Authors
Franz J Zemp, Zackariah Breckenridge, Hyojin Song, Gurveer S Gill, Taye L Louie, Kiran Narta, Hongrui Liu, Yeon Suh, Louisa Guignard, Edna Ayerim Mandujano-Tinoco, Nicolás Collao, Joanna Pyczek, Kristofor K Ellestad, Jada Curry, Jethro Langley, Cini John, Laura K Mah, Jahanara Rajwani, Danyel Evseev, Madison Turk, Sacha Benaoudia, Jonathan Alex, Victor Naumenko, Varsha Thoppey Manoharan, Mobina Kazemi Mehrabadi, Harmony A Smith, Geneece N Y Gilbert, Aaron Gillmor, Ted B Verhey, Hayley M Todesco, Katalin Osz, Bo-Young Ahn, Ana Bogossian, Colleen Anderson, Saif Sikdar, Shahrbano Rukunuddin, Tarek A Bismar, Daniel Y C Heng, Keith Lawson, W Marston Linehan, Haley Pedersen, Paul M K Gordon, John B McIntyre, John MacGregor, Livia Garzia, Kathy Brodeur-Robb, Lisa DiFrancesco, Travis Ogilvie, Patrick Schöffski, Agnieszka Wozniak, Robert A Holt, John Bell, Donna L Senger, Victor Lewis, Michael Monument, Omar Khan, Lou Baudrier, Pierre Billon, Vincent Gabriel, Jeff Biernaskie, Kyle Potts, Kiril Trpkov, Kevin Hay, Jennifer Quizi, Jennifer Chan, Ramy Saleh, Jan Willem Henning, Nicole L Prokopishyn, Mona Shafey, A Sorana Morrissy, Douglas J Mahoney
Published in
Nature cancer. Jul 01, 2026. Epub Jul 01, 2026.
Abstract
Chimeric antigen receptor (CAR) T cell therapy for solid tumors is constrained by the scarcity of safe, uniformly expressed cell-surface targets. Here we identify glycoprotein NMB (GPNMB)-an MiT/TFE-family fusion-driven protein-as being highly, homogeneously and stably expressed in primary and relapsed alveolar soft-part sarcoma (ASPS) and translocation renal cell carcinoma. We develop a GPNMB-directed CAR T cell product, GCAR1, which demonstrates potent activity against patient-matched cells, organoids and xenograft models. Post hoc interim analysis of a first-in-human open-label, individual-participant trial ( NCT07104682 ) for a participant with relapsed/refractory, metastatic ASPS showed that GCAR1 induces stable disease for up to 3 months, accompanied by resolution of many nontarget lesions (primary endpoint), and is well tolerated. GCAR1 T cells expand in peripheral blood as a polyclonal population and remain detectable for 1 month. Spatial transcriptomics identified immunosuppressive niches in a treatment-resistant lesion and immune checkpoint blockade synergized with GCAR1 in a xenograft model. Altogether, our data provide a proof of concept for treating GPNMB-expressing solid tumors with GCAR1 and more broadly targeting surface antigens driven by oncogenic gene fusions with CAR T cell therapies.
PMID:
42387022
Bibliographic data and abstract were imported from PubMed on 02 Jul 2026.
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