull window with advanced two-photon in vivo microscopy at a cellular and subcellular resolution. Aim 1: Develop a high grade glioma tumor model optimized for in vivo imaging. The goal is to induce high grade gliomas quickly and efficiently, but allow enough time to image the brain over at least 10 days through a cranial window before the tumors start causing symptoms. We will deliver oncogenic transgenes into the brain via an avian virus (RCAS), which can only infect cells that are transgenic for the TVA receptor. We will express the TVA receptor in our mice under the control of the nestin promoter, which is active in neuroglial progenitor cells. Our mice are also deficient in Cdkn2a, which makes them more susceptible to tumor induction. Aim 2: Test efficiency of different CAR T cell delivery routes. We will use in vivo two photon brain imaging, histology and flow cytometry to test how well CAR T cells can traffic to brain tumors when given either intravenously, directly into the tumor, or into the cerebrospinal fluid. Aim 3: Test whether activation of CAR T cells in the blood enhances trafficking to brain tumors. Using the tumor model optimized in Aim 1, we will express two different CAR targets in the gliomas: either a murine or a human truncated CD19. CAR T cells directed against the murine CD19 also recognize the mouse’s normal B cells, which we hypothesize will activate them and increase their ability to travel throughout the body and find the tumors in the brain. CAR T cells targeting the human CD19 will lack this extra stimulation. This work is innovative because it develops more challenging but more naturalistic immunocompetent mouse models for studying CAR T cell trafficking into brain tumors. Our team combines expertise in brain tumor modeling, in vivo neuroimaging in mice, and clinical trials of brain tumor CAR T cell therapy.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).