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; Fenghuang Zhan

doi:10.1038/s41467-024-44873-4

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

Lymphoma-Myeloma

Research output: Contribution to journal › Article › peer-review

1 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 language	English (US)
Article number	615
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-44873-4
State	Published - Dec 2024

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Sun, F., Cheng, Y., Wanchai, V., Guo, W., Mery, D., Xu, H., Gai, D., Siegel, E., Bailey, C., Ashby, C., Al Hadidi, S., Schinke, C., Thanendrarajan, S., Ma, Y., Yi, Q., Orlowski, R. Z., Zangari, M., van Rhee, F., Janz, S., ... Zhan, F. (2024). Bispecific BCMA/CD24 CAR-T cells control multiple myeloma growth. Nature communications, 15(1), Article 615. https://doi.org/10.1038/s41467-024-44873-4

Sun, F, Cheng, Y, Wanchai, V, Guo, W, Mery, D, Xu, H, Gai, D, Siegel, E, Bailey, C, Ashby, C, Al Hadidi, S, Schinke, C, Thanendrarajan, S, Ma, Y, Yi, Q, Orlowski, RZ, Zangari, M, van Rhee, F, Janz, S, Bishop, G, Tricot, G, Shaughnessy, JD & Zhan, F 2024, 'Bispecific BCMA/CD24 CAR-T cells control multiple myeloma growth', Nature communications, vol. 15, no. 1, 615. https://doi.org/10.1038/s41467-024-44873-4

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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.",

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AU - Gai, Dongzheng

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

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