CAR T cells targeting mesothelin and secreting bispecific antibodies targeting fibroblasts in pancreatic cancer

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PROJECT SUMMARY CAR T cell therapy for solid tumors is hindered by a lack of tumor-specific antigens that are safe to target and homogenously expressed throughout the tumor, difficulty infiltrating the tumor due to dense tumor stroma, and suppression of CAR T cell function by the tumor microenvironment (TME). We plan to address these issues using novel meso-FAP CAR-TEAM cells that simultaneously target mesothelin, a solid tumor antigen that has already been proven safe to target in patients, and cancer-associated fibroblasts (CAFs), which inhibit T cell infiltration and suppress T cell function in the TME. The CAFs are targeted with T cell-engaging antibody molecules (TEAMs) secreted from the CAR T cells that bind to CD3 and fibroblast activation protein (FAP), which is highly expressed on CAFs. The TEAM allows for CAF elimination by CAR and non-CAR T cells in the tumor. We have already demonstrated that meso-FAP CAR-TEAM cells kill pancreatic cancer cells and CAFs in vitro, in vivo, and in patient-derived ex vivo models and have superior anti-tumor function compared to meso-CAR T cells alone. For the UG3 phase of this project, we will further optimize meso-FAP CAR-TEAM cells by determining the best mesothelin binder to use (SS1 vs. a novel binder developed by our lab), optimal route of injection (IV vs. IP) for targeting pancreatic tumors, and rationale drug combinations that address CAR T cell limitations in solid tumors. We will improve antigen density using an ADAM17 inhibitor (INCB7839) to prevent mesothelin cleavage from pancreatic cancer cells, optimize CAR T cell killing and persistence using ibrutinib to polarize meso-FAP CAR T cells to a Th1/Th17 phenotype, and further prevent suppression by the tumor microenvironment using a PD1 inhibitor (pembrolizumab). These drugs will be singly combined with meso-FAP CAR-TEAM cells to determine which best promotes efficacy in our preclinical models. Collectively, these results will inform the design of a phase I clinical trial for pancreatic cancer patients with advanced disease. During the UH3 phase, we will determine the safety and tolerability of meso-FAP CAR-TEAM cells. We have chosen pancreatic cancer as our first solid tumor target due to the dismal prognosis of the disease, the high percentage of patients with mesothelin-expressing tumors, and the known role of CAFs in promoting tumor growth. While our primary objective will be to determine safety, we will also monitor patient outcomes (progression and survival) while performing correlative studies to determine CAR T cell phenotype and function. We will also monitor the tumor and tumor microenvironment for mechanisms of response or resistance, such as changes in antigen expression and immunosuppressive cells. Overall, this project will develop a novel CAR-TEAM design to target a solid tumor and its microenvironment while optimizing the trial design through rigorous preclinical testing. If successful, the meso-FAP CAR T cell product could be directly applied to other mesothelin-expressing solid tumors and the knowledge gained from the UG3 phase will inform on the critical aspects of CAR T cell function to optimize prior to initiating a clinical trial.