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

Nature Medicine volume 26, pages 1459–1467 (2020)Cite this article

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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 <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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Fig. 1: αCD70/decitabine combination therapy eradicates human CD34+CD38− LSCs in vitro and in vivo.
Fig. 2: The ADCC-enhanced αCD70 mAb cusatuzumab has superior efficacy in reducing LSCs than αCD70 blockade alone.
Fig. 3: Treatment schedule and response.
Fig. 4: Cusatuzumab reduces LSCs in patients with AML.

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Data availability

The patient-related clinical datasets in the paper were generated during and analyzed as part of a multicenter clinical trial (NCT03030612). The datasets are not publicly available because the trial is ongoing, but data can be requested by any qualified researcher after data lock and trial completion or upon reasonable request. All RNA raw data and analyzed sequencing data can be retrieved from the Gene Expression Omnibus and are available under accession no. GSE147989 (scRNA-seq). All other data that support the findings of the study are available from the corresponding authors upon request.

Code availability

The code used for the analysis of the single-cell sequencing data is available from the corresponding author upon request.

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Acknowledgements

We thank U. Lüthi and T. Chiorazzo for providing excellent technical assistance; the FACSlab of the Department for BioMedical Research for assistance with cell sorting; the Next Generation Sequencing Platform of the University of Bern for performing the high-throughput sequencing experiments; and the Interfaculty Bioinformatics Unit of the University of Bern for providing the high-performance computing infrastructure. We especially thank the teams of the Clinical Research Unit of the Department of Medical Oncology, Bern University Hospital and University Hospital Zürich, the University of Zürich and the histopathology laboratory at the Institute of Pathology, Bern. In addition, we thank B. Lambrecht from Ghent University for helpful discussions during the preparation of the manuscript. The preclinical work was supported by grants from the Swiss National Science Foundation (nos. 31003A_149768 and 310030B_13313 to A.F.O., and 310030_179394 to C.R.), the Swiss Cancer League (no. KLS-3346-02-2014), the Sassella Foundation, the Fondazione Dr. Carlo Gianella, the Wolfermann-Nägeli Foundation, the Olga Mayenfisch Foundation, Alfred und Anneliese Sutter-Stöttner Foundation and the Fondazione per la Ricerca sulla Trasfusione e sui Trapianti (to C.R.). The clinical study was financed by argenx. The translational work was supported by the SAKK/Gateway/Rising Tide Foundation (to A.F.O).

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Authors and Affiliations

  1. Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

    Carsten Riether, Thomas Pabst, Sabine Höpner, Magdalena Hinterbrandner & Adrian F. Ochsenbein

  2. Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland

    Carsten Riether, Sabine Höpner, Magdalena Hinterbrandner & Adrian F. Ochsenbein

  3. Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

    Ulrike Bacher

  4. Graduate School of Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland

    Magdalena Hinterbrandner

  5. Institute of Pathology, University of Bern, Bern, Switzerland

    Yara Banz

  6. Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland

    Rouven Müller & Markus G. Manz

  7. Interfaculty Bioinformatics Unit and SIB Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland

    Walid H. Gharib, David Francisco & Remy Bruggmann

  8. argenx BVBA, Zwijnaarde, Belgium

    Luc van Rompaey, Mahan Moshir, Tim Delahaye, Domenica Gandini, Ellen Erzeel, Anna Hultberg, Samson Fung, Hans de Haard & Nicolas Leupin

  9. Fung Consulting Healthcare & Life Sciences, Eching, Germany

    Samson Fung

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Contributions

C.R. and A.F.O. conceived and designed the preclinical and translational experiments. A.F.O., T.P., U.B., S.F., N.L., E.E., D.G., L.V.R. and H.D.H. conceived and designed the clinical trial. A.F.O., T.P., R.M. and M.G.M. selected and treated the patients. C.R., T.P., S.H., U.B., Y.B., M.H., R.M., L.V.R., A.H., M.M., T.D., D.G., E.E., W.H.G., D.F., R.B. and N.L. collected and assembled the data. C.R., T.P., S.H., U.B., Y.B., M.H., A.F.O., W.H.G., D.F., R.B., L.V.R., A.H., M.M., T.D., D.G., E.E., H.D.H. and N.L. analyzed and interpreted the data. C.R., T.P., U.B., A.F.O., A.H., H.D.H. and N.L. wrote the manuscripts. All authors revised the manuscript and approved its final version.

Corresponding authors

Correspondence to Carsten Riether or Adrian F. Ochsenbein.

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Competing interests

C.R. and A.F.O. are listed as investors on a patent held by the University of Bern on targeting CD70 for the treatment of AML. M.M., T.D., N.L., E.E., D.G., L.V.R., A.H. and H.D.H are employees of argenx. S.F. is a consultant for argenx. All other authors declare no competing interests related to the current study.

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Peer review information Javier Carmona was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Riether, C., Pabst, T., Höpner, S. et al. Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents. Nat Med 26, 1459–1467 (2020). https://doi.org/10.1038/s41591-020-0910-8

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