title: Cell surface delivery of TRAIL strongly augments the tumoricidal activity of T cells.
abstract: OBJECTIVE
  Adoptive T-cell therapy generally fails to induce meaningful anticancer responses in patients with solid tumors. Here, we present a novel strategy designed to selectively enhance the tumoricidal activity of T cells by targeted delivery of TNF-related apoptosis-inducing ligand (TRAIL) to the T-cell surface.
  
  
  METHODS
  We constructed two recombinant fusion proteins, anti-CD3:TRAIL and K12:TRAIL. Tumoricidal activity of T cells in the presence of these fusion proteins was assessed in solid tumor cell lines, primary patient-derived malignant cells, and in a murine xenograft model.
  
  
  RESULTS
  When added to T cells, K12:TRAIL and anti-CD3:TRAIL selectively bind to the T-cell surface antigens CD3 and CD7, respectively, leading to cell surface accretion of TRAIL. Subsequently, anti-CD3:TRAIL and K12:TRAIL increased the tumoricidal activity of T cells toward cancer cell lines and primary patient-derived malignant cells by more than 500-fold. Furthermore, T-cell surface delivery of TRAIL strongly inhibited tumor growth and increased survival time of xenografted mice more than 6-fold.
  
  
  CONCLUSIONS
  Targeted delivery of TRAIL to cell surface antigens of T cells potently enhances the tumoricidal activity of T cells. This approach may be generally applicable to enhance the efficacy of adoptive T-cell therapy.
authors.affiliation: Department of Surgery, Surgical Research Laboratories, University Medical Center Groningen (UMCG), University of Groningen, Groningen, The Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: de Bruyn
authors.forename: Yunwei
authors.initials: Y
authors.lastname: Wei
authors.forename: Valerie R
authors.initials: VR
authors.lastname: Wiersma
authors.forename: Douwe F
authors.initials: DF
authors.lastname: Samplonius
authors.forename: Harry G
authors.initials: HG
authors.lastname: Klip
authors.forename: Ate G J
authors.initials: AG
authors.lastname: van der Zee
authors.forename: Baofeng
authors.initials: B
authors.lastname: Yang
authors.forename: Wijnand
authors.initials: W
authors.lastname: Helfrich
authors.forename: Edwin
authors.initials: E
authors.lastname: Bremer
mesh_terms: D000818:Animals; D019011:Antigens, CD7 / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D020350:Graft vs Tumor Effect; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology; D011993:Recombinant Fusion Proteins; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D019011:Antigens, CD7; D017252:CD3 Complex; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse