Uchibori Ryosuke, Ohmine Ken, Teruya Takeshi, Mineno Junichi, Ozawa Keiya
Division Gene and Cell Therapy for Intractable Diseases, Department of Medicine, Jichi Medical University, Shimotsuke, Japan.
Division of Hematology, Department of Medicine, Jichi Medical University, Shimotsuke-shi, Japan.
Hum Gene Ther. 2025 Jun;36(11-12):902-913. doi: 10.1089/hum.2024.263. Epub 2025 May 15.
Multiple myeloma (MM) is an incurable hematological malignancy of plasma cells. Myeloma cells interfere with hematopoietic activities of the bone marrow, often leading to anemia, and can cause the bones to develop osteoporotic and lytic lesions. Clinical experience with chimeric antigen receptor T-cell (CAR-T) therapy targeting B-cell maturation antigen (BCMA) has been promising, with good response rates, favorable safety profiles, and low incidences of severe cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. However, CAR-T therapy in MM is accompanied by several new challenges, including therapeutic failure and relapse, and much attention has been paid to the further development of B-cell maturation antigen-chimeric antigen receptor (BCMA-CAR). Although most of the reported benefits of BCMA-CAR have been discussed, whether cancer can be eliminated, as well as the efficacy of CAR-T therapy for anemia and bone lesions, both myeloma-defining events, have not yet been reported in any animal model. In this study, we designed and verified a novel BCMA-specific chimeric antigen receptor (CAR). Our BCMA-CAR demonstrated the fundamental properties of CAR-T cells, including target-specific cytotoxic activity, cytokine production, and antitumor effects. In addition, we evaluated the therapeutic effect of BCMA-CAR in mice by imaging bone lesions and conducting blood examinations. Tumor mouse models showed systemic progression of MM in the bone marrow, and mice treated with saline or nongene modified T cells showed continued tumor progression, progressive bone lesions, and prolonged anemia. In contrast, all mice treated with gene modified T cells achieved a complete response, improved anemia to the level observed in normal mice, and suppressed progression of bone lesions. We concluded that anemia was improved with BCMA-CAR-T cell therapy. However, novel strategies to support the recovery of bone lesions by enhancing CAR-T cell function must be developed.
多发性骨髓瘤（MM）是一种无法治愈的浆细胞血液系统恶性肿瘤。骨髓瘤细胞会干扰骨髓的造血活动，常导致贫血，并可使骨骼出现骨质疏松和溶骨性病变。针对B细胞成熟抗原（BCMA）的嵌合抗原受体T细胞（CAR-T）疗法的临床经验令人鼓舞，其具有良好的缓解率、良好的安全性，以及严重细胞因子释放综合征和免疫效应细胞相关神经毒性综合征的低发生率。然而，MM中的CAR-T疗法伴随着几个新的挑战，包括治疗失败和复发，并且人们对B细胞成熟抗原嵌合抗原受体（BCMA-CAR）的进一步发展给予了很多关注。尽管已经讨论了BCMA-CAR的大部分已报道益处，但在任何动物模型中都尚未报道过癌症是否能够被消除，以及CAR-T疗法对贫血和骨病变（这两个骨髓瘤定义性事件）的疗效。在本研究中，我们设计并验证了一种新型的BCMA特异性嵌合抗原受体（CAR）。我们的BCMA-CAR展示了CAR-T细胞的基本特性，包括靶标特异性细胞毒性活性、细胞因子产生和抗肿瘤作用。此外，我们通过对骨病变进行成像和血液检查来评估BCMA-CAR在小鼠中的治疗效果。肿瘤小鼠模型显示MM在骨髓中出现全身进展，用生理盐水或未基因修饰的T细胞治疗的小鼠显示肿瘤持续进展、进行性骨病变和持续性贫血。相比之下，所有用基因修饰的T细胞治疗的小鼠都实现了完全缓解，贫血改善至正常小鼠观察到的水平，并抑制了骨病变的进展。我们得出结论，BCMA-CAR-T细胞疗法改善了贫血。然而，必须开发通过增强CAR-T细胞功能来支持骨病变恢复的新策略。
