Bispecific BCMA/CD24 CAR-T cells control multiple myeloma growth
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Published:2024-01-19
Issue:1
Volume:15
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Sun Fumou, Cheng YanORCID, Wanchai VisanuORCID, Guo Wancheng, Mery David, Xu Hongwei, Gai Dongzheng, Siegel EricORCID, Bailey Clyde, Ashby CodyORCID, Al Hadidi SamerORCID, Schinke CarolinaORCID, Thanendrarajan Sharmilan, Ma Yupo, Yi QingORCID, Orlowski Robert Z., Zangari Maurizio, van Rhee FritsORCID, Janz SiegfriedORCID, Bishop GailORCID, Tricot Guido, Shaughnessy John D., Zhan FenghuangORCID
Abstract
AbstractAnti-multiple myeloma B cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapies represent a promising treatment strategy with high response rates in myeloma. However, durable cures following anti-BCMA CAR-T cell treatment of myeloma are rare. One potential reason is that a small subset of minimal residual myeloma cells seeds relapse. Residual myeloma cells following BCMA-CAR-T-mediated treatment show less-differentiated features and express stem-like genes, including CD24. CD24-positive myeloma cells represent a large fraction of residual myeloma cells after BCMA-CAR-T therapy. In this work, we develop CD24-CAR-T cells and test their ability to eliminate myeloma cells. We find that CD24-CAR-T cells block the CD24-Siglec-10 pathway, thereby enhancing macrophage phagocytic clearance of myeloma cells. Additionally, CD24-CAR-T cells polarize macrophages to a M1-like phenotype. A dual-targeted BCMA-CD24-CAR-T exhibits improved efficacy compared to monospecific BCMA-CAR-T-cell therapy. This work presents an immunotherapeutic approach that targets myeloma cells and promotes tumor cell clearance by macrophages.
Funder
Foundation for the National Institutes of Health U.S. Department of Defense Myeloma Crowd Research Initiative Award, Paula and Rodger Riney Foundation, Myeloma Solution Fund, UAMS Winthrop P. Rockefeller Cancer Institute (WRCRI) Fund Arkansas Breast Cancer Research Program
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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