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

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

35 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
Pages (from-to)	615
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-44873-4
State	Published - Jan 19 2024

Keywords

Humans
Receptors, Chimeric Antigen
Multiple Myeloma/pathology
T-Lymphocytes
B-Cell Maturation Antigen/genetics
Neoplasm Recurrence, Local
Antibodies
CD24 Antigen

ASJC Scopus subject areas

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

Divisions

Medical Oncology

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10.1038/s41467-024-44873-4

Cite this

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), 615. 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, pp. 615. https://doi.org/10.1038/s41467-024-44873-4

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title = "Bispecific BCMA/CD24 CAR-T cells control multiple myeloma growth",

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.",

keywords = "Humans, Receptors, Chimeric Antigen, Multiple Myeloma/pathology, T-Lymphocytes, B-Cell Maturation Antigen/genetics, Neoplasm Recurrence, Local, Antibodies, CD24 Antigen",

author = "Fumou Sun and Yan Cheng and Visanu Wanchai and Wancheng Guo and David Mery and Hongwei Xu and Dongzheng Gai and Eric Siegel and Clyde Bailey and Cody Ashby and \{Al Hadidi\}, Samer and Carolina Schinke and Sharmilan Thanendrarajan and Yupo Ma and Qing Yi and Orlowski, \{Robert Z.\} and Maurizio Zangari and \{van Rhee\}, Frits and Siegfried Janz and Gail Bishop and Guido Tricot and Shaughnessy, \{John D.\} and Fenghuang Zhan",

note = "Publisher Copyright: {\textcopyright} 2024, The Author(s).",

year = "2024",

month = jan,

day = "19",

doi = "10.1038/s41467-024-44873-4",

language = "English (US)",

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AU - Sun, Fumou

AU - Cheng, Yan

AU - Wanchai, Visanu

AU - Guo, Wancheng

AU - Mery, David

AU - Xu, Hongwei

AU - Gai, Dongzheng

AU - Siegel, Eric

AU - Bailey, Clyde

AU - Ashby, Cody

AU - Al Hadidi, Samer

AU - Schinke, Carolina

AU - Thanendrarajan, Sharmilan

AU - Ma, Yupo

AU - Yi, Qing

AU - Orlowski, Robert Z.

AU - Zangari, Maurizio

AU - van Rhee, Frits

AU - Janz, Siegfried

AU - Bishop, Gail

AU - Tricot, Guido

AU - Shaughnessy, John D.

AU - Zhan, Fenghuang

PY - 2024/1/19

Y1 - 2024/1/19

N2 - 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.

AB - 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.

KW - Humans

KW - Receptors, Chimeric Antigen

KW - Multiple Myeloma/pathology

KW - T-Lymphocytes

KW - B-Cell Maturation Antigen/genetics

KW - Neoplasm Recurrence, Local

KW - Antibodies

KW - CD24 Antigen

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AN - SCOPUS:85182665152

SN - 2041-1723

VL - 15

SP - 615

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 615

ER -

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

Abstract

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