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A novel CD34-specific T-cell engager efficiently depletes acute myeloid leukemia and leukemic stem cells in vitro and in vivo
Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..ORCID iD: 0000-0002-0251-5628
Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, Stockholm, Sweden..
Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada..
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2022 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 107, no 8, p. 1786-1795Article in journal (Refereed) Published
Abstract [en]

Less than a third of patients with acute myeloid leukemia (AML) are cured by chemotherapy and/or hematopoietic stem cell transplantation, highlighting the need to develop more efficient drugs. The low efficacy of standard treatments is associated with inadequate depletion of CD34(+) blasts and leukemic stem cells, the latter a drug-resistant subpopulation of leukemia cells characterized by the CD34(+)CD38(-) phenotype. To target these drug-resistant primitive leukemic cells better, we have designed a CD34/CD3 bi-specific T-cell engager (BTE) and characterized its anti-leukemia potential in vitro, ex vivo and in vivo. Our results show that this CD34-specific BTE induces CD34-dependent T-cell activation and subsequent leukemia cell killing in a dose-dependent manner, further corroborated by enhanced T-cell-mediated killing at the singlecell level. Additionally, the BTE triggered efficient T-cell-mediated depletion of CD34(+) hematopoietic stem cells from peripheral blood stem cell grafts and CD34(+) blasts from AML patients. Using a humanized AML xenograft model, we confirmed that the CD34-specific BTE had in vivo efficacy by depleting CD34(+) blasts and leukemic stem cells without side effects. Taken together, these data demonstrate that the CD34-specific BTE has robust antitumor effects, supporting development of a novel treatment modality with the aim of improving outcomes of patients with AML and myelodysplastic syndromes.

Place, publisher, year, edition, pages
Ferrata Storti Foundation (Haematologica) , 2022. Vol. 107, no 8, p. 1786-1795
National Category
Hematology Respiratory Medicine and Allergy Cancer and Oncology
Identifiers
URN: urn:nbn:se:kth:diva-317010DOI: 10.3324/haematol.2021.279486ISI: 000841120700009PubMedID: 35142149Scopus ID: 2-s2.0-85131531317OAI: oai:DiVA.org:kth-317010DiVA, id: diva2:1693170
Note

QC 20220906

Available from: 2022-09-06 Created: 2022-09-06 Last updated: 2022-09-06Bibliographically approved

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Sanchez-Rivera, LauraAlves, Renato M. P.de Moura, Tales RochaMim, CarstenÖnfelt, BjörnUhlin, Michael

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Stikvoort, ArwenSanchez-Rivera, LauraAlves, Renato M. P.de Moura, Tales RochaMim, CarstenDick, John E.Önfelt, BjörnUhlin, Michael
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Science for Life Laboratory, SciLifeLabAffinity ProteomicsApplied PhysicsBiomedical Engineering and Health SystemsStructural BiotechnologyBiophysics
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