1. Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents
- Author
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Riether, Carsten, Pabst, Thomas, Höpner, Sabine, Bacher, Ulrike, Hinterbrandner, Magdalena, Banz, Yara, Muller, Rouven, Manz, Markus G., Gharib, Walid H., Francisco, David, Bruggmann, Remy, van Rompaey, Luc, Moshir, Mahan, Delahaye, Tim, Gandini, Domenica, Erzeel, Ellen, Hultberg, Anna, Fung, Samson, de Haard, Hans, Leupin, Nicolas, and Ochsenbein, Adrian F.
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Stem cells -- Health aspects ,Tumor necrosis factor inhibitors -- Testing ,Monoclonal antibodies -- Usage -- Testing ,Biological sciences ,Health - Abstract
Acute myeloid leukemia (AML) is driven by leukemia stem cells (LSCs) that resist conventional chemotherapy and are the major cause of relapse.sup.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.sup.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 ((https://clinicaltrials.gov/ct2/show/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 A phase 1 dose-escalating trial evaluating CD70 inhibition in combination with hypomethylating therapy results in the elimination of leukemia stem cells and achieves clinical activity in untreated patients with acute myeloid leukemia., Author(s): Carsten Riether [sup.1] [sup.2] , Thomas Pabst [sup.1] , Sabine Höpner [sup.1] [sup.2] , Ulrike Bacher [sup.3] , Magdalena Hinterbrandner [sup.1] [sup.2] [sup.4] , Yara Banz [sup.5] , Rouven [...]
- Published
- 2020
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