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。
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