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靶向CD70可消除急性髓系白血病干细胞
2020-06-30 21:20

瑞士伯尔尼大学Adrian F. Ochsenbein、Carsten Riether等研究人员合作发现,用cusatuzumab靶向CD70可消除低甲基化药物治疗患者的急性髓细胞白血病干细胞。2020年6月29日,《自然—医学》在线发表了这一成果。

据研究人员介绍,急性髓性白血病(AML)由抵抗常规化疗的白血病干细胞(LSC)所驱动,也是复发的主要原因。低甲基化剂(HMA)是治疗年龄较大或不适合的AML患者的标准治疗方法,但反应中等且不持久。
 
研究人员证明LSC响应HMA治疗而上调肿瘤坏死因子家族配体CD70,导致CD70/CD27信号增加。用cusatuzumab(一种具有增强的抗体依赖性细胞毒性作用的人源αCD70单克隆抗体)阻断CD70/CD27信号并靶向表达CD70的LSC,可以在体外和异种移植实验中消除LSC。基于这些临床前结果,研究人员对先前未接受治疗的AML老年患者进行了1/2期临床试验,采用单剂量cusatuzumab单药治疗,然后与HMA阿扎胞苷(NCT03030612)联合治疗。
 
研究人员报告了临床试验第一阶段剂量递增部分的结果。入组的12例患者的血液学反应包括8例完全缓解、2例完全血液计数恢复但不完全缓解以及2例部分缓解,其中4例实现最小的残留疾病阴性率(流式结果小于10-3)。中位反应时间为3.3个月。
 
数据截止时,研究尚未达到中位无进展生存期。没有剂量限制性毒性的报道,未达到cusatuzumab的最大耐受剂量。重要的是,cusatuzumab治疗可大大降低LSC并触发与髓样分化和凋亡相关的基因标记。
 
附:英文原文

Title: Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents

Author: Carsten Riether, Thomas Pabst, Sabine Hpner, Ulrike Bacher, Magdalena Hinterbrandner, Yara Banz, Rouven Mller, Markus G. Manz, Walid H. Gharib, David Francisco, Remy Bruggmann, Luc van Rompaey, Mahan Moshir, Tim Delahaye, Domenica Gandini, Ellen Erzeel, Anna Hultberg, Samson Fung, Hans de Haard, Nicolas Leupin, Adrian F. Ochsenbein

Issue&Volume: 2020-06-29

Abstract: Acute myeloid leukemia (AML) is driven by leukemia stem cells (LSCs) that resist conventional chemotherapy and are the major cause of relapse1,2. Hypomethylating agents (HMAs) are the standard of care in the treatment of older or unfit patients with AML, but responses are modest and not durable3,4,5. Here we demonstrate that LSCs upregulate the tumor necrosis factor family ligand CD70 in response to HMA treatment resulting in increased CD70/CD27 signaling. Blocking CD70/CD27 signaling and targeting CD70-expressing LSCs with cusatuzumab, a human αCD70 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity activity, eliminated LSCs in vitro and in xenotransplantation experiments. Based on these preclinical results, we performed a phase 1/2 trial in previously untreated older patients with AML with a single dose of cusatuzumab monotherapy followed by a combination therapy with the HMA azacitidine (NCT03030612). We report results from the phase 1 dose escalation part of the clinical trial. Hematological responses in the 12 patients enrolled included 8 complete remission, 2 complete remission with incomplete blood count recovery and 2 partial remission with 4 patients achieving minimal residual disease negativity by flow cytometry at <103. Median time to response was 3.3 months. Median progression-free survival was not reached yet at the time of the data cutoff. No dose-limiting toxicities were reported and the maximum tolerated dose of cusatuzumab was not reached. Importantly, cusatuzumab treatment substantially reduced LSCs and triggered gene signatures related to myeloid differentiation and apoptosis.

DOI: 10.1038/s41591-020-0910-8

Source: https://www.nature.com/articles/s41591-020-0910-8

Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:30.641
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex


本期文章:《自然—医学》:Online/在线发表

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