title: Selective gene transfer into primary human gastric tumors using epithelial cell adhesion molecule-targeted adenoviral vectors with ablated native tropism.
abstract: Currently, application of adenoviral vectors (AdV) in gastric cancer gene therapy would be improved by increases in the specificity of transduction. Previously, we found that epithelial cell adhesion molecule (EpCAM) was expressed on gastric tumors but not on gastric epithelium. In this study, we evaluated doubly-ablated AdV lacking native binding ability together with bispecific single-chain antibodies targeted toward EpCAM for gene therapy of gastric cancer. Specific binding to EpCAM augmented the gene transfer efficiency of doubly-ablated AdV on gastric cancer cell lines up to 144-fold, reaching levels similar to or exceeding those achieved with native AdV. In contrast, EpCAM-targeted doubly-ablated AdV-mediated gene transfer into an EpCAM-negative cell line was reduced 38-fold compared with transduction by native AdV. Most importantly, EpCAM-targeted doubly-ablated AdV showed selectivity for primary human gastric tumors versus the surrounding nonneoplastic gastric mucosa of the same patients and normal liver tissue samples. Targeting these doubly-ablated AdV toward EpCAM resulted in similar transduction efficiency as obtained with native AdV for EpCAM-expressing primary human gastric tumors, whereas transduction of gastric epithelium and liver tissue was reduced at least 10-fold. This study thus indicates that application of EpCAM-targeted doubly-ablated AdV for gastric cancer gene therapy results in a favorable tumor-over-normal tissue transduction ratio.
authors.affiliation: Division of Gene Therapy, Department of Medical Oncology, Vrije Universiteit Medical Center, 1007 MB Amsterdam, The Netherlands.
authors.forename: Daniëlle A M
authors.initials: DA
authors.lastname: Heideman
authors.forename: Victor W
authors.initials: VW
authors.lastname: van Beusechem
authors.forename: G Johan A
authors.initials: GJ
authors.lastname: Offerhaus
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wickham
authors.forename: Peter W
authors.initials: PW
authors.lastname: Roelvink
authors.forename: Mikael E
authors.initials: ME
authors.lastname: Craanen
authors.forename: Herbert M
authors.initials: HM
authors.lastname: Pinedo
authors.forename: Chris J L M
authors.initials: CJ
authors.lastname: Meijer
authors.forename: Winald R
authors.initials: WR
authors.lastname: Gerritsen
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000260:Adenoviruses, Human / Q000502:physiology*; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D001254:Astrocytoma / Q000473:pathology; D018279:Carcinoma, Signet Ring Cell / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured / Q000378:metabolism; D003587:Cytomegalovirus / Q000235:genetics; D003673:Defective Viruses / Q000502:physiology*; D016503:Drug Delivery Systems; D000071858:Epithelial Cell Adhesion Molecule; D005753:Gastric Mucosa / Q000378:metabolism; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage*; D008156:Luciferases / Q000235:genetics; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000473:pathology*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D018796:Immunoconjugates; D008156:Luciferases