Bispecific BCMA/CD24 CAR-T cells control multiple myeloma growth

Fumou Sun, Yan Cheng, Visanu Wanchai, Wancheng Guo, David Mery, Hongwei Xu, Dongzheng Gai, Eric Siegel, Clyde Bailey, Cody Ashby, Samer Al Hadidi, Carolina Schinke, Sharmilan Thanendrarajan, Yupo Ma, Qing Yi, Robert Z. Orlowski, Maurizio Zangari, Frits van Rhee, Siegfried Janz, Gail Bishop, Guido Tricot, John D. Shaughnessy and Fenghuang Zhan ()
Additional contact information
Fumou Sun: University of Arkansas for Medical Sciences
Yan Cheng: University of Arkansas for Medical Sciences
Visanu Wanchai: University of Arkansas for Medical Sciences
Wancheng Guo: University of Arkansas for Medical Sciences
David Mery: University of Arkansas for Medical Sciences
Hongwei Xu: University of Arkansas for Medical Sciences
Dongzheng Gai: University of Arkansas for Medical Sciences
Eric Siegel: University of Arkansas for Medical Sciences
Clyde Bailey: University of Arkansas for Medical Sciences
Cody Ashby: University of Arkansas for Medical Sciences
Samer Al Hadidi: University of Arkansas for Medical Sciences
Carolina Schinke: University of Arkansas for Medical Sciences
Sharmilan Thanendrarajan: University of Arkansas for Medical Sciences
Yupo Ma: Research & Development Division
Qing Yi: Houston Methodist Cancer Center, Houston Methodist Research Institute
Robert Z. Orlowski: The University of Texas MD Anderson Cancer Center
Maurizio Zangari: University of Arkansas for Medical Sciences
Frits van Rhee: University of Arkansas for Medical Sciences
Siegfried Janz: Medical College of Wisconsin
Gail Bishop: University of Iowa and VA Medical Center
Guido Tricot: University of Arkansas for Medical Sciences
John D. Shaughnessy: University of Arkansas for Medical Sciences
Fenghuang Zhan: University of Arkansas for Medical Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Anti-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.

Date: 2024
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DOI: 10.1038/s41467-024-44873-4

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