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. 2025 Dec 1;27(12):3104-3118.
doi: 10.1093/neuonc/noaf155.

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

Rishab Ramapriyan  1 , Fred G Barker 2nd  1 , Leland G Richardson  1 , Jing Sun  1 , Gust Vandecandelaere  1 , Jane M Shim  1 , Guillaume De Vlaminck  1 , Matthew Gaffey  1 , Eric P Grewal  2 , Masih Tazhibi  1 , Kourosh Morshedy  3   4 , Amir R Aref  5   4 , Syeda M Batool  1 , Xiaopeng Guo  6 , Nazanin Ijad  4 , Leonora Balaj  1 , Hiroaki Wakimoto  1 , Maria Martinez-Lage, Matthew J Frigault  7 , Mark B Leick  7 , Joshua D Bernstock  1 , Wenya Linda Bi  1 , Bob S Carter  1 , E Antonio Chiocca  1 , Jorg Dietrich  8 , Elizabeth R Gerstner  8 , Genevieve M Boland  5 , Brian V Nahed  1 , Scott R Plotkin  8 , Russell W Jenkins  9   3   4 , Priscilla K Brastianos  8   4 , William T Curry  1 , Marcela V Maus  7 , Bryan D Choi  1
Affiliations

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

Rishab Ramapriyan et al. Neuro Oncol. .

Abstract

Background: Meningioma is the most common primary CNS tumor, with high-grade cases exhibiting aggressive behavior, frequent recurrence, and poor prognosis. Currently, no systemic therapies are approved for recurrent or malignant meningiomas. 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 a viable immunotherapeutic target. This study aimed to evaluate mesothelin as a CAR T-cell target in meningiomas.

Methods: Mesothelin expression was analyzed in patient-derived meningioma samples using immunohistochemistry, flow cytometry, and droplet digital PCR. Mesothelin-specific CAR T-cells were generated and evaluated invitro, exvivo using patient-derived organotypic tumor spheroids (PDOTS), and invivo 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 across all meningioma grades at the transcript and protein levels, with surface expression confirmed in patient-derived primary cells. Mesothelin-specific CAR T-cells exhibited potent and specific cytotoxicity, T-cell activation, and cytokine secretion in vitro and effectively eliminated PDOTS. In orthotopic human xenograft models, mesothelin CAR T-cell therapy led to significant tumor regression and prolonged survival.

Conclusions: Mesothelin is a viable 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.

Keywords: CAR T-Cell therapy; brain neoplasms; immunotherapy; meningioma; mesothelin.

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Conflict of interest statement

M.B.L. has been a contributor to patent filings on CAR T-cell technology that are held by the Massachusetts General Hospital. M.B.L. has consulted for BioNtech, Cabaletta Bio, Onclive, and Adaptimmune. M.B.L. holds equity in Abbvie, Eli Lily, and Novo Nordisk. J.D.B. has an equity position in Treovir Inc. and UpFront Diagnostics. J.D.B. is also a cofounder of Centile Bioscience and on the NeuroX1 and QV Bioelectronics scientific advisory boards. G.M.B. has sponsored research agreements through her institution with Olink Proteomics, Teiko Bio, InterVenn Biosciences, and Palleon Pharmaceuticals. G.M.B. served on advisory boards for Iovance, Merck, Moderna, Nektar Therapeutics, Novartis, Replimune, and Ankyra Therapeutics. G.M.B. consults for Merck, InterVenn Biosciences, Iovance, and Ankyra Therapeutics. G.M.B. holds equity in Ankyra Therapeutics. R.W.J. is a member of the advisory board for and has a financial interest in Xsphera Biosciences Inc. R.W.J. has received honoraria from Incyte (invited speaker), G1 Therapeutics (advisory board), Bioxcel Therapeutics (invited speaker). R.W.J. has ownership interest in U.S. patents US20200399573A9 and US20210363595A1. Unrelated to this manuscript, P.K.B. has consulted for Voyager Therapeutics, Tesaro, SK Life Science, Sintetica, Pfizer, Merck, ElevateBio, Dantari, Angiochem, MPM, Medscape, Kazia, InCephalo, Genentech, Eli Lilly, CraniUS, Axiom, Atavistik and Advise Connect Inspire, serves on the Scientific Advisory Board for Kazia and CraniUS, and has received Speaker’s Honoraria from Genentech and Pfizer. P.K.B. has received institutional research support (to Massachusetts General Hospital) from Kinnate, Mirati, Merck and Eli Lilly. M.V.M. is an inventor on patents related to adoptive cell therapies, held by Massachusetts General Hospital (some licensed to Promab and Luminary) and University of Pennsylvania (some licensed to Novartis). M.V.M. receives Grant/Research support from: Kite Pharma, Moderna, and Sobi. M.V.M. has served as a consultant for multiple companies involved in cell therapies. M.V.M. holds Equity in 2SeventyBio, A2Bio, Affyimmune, and Model T bio. M.V.M. serves on the Board of Directors of 2Seventy Bio. B.D.C. is an inventor on patents related to biologic and adoptive cell therapies, held by Massachusetts General Hospital and Duke University, and has served as a consultant for multiple companies not directly related to this manuscript. The other authors declare no competing interests.

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