Nasiri Fatemeh, Asaadi Yasaman, Mirzadeh Farzaneh, Abdolahi Shahrokh, Molaei Sedigheh, Gavgani Somayeh Piri, Rahbarizadeh Fatemeh
Department of Internal Medicine, College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran.
Biomark Res. 2024 Sep 12;12(1):102. doi: 10.1186/s40364-024-00634-5.
Multiple myeloma (MM) is a hematological cancer characterized by the abnormal proliferation of plasma cells. Initial treatments often include immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (mAbs). Despite salient progress in diagnosis and treatment, most MM patients typically have a median life expectancy of only four to five years after starting treatment. In recent developments, the success of chimeric antigen receptor (CAR) T-cells in treating B-cell malignancies exemplifies a new paradigm shift in advanced immunotherapy techniques with promising therapeutic outcomes. Ide-cel and cilta-cel stand as the only two FDA-approved BCMA-targeted CAR T-cells for MM patients, a recognition achieved despite extensive preclinical and clinical research efforts in this domain. Challenges remain regarding certain aspects of CAR T-cell manufacturing and administration processes, including the lack of accessibility and durability due to T-cell characteristics, along with expensive and time-consuming processes limiting health plan coverage. Moreover, MM features, such as tumor antigen heterogeneity, antigen presentation alterations, complex tumor microenvironments, and challenges in CAR-T trafficking, contribute to CAR T-cell exhaustion and subsequent therapy relapse or refractory status. Additionally, the occurrence of adverse events such as cytokine release syndrome, neurotoxicity, and on-target, off-tumor toxicities present obstacles to CAR T-cell therapies. Consequently, ongoing CAR T-cell trials are diligently addressing these challenges and barriers. In this review, we provide an overview of the effectiveness of currently available CAR T-cell treatments for MM, explore the primary resistance mechanisms to these treatments, suggest strategies for improving long-lasting remissions, and investigate the potential for combination therapies involving CAR T-cells.
多发性骨髓瘤（MM）是一种血液系统癌症，其特征为浆细胞异常增殖。初始治疗通常包括免疫调节药物（IMiDs）、蛋白酶体抑制剂（PIs）和单克隆抗体（mAbs）。尽管在诊断和治疗方面取得了显著进展，但大多数MM患者在开始治疗后的中位预期寿命通常仅为四到五年。在最近的进展中，嵌合抗原受体（CAR）T细胞在治疗B细胞恶性肿瘤方面的成功体现了先进免疫治疗技术的一种新的范式转变，具有有前景的治疗效果。Ide-cel和cilta-cel是仅有的两种获得美国食品药品监督管理局（FDA）批准的用于MM患者的靶向B细胞成熟抗原（BCMA）的CAR T细胞，尽管在该领域进行了广泛的临床前和临床研究工作，但才获得这一认可。在CAR T细胞制造和给药过程的某些方面仍然存在挑战，包括由于T细胞特性导致的可及性和持久性不足，以及昂贵且耗时的过程限制了医保覆盖范围。此外，MM的特征，如肿瘤抗原异质性、抗原呈递改变、复杂的肿瘤微环境以及CAR-T细胞归巢方面的挑战，导致CAR T细胞耗竭以及随后的治疗复发或难治状态。此外，细胞因子释放综合征、神经毒性和靶向非肿瘤毒性等不良事件的发生为CAR T细胞疗法带来了障碍。因此，正在进行的CAR T细胞试验正在努力应对这些挑战和障碍。在本综述中，我们概述了目前可用的CAR T细胞治疗MM的有效性，探讨了这些治疗的主要耐药机制，提出了改善长期缓解的策略，并研究了涉及CAR T细胞的联合疗法的潜力。
