Division of Tumor Immunology, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Int J Hematol. 2024 Jul;120(1):15-22. doi: 10.1007/s12185-024-03794-0. Epub 2024 May 23.
Currently available chimeric antigen receptor (CAR)-engineered T-cell therapies targeting B-cell maturation antigen (BCMA), namely, idecabtagene vicleucel and ciltacabtagene autoleucel, have shown marked efficacy against relapsed and refractory multiple myeloma. However, further improvement in CAR-T-cell function is warranted as most patients treated with these products eventually relapse due to various mechanisms such as antigen loss and T-cell dysfunction or disappearance. Strategies for improving CAR-T-cell function include targeting of dual antigens, enhancing cell longevity through genetic modification, and eliminating the immunosuppressive tumor microenvironment. Serious side effects can also occur after CAR-T-cell infusions. Although understanding of the molecular pathogenesis of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome is growing, the unique movement disorder caused by BCMA-targeted therapy is less understood, and its molecular mechanisms must be further elucidated to establish better management strategies. In this article, we will review the current status of BCMA-targeting CAR-T-cell therapy. We will also highlight progress in the development of CAR-T cells targeting other antigens, as well as universal allogeneic CAR-T cells and bispecific antibodies.
目前针对 B 细胞成熟抗原(BCMA)的嵌合抗原受体(CAR)工程 T 细胞疗法,即 idecabtagene vicleucel 和 ciltacabtagene autoleucel,已显示出对复发性和难治性多发性骨髓瘤的显著疗效。然而,由于抗原丢失和 T 细胞功能障碍或消失等多种机制,大多数接受这些产品治疗的患者最终仍会复发,因此需要进一步提高 CAR-T 细胞的功能。提高 CAR-T 细胞功能的策略包括靶向双重抗原、通过基因修饰延长细胞寿命以及消除免疫抑制性肿瘤微环境。CAR-T 细胞输注后也会发生严重的副作用。尽管人们对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分子发病机制的认识不断提高,但对 BCMA 靶向治疗引起的独特运动障碍的了解较少,必须进一步阐明其分子机制,以制定更好的管理策略。本文将综述 BCMA 靶向 CAR-T 细胞治疗的现状。我们还将重点介绍针对其他抗原的 CAR-T 细胞、通用异体 CAR-T 细胞和双特异性抗体的开发进展。