2. Academic Validation
  3. Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents

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

  • Nat Med. 2020 Sep;26(9):1459-1467. doi: 10.1038/s41591-020-0910-8.
Carsten Riether 1 2,  Thomas Pabst 3,  Sabine Höpner 3 4,  Ulrike Bacher 5,  Magdalena Hinterbrandner 3 4 6,  Yara Banz 7,  Rouven Müller 8,  Markus G Manz 8,  Walid H Gharib 9,  David Francisco 9,  Remy Bruggmann 9,  Luc van Rompaey 10,  Mahan Moshir 10,  Tim Delahaye 10,  Domenica Gandini 10,  Ellen Erzeel 10,  Anna Hultberg 10,  Samson Fung 10 11,  Hans de Haard 10,  Nicolas Leupin 10,  Adrian F Ochsenbein 12 13
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. [email protected].
  • 2 Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland. [email protected].
  • 3 Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  • 4 Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.
  • 5 Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  • 6 Graduate School of Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
  • 7 Institute of Pathology, University of Bern, Bern, Switzerland.
  • 8 Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
  • 9 Interfaculty Bioinformatics Unit and SIB Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland.
  • 10 argenx BVBA, Zwijnaarde, Belgium.
  • 11 Fung Consulting Healthcare & Life Sciences, Eching, Germany.
  • 12 Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. [email protected].
  • 13 Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland. [email protected].
PMID: 32601337 DOI: 10.1038/s41591-020-0910-8
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 durable3-5. 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.

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