title: Antigen receptor-redirected T cells derived from hematopoietic precursor cells lack expression of the endogenous TCR/CD3 receptor and exhibit specific antitumor capacities.
abstract: Recent clinical studies indicate that adoptive T-cell therapy and especially chimeric antigen receptor (CAR) T-cell therapy is a very potent and potentially curative treatment for B-lineage hematologic malignancies. Currently, autologous peripheral blood T cells are used for adoptive T-cell therapy. Adoptive T cells derived from healthy allogeneic donors may have several advantages; however, the expected occurrence of graft versus host disease (GvHD) as a consequence of the diverse allogeneic T-cell receptor (TCR) repertoire expressed by these cells compromises this approach. Here, we generated T cells from cord blood hematopoietic progenitor cells (HPCs) that were transduced to express an antigen receptor (AR): either a CAR or a TCR with or without built-in CD28 co-stimulatory domains. These AR-transgenic HPCs were culture-expanded on an OP9-DL1 feeder layer and subsequently differentiated to CD5+CD7+T-lineage precursors, to CD4+CD8+double positive cells and finally to mature AR+T cells. The AR+T cells were largely naive CD45RA+CD62L+T cells. These T cells had mostly germline TCRα and TCRβ loci and therefore lacked surface-expressed CD3/TCRαβ complexes. The CD3-AR-transgenic cells were mono-specific, functional T cells as they displayed specific cytotoxic activity. Cytokine production, including IL-2, was prominent in those cells bearing ARs with built-in CD28 domains. Data sustain the concept that cord blood HPC derived,in vitrogenerated allogeneic CD3-AR+T cells can be used to more effectively eliminate malignant cells, while at the same time limiting the occurrence of GvHD.
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University , Ghent, Belgium.
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Van Caeneghem
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University , Ghent, Belgium.
authors.forename: Stijn
authors.initials: S
authors.lastname: De Munter
authors.affiliation: Department of Biopharmacy and Institute for Medical Immunology, Université Libre de Bruxelles (ULB) , Brussels, Belgium.
authors.forename: Paola
authors.initials: P
authors.lastname: Tieppo
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University , Ghent, Belgium.
authors.forename: Glenn
authors.initials: G
authors.lastname: Goetgeluk
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University , Ghent, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Weening
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University , Ghent, Belgium.
authors.forename: Greet
authors.initials: G
authors.lastname: Verstichel
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University , Ghent, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bonte
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University , Ghent, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Taghon
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University , Ghent, Belgium.
authors.forename: Georges
authors.initials: G
authors.lastname: Leclercq
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University , Ghent, Belgium.
authors.forename: Tessa
authors.initials: T
authors.lastname: Kerre
authors.affiliation: Laboratory of Tumor Immunology, Department of Medical Immunology, Erasmus MC Cancer Center , Rotterdam, the Netherlands.
authors.forename: Reno
authors.initials: R
authors.lastname: Debets
authors.affiliation: Department of Biopharmacy and Institute for Medical Immunology, Université Libre de Bruxelles (ULB) , Brussels, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Vermijlen
authors.affiliation: Center for Molecular Medicine Cologne (CMMC) and Department of Internal Medicine, University of Cologne , Cologne, Germany.
authors.forename: Hinrich
authors.initials: H
authors.lastname: Abken
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University , Ghent, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Vandekerckhove
keywords: Chimeric antigen receptor; T cell; cord blood; hematopoietic precursor cell; hematopoietic stem cell; immunotherapy