Journal
NATURE MEDICINE
Volume 26, Issue 9, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41591-020-0910-8
Keywords
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Funding
- Swiss National Science Foundation [31003A_149768, 310030B_13313, 310030_179394]
- Swiss Cancer League [KLS-3346-02-2014]
- Sassella Foundation
- Fondazione Dr. Carlo Gianella
- Wolfermann-Nageli Foundation
- Olga Mayenfisch Foundation
- Alfred und Anneliese Sutter-Stottner Foundation
- Fondazione per la Ricerca sulla Trasfusione e sui Trapianti
- argenx
- SAKK/Gateway/Rising Tide Foundation
- Swiss National Science Foundation (SNF) [31003A_149768, 310030_179394] Funding Source: Swiss National Science Foundation (SNF)
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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(3-5). 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 alpha CD70 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.
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