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 BishopGuido Tricot, John D. Shaughnessy, Fenghuang Zhan

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Article number615
JournalNature Communications
Volume15
Issue number1
DOIs
StatePublished - Dec 2024

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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