Just scratching the surface: novel treatment approaches for multiple myeloma targeting cell membrane proteins

IF 81.1 1区 医学 Q1 ONCOLOGY Nature Reviews Clinical Oncology Pub Date : 2024-07-03 DOI:10.1038/s41571-024-00913-y
Paola Neri, Noémie Leblay, Holly Lee, Annamaria Gulla, Nizar J. Bahlis, Kenneth C. Anderson
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Abstract

A better understanding of the roles of the adaptive and innate immune systems in the oncogenesis of cancers including multiple myeloma (MM) has led to the development of novel immune-based therapies. B cell maturation antigen (BCMA), G protein-coupled receptor family C group 5 member D (GPRC5D) and Fc receptor-like protein 5 (FcRL5, also known as FcRH5) are cell-surface transmembrane proteins expressed by plasma cells, and have been identified as prominent immunotherapeutic targets in MM, with promising activity demonstrated in patients with heavily pretreated relapsed and/or refractory disease. Indeed, since 2020, antibody–drug conjugates, bispecific T cell engagers and autologous chimeric antigen receptor T cells targeting BCMA or GPRC5D have been approved for the treatment of relapsed and/or refractory MM. However, responses to these therapies are not universal, and acquired resistance invariably occurs. In this Review, we discuss the various immunotherapeutic approaches targeting BCMA, GPRC5D and FcRL5 that are currently either available or in clinical development for patients with MM. We also review the mechanisms underlying resistance to such therapies, and discuss potential strategies to overcome these mechanisms and improve patient outcomes. Novel immunotherapeutic strategies based on targeting specific tumour-associated antigens with antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T cells and bispecific T cell engagers (BTEs) are revolutionizing the treatment of multiple myeloma. In this Review, the authors describe the clinical experience to date with ADCs, CAR T cells and BTEs targeting B cell maturation antigen, G protein-coupled receptor family C group 5 member D and Fc receptor-like protein 5. In addition, they discuss the mechanisms of resistance to such therapies, and potential strategies by which resistance could be overcome to improve patient outcomes.

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浅尝辄止:针对细胞膜蛋白的多发性骨髓瘤新型治疗方法。
随着人们对适应性免疫系统和先天性免疫系统在包括多发性骨髓瘤(MM)在内的癌症致癌过程中的作用有了更深入的了解,基于免疫的新型疗法应运而生。B细胞成熟抗原(BCMA)、G蛋白偶联受体C家族第5组成员D(GPRC5D)和Fc受体样蛋白5(FcRL5,又称FcRH5)是浆细胞表达的细胞表面跨膜蛋白,已被确定为MM的主要免疫治疗靶点,在重度预处理复发和/或难治性疾病患者中显示出良好的活性。事实上,自2020年以来,以BCMA或GPRC5D为靶点的抗体-药物共轭物、双特异性T细胞吸引剂和自体嵌合抗原受体T细胞已被批准用于治疗复发和/或难治性MM。然而,对这些疗法的反应并不普遍,而且总会出现获得性耐药。在本综述中,我们将讨论针对BCMA、GPRC5D和FcRL5的各种免疫治疗方法,这些方法目前已经上市或正在临床开发中,可用于治疗MM患者。我们还回顾了此类疗法产生耐药性的机制,并讨论了克服这些机制和改善患者预后的潜在策略。
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来源期刊
CiteScore
99.40
自引率
0.40%
发文量
114
审稿时长
6-12 weeks
期刊介绍: Nature Reviews publishes clinical content authored by internationally renowned clinical academics and researchers, catering to readers in the medical sciences at postgraduate levels and beyond. Although targeted at practicing doctors, researchers, and academics within specific specialties, the aim is to ensure accessibility for readers across various medical disciplines. The journal features in-depth Reviews offering authoritative and current information, contextualizing topics within the history and development of a field. Perspectives, News & Views articles, and the Research Highlights section provide topical discussions, opinions, and filtered primary research from diverse medical journals.
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