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Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents
- Publication Year :
- 2020
-
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
- Subjects :
- 0301 basic medicine
Oncology
medicine.medical_specialty
Myeloid
Combination therapy
Azacitidine
Antineoplastic Agents
Apoptosis
610 Medicine & health
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
0302 clinical medicine
1300 General Biochemistry, Genetics and Molecular Biology
Internal medicine
Antineoplastic Combined Chemotherapy Protocols
Humans
Medicine
CD70
business.industry
Antibodies, Monoclonal
Myeloid leukemia
General Medicine
DNA Methylation
medicine.disease
Tumor Necrosis Factor Receptor Superfamily, Member 7
Clinical trial
Leukemia, Myeloid, Acute
Leukemia
Treatment Outcome
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
10032 Clinic for Oncology and Hematology
Neoplastic Stem Cells
570 Life sciences
biology
Stem cell
business
CD27 Ligand
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....69bd75a7a31c6457437ffc638a812048