EXTH-47. Mesothelin is a surface antigen present on human meningioma and can be effectively targeted by CAR T-cells
Year: 2025
Type: conference-abstract
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.
Source: Neuro-Oncology
Authors: Rishab Ramapriyan, Fred Barker 2nd, Leland Richardson, Jing Sun, Gust Vandecandelaere, Jane Shim, Guillaume De Vlaminck, Matthew Gaffey, Eric Grewal, Masih Tazhibi, Kourosh Morshedy, Amir Aref, Syeda Batool, Xiaopeng Guo, Nazanin Ijad, Leonora Balaj, Hiroaki Wakimoto, Maria Martinez-Lage, Matthew Frigault, Mark Leick, Joshua Bernstock, Wenya Linda Bi, Bob Carter, E Antonio Chiocca, Jorg Dietrich, Elizabeth Gerstner, Genevieve Boland, Brian Nahed, Scott Plotkin, Russell Jenkins, Priscilla Brastianos, William Curry, Marcela Maus, Bryan Choi
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4416140167
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