Dhakal Binod, Hari Parameswaran N, Usmani Saad Z, Hamadani Mehdi
BMT and Cellular Therapy Program, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Atrium Health, Charlotte, NC, 28204, USA.
Bone Marrow Transplant. 2021 Jan;56(1):9-19. doi: 10.1038/s41409-020-01023-w. Epub 2020 Aug 7.
Despite a sea change in the therapeutic landscape, multiple myeloma (MM), a cancer of antibody producing plasma cells, remains incurable requiring continued intervention for disease control. In this context, chimeric antigen receptor (CAR) T cell therapy has emerged as a promising immunotherapeutic approach with unprecedented results in heavily treated relapsed and/or refractory MM patients. Although B cell maturation antigen (BCMA) is the current lead target for CAR-T cell therapy in MM, several other antigenic targets are also being investigated. Relapses, however, are inevitable in spite of the promising early responses, and may be mediated by antigenic modulation, poor persistence and "immunostat" in tumor microenvironment. Akin to multi-agent chemotherapy, multi-targeted CAR-T antigens and combinatorial approaches are underway to overcome the resistance mechanisms. Further, CAR-T specific toxicity concerns such as cytokine release syndrome and neurotoxicity, as well as manufacturing time lag are other key challenges. Allogeneic CAR that offers "off-the-shelf" options, and mRNA transfected CAR are being developed to mitigate the access and safety issues. In this review we provide the comprehensive review of the most current clinical trial data for CAR-T in myeloma, challenges associated with this therapy and discuss its future in myeloma therapeutics.
尽管治疗格局发生了巨大变化，但多发性骨髓瘤（MM），一种产生抗体的浆细胞癌症，仍然无法治愈，需要持续干预以控制疾病。在这种背景下，嵌合抗原受体（CAR）T细胞疗法已成为一种有前途的免疫治疗方法，在经过大量治疗的复发和/或难治性MM患者中取得了前所未有的成果。虽然B细胞成熟抗原（BCMA）是目前MM中CAR-T细胞疗法的主要靶点，但其他几个抗原靶点也在研究中。然而，尽管早期反应很有希望，但复发是不可避免的，可能由抗原调节、持久性差和肿瘤微环境中的“免疫稳态”介导。与多药化疗类似，正在进行多靶点CAR-T抗原和联合方法来克服耐药机制。此外，CAR-T特异性毒性问题，如细胞因子释放综合征和神经毒性，以及生产时间延迟是其他关键挑战。提供“现货”选择的同种异体CAR和mRNA转染的CAR正在开发中，以缓解可及性和安全性问题。在这篇综述中，我们全面回顾了CAR-T治疗骨髓瘤的最新临床试验数据、与该疗法相关的挑战，并讨论了其在骨髓瘤治疗中的未来。
