1区 · 综合性期刊
ArticleOA
作者: Tricot, Guido ; Orlowski, Robert Z ; Zhan, Fenghuang ; Sun, Fumou ; Xu, Hongwei ; Guo, Wancheng ; Ma, Yupo ; Zangari, Maurizio ; Bishop, Gail ; Thanendrarajan, Sharmilan ; Siegel, Eric ; Bailey, Clyde ; Shaughnessy, John D ; van Rhee, Frits ; Yi, Qing ; Janz, Siegfried ; Schinke, Carolina ; Cheng, Yan ; Wanchai, Visanu ; Mery, David ; Ashby, Cody ; Al Hadidi, Samer ; Gai, Dongzheng
AbstractAnti-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.
