李莫菲特癌症中心和研究所Fabiana Perna研究小组在研究中取得进展。他们报道了开发SEMA4A导向的CAR T细胞以克服多发性骨髓瘤中BCMA抗原密度低的问题。相关论文于2025年10月9日发表在《癌细胞》杂志上。

该团队定量分析了一组BCMA CAR - T治疗后复发患者的抗原密度，显示在BCMA密度低的地方，SEMA4A分子/细胞数量高。SEMA4A缺失限制MM细胞生长、迁移、组织浸润和破骨细胞形成，同时延长母细胞存活时间。该课题组研究人员产生靶向SEMA4A细胞外结构域的单克隆抗体，用于CAR构建，筛选工程T细胞的扩增，细胞因子释放和对MM细胞的细胞毒性。铅构建体对正常非造血组织缺乏反应性。SEMA4A CAR - T细胞在次优剂量的BCMA CAR - T细胞下，对患者源性BCMAlow肿瘤和MM细胞的清除效果优于BCMA CAR - T细胞。该研究准备用SEMA4A靶向CAR - T细胞治疗MM的1期临床试验。

据悉，靶向B细胞成熟抗原（BCMA）的嵌合抗原受体（CAR） T细胞治疗多发性骨髓瘤（MM）是有效的，但与BCMA低至阴性表达相关的复发是常见的，这表明需要额外的靶点。

附：英文原文

Title: Developing SEMA4A-directed CAR T cells to overcome low BCMA antigen density in multiple myeloma

Author: Francesco Di Meo, Francesca Albano, Annamaria Cesarano, Yunfei Wang, Brandon Kale, Kenneth Shain, Ariosto Silva, Noriyoshi Kurihara, Hirofumi Tenshin, David Jellyman, Xiaofei Song, Sasan Ghaffari, Hector Mesa, Ben Creelan, Ciara Freeman, Xiaohong Zhao, Mark B. Meads, Paulo C. Rodriguez, Silvia Marino, Frederick Locke, Patrick Hwu, David Roodman, Jorge Mansilla-Soto, Fabiana Perna

Issue&Volume: 2025-10-09

Abstract: Chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) for multiple myeloma (MM) is effective, but relapses associated with low-to-negative BCMA expression are common, indicating the need for additional targets. We quantitatively profile antigen density in a cohort of patients relapsed after BCMA CAR T therapy, showing high number of SEMA4A molecules/cell where BCMA density is low. SEMA4A deletion limits MM cell growth, migration, tissue infiltration, and osteoclast formation, while extending mouse survival. We generate monoclonal antibodies targeting SEMA4A-extracellular domain for CAR construction, screen engineered T cells for expansion, cytokine release, and cytotoxicity against MM cells. Lead constructs lack reactivity against normal non-hematopoietic tissues. SEMA4A CAR T cells show superior efficacy than BCMA CAR T cells eliminating patient-derived BCMAlow tumors and MM cells progressing under suboptimal doses of BCMA CAR T cells. This study prepares for a phase 1 clinical trial with SEMA4A-directed CAR T cells for MM.

DOI: 10.1016/j.ccell.2025.09.007

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00399-X