CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Targeting degradation of IKZF1 and IKZF3 through modulation of the E3 ligase substrates in the context of cellular therapies for multiple myeloma.
Targeting degradation of IKZF1 and IKZF3 through modulation of the E3 ligase substrates in the context of cellular therapies for multiple myeloma.
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多发性骨髓瘤（MM）是一种以浆细胞克隆演化为特征的血液癌症。2022 年全球估计有 118,000 例 MM 病例和 121,000 例死亡。近几十年来，MM 治疗格局发生显著变化，从传统化疗转向更具靶向性的方案。为克服常限制单药疗效的内在和获得性耐药机制，研究者开发了同时靶向多条致病通路的联合用药策略。在免疫调节剂成功基础上，CRBN E3 连接酶调节剂（CELMoD）iberdomide（CC-220）和 mezigdomide（CC-92480）被开发为有前景且选择性更高的药物。与传统免疫调节剂相比，CELMoD 的结合能力高 10–20 倍，可更深、更快地促进 Ikaros 和 Aiolos 降解。
根据美国国家癌症研究所监测项目数据，身体状况良好患者的中位生存期超过 10 年，美国总体 MM 患者的 5 年生存率接近 60%。尽管这些数据令人鼓舞，MM 仍无法治愈，多数患者最终复发并需接受后续治疗。CELMoD 与细胞疗法联用可显著提高 MM 患者缓解率。本文依据 2020–2025 年美国血液学会（ASH）、美国临床肿瘤学会（ASCO）、国际骨髓瘤学会（IMS）和欧洲血液学协会（EHA）年会公布的研究，探讨 CELMoD 联合免疫疗法的理论依据和新兴证据，以及其作为移植桥接治疗或自体造血干细胞移植（ASCT）后维持治疗的应用。
Multiple myeloma (MM) is a blood cancer characterized by the clonal evolution of plasma cells. In 2022, there were an estimated 118 000 MM cases and 121 000 deaths worldwide. The treatment landscape of MM has undergone a dramatic transformation in recent decades, shifting from conventional chemotherapy to more targeted approaches. In order to overcome intrinsic and acquired resistance mechanisms that frequently restrict the efficacy of single-agent therapies, drug combination strategies have been developed to simultaneously target multiple pathogenetic pathways. Building on the success of immunomodulatory agents, CRBN E3 ligase modulators (CELMoDs), iberdomide (CC-220) and mezigdomide (CC-92480), have been designed as promising and more selective agents. CELMoDs demonstrate a 10-20 times higher binding capacity and they promote a more profound and rapid breakdown of Ikaros and Aiolos compared to traditional immunomodulatory agents.
According to the National Cancer Institute Surveillance Program, the median survival for fit patients is greater than ten years, and the 5-year survival for the general MM patient population in the US approaches 60%. Despite these encouraging numbers, MM is still an incurable disease, and the majority of patients eventually relapse and require additional lines of therapy. Combining CELMoDs with cellular therapies significantly improves the response rate in MM patients.
In this paper, based on the literature presented at the Annual Meeting of the American Society of Hematology (ASH), the American Society of Clinical Oncology (ASCO), the International Myeloma Society (IMS), and the European Hematology Association (EHA) in the 2020-2025 timeframe, we explore the rationale and emerging evidence of combining CELMoDs with immunotherapies, and their use as a bridge to transplant or as post-ASCT maintenance therapy in MM.
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