Intravesical therapies are the mainstay of bladder cancer (BCa) management, but their efficacy is limited by toxicities and recurrences. While CAR T cell therapy has shown promise in hematologic malignancies, its application in solid tumors is limited by poor trafficking and on-target off-tumor toxicities. Here, we identify and validate MUC16 as a clinically relevant target for BCa, noting enriched expression in tumors recalcitrant to existing therapies. We engineered a second-generation mesothelin-based CAR (MSLN-28z) and demonstrated robust activity across multiple BCa cell lines and patient-derived tumor organoids. Intravesical delivery of MSLN-28z CAR T cells in xenograft BCa models conferred superior tumor control compared with intravenous transfer, while attenuating systemic T cell engraftment. Intravesical adoptive transfer uncouples local antitumor efficacy from potential systemic toxicity—a feature conserved across several T cell immunotherapies with on-target off-tumor activity. Collectively, these findings substantiate MUC16 as a therapeutic candidate and validate intravesical delivery as a platform for T cell immunotherapies in the management of organ-confined BCa.
Intravesical mesothelin-based CAR T cells targeting MUC16 effectively control bladder cancer in preclinical models
Disclosures: P. Abrahimi reported personal fees from Ferring Pharmaceuticals outside the submitted work; in addition, P. Abrahimi had a patent number 20240189426 pending. J.F. Khan reported a patent to antigen-recognizing receptors targeting B7-H3 pending. N. Chen reported a patent to chimeric receptors targeting MUC16 and uses thereof pending. M. Hamieh reported a patent to CAR T cell field licensed. B. Faltas reported grants from Eli Lilly, personal fees from UroToday, other from Guardant, and grants from Caris outside the submitted work. T.M. Carroll reported personal fees from Numen, nonfinancial support from Numen, and other from Numen during the conduct of the study; in addition, T.M. Carroll had a patent to Numen, related to methods of biomarker detection, pending. M.L. Everitt reported personal fees from Numen, nonfinancial support from Numen, and other from Numen during the conduct of the study. H.K. Subramanian reported personal fees from Numen during the conduct of the study and other from Numen outside the submitted work; in addition, H.K. Subramanian had a patent to Numen, related to methods of biomarker detection pending. H.A. Al-Ahmadie reported personal fees from AstraZeneca, Novartis, Janssen, and Pfizer outside the submitted work. O. Elemento reported personal fees from Volastra Therapeutics, other from Owkin and Harmonic, and grants from Eli Lilly outside the submitted work. R. Brentjens reported grants from BMS and personal fees from Atara Biotherapeutics, Triumvira, Cargo Tx, Legend Bio, Gracell Biotechnologies, and CoImmune outside the submitted work; in addition, R. Brentjens had patents to BMS, Caribou, and Sanofi with royalties paid. J.D. Wolchok reported grants from Bristol Myers Squibb during the conduct of the study; personal fees from Bristol Myers Squibb, Ascentage Pharma, Ankyra Therapeutics, Arsenal Biosciences, Imvaq Therapeutics, Tizona Therapeutics, Immunocore (Data Safety Board), Scancell, Apricity, XenImmune, Georgiamune, Linnaeus, and CellCarta outside the submitted work; in addition, J.D. Wolchok had a patent to xenogeneic DNA vaccines licensed (Merial), a patent to Newcastle disease viruses for cancer therapy licensed (Merck), a patent to myeloid-derived suppressor cell assay licensed (Caprion), a patent to anti-PD1 antibody licensed (Agenus), a patent to anti-CTLA4 antibodies licensed (Agenus), a patent to anti-GITR antibodies and methods of use thereof licensed (Agenus/Incyte), a patent to prediction of responsiveness to treatment with immunomodulatory therapeutics and method of monitoring abscopal effects during such treatment licensed (CellCarta), and a patent to antigen-recognizing receptors targeting B7-H3 and uses thereof pending. T. Merghoub reported a patent to WO2023034781A1; US20240189426A1 issued (NA), and acted in the capacity of consultant for ImmunOs Therapeutics, Daiichi Sankyo Co, TigaTx, Normunity, Pfizer, and LIfT BioSciences. T. Merghoub is a cofounder of and equity holder in IMVAQ Therapeutics and has received research support from Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, Aprea Therapeutics, Enterome SA, ReAlta Life Sciences, and Bristol Myers Squibb. T. Merghoub is also an inventor on patent applications related to work on oncolytic viral therapy, alpha virus–based vaccine, neoantigen modeling, immunomodulatory nanoparticles, bispecific activators, FLT3L, CD40, GITR, OX40, PD-1, CTLA-4, and chimeric receptors targeting melanoma differentiation antigens and B7-H3, and is listed as an inventor on a Provisional Patent Application related to work on CD47 and TSP-1. No other disclosures were reported.
- Award Id(s): C-04306
Parwiz Abrahimi, Jonathan F. Khan, Alyssa Duren-Lubanski, Winson Cai, Yacine Marouf, Nan Chen, Daniel Hirschhorn, Renata Mammone, Ileana C. Miranda, Jacob E. Tallman, Alejandra Vela-Moreno, Mohamad Hamieh, Bishoy M. Faltas, Thomas M. Carroll, Micaela L. Everitt, Hari K.K. Subramanian, Hikmat A. Al-Ahmadie, Olivier Elemento, Benjamin D. Hopkins, Douglas S. Scherr, Renier J. Brentjens, Jedd D. Wolchok, Taha Merghoub; Intravesical mesothelin-based CAR T cells targeting MUC16 effectively control bladder cancer in preclinical models. J Exp Med 6 July 2026; 223 (7): e20250699. doi: https://doi.org/10.1084/jem.20250699
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