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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 Thanendraraja, 2024. "Bispecific BCMA/CD24 CAR-T cells control multiple myeloma growth," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44873-4
    DOI: 10.1038/s41467-024-44873-4
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    References listed on IDEAS

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    1. Mehmet Kemal Samur & Mariateresa Fulciniti & Anil Aktas Samur & Abdul Hamid Bazarbachi & Yu-Tzu Tai & Rao Prabhala & Alejandro Alonso & Adam S. Sperling & Timothy Campbell & Fabio Petrocca & Kristen H, 2021. "Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma," Nature Communications, Nature, vol. 12(1), pages 1-7, December.
    2. Amira A. Barkal & Rachel E. Brewer & Maxim Markovic & Mark Kowarsky & Sammy A. Barkal & Balyn W. Zaro & Venkatesh Krishnan & Jason Hatakeyama & Oliver Dorigo & Layla J. Barkal & Irving L. Weissman, 2019. "CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy," Nature, Nature, vol. 572(7769), pages 392-396, August.
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