title: PRAME-specific Allo-HLA-restricted T cells with potent antitumor reactivity useful for therapeutic T-cell receptor gene transfer.
abstract: OBJECTIVE
  In human leukocyte antigen (HLA)-matched stem cell transplantation (SCT), it has been shown that beneficial immune response mediating graft-versus-tumor (GVT) responses can be separated from graft-versus-host disease (GVHD) immune responses. In this study, we investigated whether it would be possible to dissect the beneficial immune response of allo-HLA-reactive T cells with potent antitumor reactivity from GVHD-inducing T cells present in the detrimental immune response after HLA-mismatched SCT.
  
  
  METHODS
  The presence of specific tumor-reactive T cells in the allo-HLA repertoire was analyzed at the time of severe GVHD after HLA-mismatched SCT, using tetramers composed of different tumor-associated antigens (TAA).
  
  
  RESULTS
  High-avidity allo-HLA-restricted T cells specific for the TAA preferentially expressed antigen on melanomas (PRAME) were identified that exerted highly single-peptide-specific reactivity. The T cells recognized multiple different tumor cell lines and leukemic cells, whereas no reactivity against a large panel of nonmalignant cells was observed. These T cells, however, also exerted low reactivity against mature dendritic cells (DC) and kidney epithelial cells, which was shown to be because of low PRAME expression.
  
  
  CONCLUSIONS
  On the basis of potential beneficial specificity and high reactivity, the T-cell receptors of these PRAME-specific T cells may be effective tools for adoptive T-cell therapy. Clinical studies have to determine the significance of the reactivity observed against mature DCs and kidney epithelial cells.
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Avital L
authors.initials: AL
authors.lastname: Amir
authors.forename: Dirk M
authors.initials: DM
authors.lastname: van der Steen
authors.forename: Marleen M
authors.initials: MM
authors.lastname: van Loenen
authors.forename: Renate S
authors.initials: RS
authors.lastname: Hagedoorn
authors.forename: Renate
authors.initials: R
authors.lastname: de Boer
authors.forename: Michel D G
authors.initials: MD
authors.lastname: Kester
authors.forename: Arnoud H
authors.initials: AH
authors.lastname: de Ru
authors.forename: Gert-Jan
authors.initials: GJ
authors.lastname: Lugthart
authors.forename: Cees
authors.initials: C
authors.lastname: van Kooten
authors.forename: Pieter S
authors.initials: PS
authors.lastname: Hiemstra
authors.forename: Inge
authors.initials: I
authors.lastname: Jedema
authors.forename: Marieke
authors.initials: M
authors.lastname: Griffioen
authors.forename: Peter A
authors.initials: PA
authors.lastname: van Veelen
authors.forename: J H Frederik
authors.initials: JH
authors.lastname: Falkenburg
authors.forename: Mirjam H M
authors.initials: MH
authors.lastname: Heemskerk
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D018014:Gene Transfer Techniques; D019672:Genes, T-Cell Receptor; D006086:Graft vs Host Disease; D020350:Graft vs Tumor Effect; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive; D007668:Kidney / Q000276:immunology; D009369:Neoplasms / Q000628:therapy*; D034622:RNA Interference; D034741:RNA, Small Interfering; D033581:Stem Cell Transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; C404944:PRAME protein, human; D034741:RNA, Small Interfering