Acute myeloid leukemia (AML) is driven by leukemia stem cells (LSCs) that resist conventional chemotherapy and are the major cause of relapse^1,2. Hypomethylating agents (HMAs) are the standard of care in the treatment of older or unfit patients with AML, but responses are modest and not durable^3,4,5. 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 <10⁻³. 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.

急性髓细胞性白血病（AML）由抗常规化疗的白血病干细胞（LSC）驱动，是复发^1,2的主要原因。次甲基化剂（HMA）是治疗年龄较大或不适合的AML患者的标准治疗方法，但反应缓慢且不持久^3,4,5。在这里，我们证明LSCs响应HMA治疗而上调肿瘤坏死因子家族配体CD70，导致CD70 / CD27信号转导增加。用cusatuzumab（一种具有增强的抗体依赖性细胞毒性作用的人αCD70单克隆抗体）阻断CD70 / CD27信号传导并靶向表达CD70的LSC，可在体外和异种移植实验中消除LSC。基于这些临床前结果，我们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。我们报告了临床试验第一阶段剂量递增部分的结果。纳入的12例患者的血液学反应包括8例完全缓解，^{− 3}。中位反应时间为3.3个月。数据截止时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LSCs并触发与髓样分化和凋亡相关的基因标记。