A novel CD34-specific T-cell engager efficiently depletes acute myeloid leukemia and leukemic stem cells <i>in vitro</i> and <i>in vivo</i>
Lucas C. M. Arruda,
Arwen Stikvoort,
Melanie Lambert,
Liqing Jin,
Laura Sanchez Rivera,
Renato M. P. Alves,
Tales Rocha de Moura,
Carsten Mim,
Sören Lehmann,
Rebecca Axelsson-Robertson,
John E. Dick,
Jonas Mattsson,
Björn Önfelt,
Mattias Carlsten,
Michael Uhlin
Affiliations
Lucas C. M. Arruda
Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm
Arwen Stikvoort
Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm
Melanie Lambert
Center for Hematology and Regenerative Medicine, Department of Medicine, Huddinge, Karolinska Institutet, Stockholm
Liqing Jin
Princess Margaret Cancer Centre, University Health Network, Toronto
Laura Sanchez Rivera
Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm
Renato M. P. Alves
Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm
Tales Rocha de Moura
Department for Biomedical Engineering and Health Systems, KTH Royal Institute of Technology Stockholm
Carsten Mim
Department for Biomedical Engineering and Health Systems, KTH Royal Institute of Technology Stockholm
Sören Lehmann
Center for Hematology and Regenerative Medicine, Department of Medicine, Huddinge, Karolinska Institutet, Stockholm
Rebecca Axelsson-Robertson
Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm, Sweden; Department of Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm
John E. Dick
Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Department of Molecular Genetics, University of Toronto
Jonas Mattsson
Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Gloria and Seymour Epstein Chair in Cell Therapy and Transplantation, Princess Margaret Cancer Centre, University Health Network, Toronto
Björn Önfelt
Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden; Department of Microbiology, Tumor and Cell Biology, Science for Life Laboratory, Karolinska Institutet, Stockholm
Mattias Carlsten
Center for Hematology and Regenerative Medicine, Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden; Center for Cell Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm
Michael Uhlin
Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm, Sweden; Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden; Department of Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm
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.
