EXTH-47. Mesothelin is a surface antigen present on human meningioma and can be effectively targeted by CAR T-cells

Abstract BACKGROUND Meningioma is the most common primary CNS tumor, with high-grade cases exhibiting aggressive behavior, recurrence, and poor prognosis. Chimeric antigen receptor (CAR) T-cell therapy has shown efficacy in hematologic malignancies and promise for solid tumors but its use for meningiomas has been underexplored. Mesothelin, a glycoprotein overexpressed in several solid tumors of mesodermal origin, may serve as an immunotherapeutic target. This study aimed to evaluate the efficacy of mesothelin-specific CAR T-cells against meningioma models. METHODS Mesothelin expression was analyzed in patient-derived meningioma samples using immunohistochemistry, flow cytometry, single-cell RNA sequencing, and droplet digital PCR. Mesothelin-specific CAR T-cells were generated and evaluated in vitro with patient-derived malignant meningioma cells, ex vivo using patient-derived organotypic tumor spheroids (PDOTS), and in vivo using orthotopic meningioma mouse models of human xenografts. Cytotoxicity, T-cell proliferation, cytokine secretion, and tumor clearance were assessed. RESULTS Mesothelin was detected in a subset of tumors (more than 60%) across all meningioma grades at the transcript and protein levels, with surface expression confirmed in patient-derived primary cells by flow cytometry. Among positive cases, a mean of 62%, 78% and 45% of cells per slide were positive by immunohistochemistry in Grades 1, 2 and 3, respectively. When compared to untransduced donor T-cell and CD19 CAR T-cell controls, mesothelin-specific CAR T-cells exhibited potent and specific cytotoxicity, T-cell activation, and cytokine secretion against human malignant meningioma cells in vitro (all p<0.001), and they effectively eliminated multiple PDOTS (p<0.05). In two, distinct orthotopic human xenograft mouse models, mesothelin CAR T-cell therapy led to significant tumor regression (p<0.001) and prolonged survival (p<0.001) compared to controls. CONCLUSIONS Mesothelin is a feasible CAR T-cell target for meningiomas, and mesothelin-specific CAR T-cell therapy shows strong preclinical efficacy. These findings provide a rationale for early-phase clinical trials of mesothelin CAR T-cell therapy in patients with refractory meningiomas.