T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes
Nature Biotechnology, vol. 40, pp. 488–498
Abstract
Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice. TdT is an attractive cancer target as it is highly and homogeneously expressed in 80-94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes.
Authors 33
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Oslo University Hospital · University of Oslo
Affiliation as printed
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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Oslo University Hospital · University of Oslo
Affiliation as printed
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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Oslo University Hospital · University of Oslo
Affiliation as printed
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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Affiliation as printed
Department of Medicine, Huddinge Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
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Affiliation as printed
Department of Medicine, Huddinge Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
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Oslo University Hospital · University of Oslo
Affiliation as printed
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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Oslo University Hospital · University of Oslo
Affiliation as printed
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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Charité - Universitätsmedizin Berlin
Affiliation as printed
Charité - Universitätsmedizin Berlin, Institute of Immunology, Berlin, Germany
Charité – Universitätsmedizin Berlin, Institute of Immunology, Berlin, Germany
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Oslo University Hospital · University of Oslo
Affiliation as printed
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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Howard Hughes Medical Institute · Parker Institute for Cancer Immunotherapy · Stanford Medicine · Stanford University
Affiliation as printed
Parker Institute for Cancer Immunotherapy, Howard Hughes Medical Institute, Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA
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Oslo University Hospital · University of Oslo
Affiliation as printed
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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Oslo University Hospital · University of Oslo
Affiliation as printed
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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Oslo University Hospital · University of Oslo
Affiliation as printed
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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Oslo University Hospital · University of Oslo
Affiliation as printed
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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The Netherlands Cancer Institute
Affiliation as printed
Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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Affiliation as printed
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
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Affiliation as printed
Department of Medicine, Huddinge Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
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Leiden University Medical Center
Affiliation as printed
Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands
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Leiden University Medical Center
Affiliation as printed
Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands
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Oslo University Hospital · University of Oslo
Affiliation as printed
Department of Oncology, Oslo University Hospital Radiumhospitalet, Oslo, Norway
K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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Oslo University Hospital · University of Oslo
Affiliation as printed
Department of Haematology, Oslo University Hospital and KG Jebsen Center for B cell malignancies, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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Oslo University Hospital · University of Oslo
Affiliation as printed
Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway
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Leiden University Medical Center
Affiliation as printed
Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands
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Uppsala University Hospital · Karolinska Institutet
Affiliation as printed
Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden
Department of Medicine, Huddinge Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
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Affiliation as printed
Department of Immunology, Oslo University Hospital, Oslo, Norway
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Affiliation as printed
Department of Pediatric Hematology and Oncology, Oslo University Hospital, Oslo, Norway
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Howard Hughes Medical Institute · Parker Institute for Cancer Immunotherapy · Stanford Medicine · Stanford University
Affiliation as printed
Parker Institute for Cancer Immunotherapy, Howard Hughes Medical Institute, Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA
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Leiden University Medical Center · The Netherlands Cancer Institute
Affiliation as printed
Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center, Leiden, the Netherlands
Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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Leiden University Medical Center
Affiliation as printed
Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands
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German Cancer Research Center · University of Chicago · Deutsches Konsortium für Translationale Krebsforschung · Charité - Universitätsmedizin Berlin
Affiliation as printed
Charité - Universitätsmedizin Berlin, Institute of Immunology, Berlin, Germany
David and Etta Jonas Center for Cellular Therapy, The University of Chicago, Chicago, IL, USA
German Cancer Consortium, partner site Berlin, Berlin, Germany
German Cancer Research Center, Heidelberg, Germany
Charité – Universitätsmedizin Berlin, Institute of Immunology, Berlin, Germany
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Karolinska University Hospital · Karolinska Institutet · University of Oxford · MRC Weatherall Institute of Molecular Medicine · MRC Molecular Haematology Unit
Affiliation as printed
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
Department of Medicine, Huddinge Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
Karolinska University Hospital, Stockholm, Sweden
MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
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Affiliation as printed
Department of Medicine, Huddinge Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
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Johanna Olweus corresponding
Oslo University Hospital · University of Oslo
Affiliation as printed
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway. johanna.olweus@medisin.uio.no
K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. johanna.olweus@medisin.uio.no
K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
Cited by 37 stored of 36
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