title: Secretory TRAIL-Armed Natural Killer Cell-Based Therapy: In Vitro and In Vivo Colorectal Peritoneal Carcinomatosis Xenograft.
abstract: Since its discovery in 1995, TNF-related apoptosis-inducing ligand (TRAIL) has sparked growing interest among oncologists due to its remarkable ability to induce apoptosis in malignant human cells, but not in most normal cells. However, one major drawback is its fast clearance rate in vivo Thus, the development of an alternative means of delivery may increase the effectiveness of TRAIL-based therapy. In this study, we developed a secretory TRAIL-armed natural killer (NK) cell-based therapy and assessed its cytotoxic effects on colorectal cancer cells and its tumoricidal efficacy on colorectal peritoneal carcinomatosis xenograft. We generated genetically modified NK cells by transduction with a lentiviral vector consisting of a secretion signal domain, a trimerization domain, and an extracellular domain of the TRAIL gene. These NK cells secreted a glycosylated form of TRAIL fusion protein that induced apoptotic death. Intraperitoneally, but not intravenously, injected NK cells effectively accumulated at tumor sites, infiltrated tumor tissue, induced apoptosis, and delayed tumor growth. These results shed light on the therapeutic potential of genetically engineered NK cells to treat peritoneal carcinomatosis. Mol Cancer Ther; 15(7); 1591-601. ©2016 AACR.
authors.affiliation: Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Se-Hoon
authors.initials: SH
authors.lastname: Hong
authors.affiliation: Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: William T
authors.initials: WT
authors.lastname: Kwon
authors.affiliation: Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Bailey
authors.affiliation: Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Per
authors.initials: P
authors.lastname: Basse
authors.affiliation: Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: David L
authors.initials: DL
authors.lastname: Bartlett
authors.affiliation: Protein Metabolism Medical Research Center and Department of Biomedical Science, College of Medicine, Seoul National University, Seoul, Korea.
authors.forename: Yong Tae
authors.initials: YT
authors.lastname: Kwon
authors.affiliation: Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. leeyj@upmc.edu.
authors.forename: Yong J
authors.initials: YJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D023061:Gene Order; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D016219:Immunotherapy, Adoptive; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D010534:Peritoneal Neoplasms / Q000276:immunology* / Q000473:pathology / Q000556:secondary / Q000628:therapy; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand