title: Oncolytic Adenovirus Expressing Monoclonal Antibody Trastuzumab for Treatment of HER2-Positive Cancer.
abstract: Monoclonal anti-HER2 antibody trastuzumab has significantly improved the survival of patients with HER2-overexpressing tumors. Nevertheless, systemic antibody therapy is expensive, limited in efficacy due to physical tumor barriers, and carries the risk of severe side effects such as cardiomyopathy. Oncolytic viruses mediate cancer-selective transgene expression, kill infected cancer cells while mounting antitumor immune responses, and have recently demonstrated promising efficacy in combination treatments. Here, we armed an oncolytic adenovirus with full-length trastuzumab to achieve effective in situ antibody production coupled with progressive oncolytic cancer cell killing. We constructed an infectivity-enhanced serotype 5 oncolytic adenovirus, Ad5/3-Δ24-tras, coding for human trastuzumab antibody heavy- and light-chain genes, connected by an internal ribosome entry site. Infected cancer cells were able to assemble full-length functional antibody, as confirmed by Western blot, ELISA, and antibody-dependent cell-mediated cytotoxicity assay. Importantly, oncolysis was required for release of the antibody into tumors, providing additional spatial selectivity. Ad5/3-Δ24-tras showed potent in vitro cytotoxicity and enhanced antitumor efficacy over oncolytic control virus Ad5/3-Δ24 or commercial trastuzumab in HER2-positive cancer models in vivo (both P < 0.05). Furthermore, Ad5/3-Δ24-tras resulted in significantly higher tumor-to-systemic antibody concentrations (P < 0.001) over conventional delivery. Immunological analyses revealed dendritic cell activation and natural killer cell accumulation in tumor-draining lymph nodes. Thus, Ad5/3-Δ24-tras is an attractive anticancer approach combining oncolytic immunotherapy with local trastuzumab production, resulting in improved in vivo efficacy and immune cell activation in HER2-positive cancer. Moreover, the finding that tumor cells can produce functional antibody as directed by oncolytic virus could lead to many valuable antitumor approaches. Mol Cancer Ther; 15(9); 2259-69. ©2016 AACR.
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Division of Biological Sciences, University of California San Diego, La Jolla, California.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Liikanen
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Siri
authors.initials: S
authors.lastname: Tähtinen
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Kilian
authors.initials: K
authors.lastname: Guse
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Paul Langerhans Institute Dresden of the Helmholtz Centre Munich, University Clinic Carl Gustav Carus, TU Dresden, Dresden, Germany.
authors.forename: Theresia
authors.initials: T
authors.lastname: Gutmann
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Paula
authors.initials: P
authors.lastname: Savola
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Minna
authors.initials: M
authors.lastname: Oksanen
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kanerva
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland. TILT Biotherapeutics, Ltd., Helsinki, Finland. akseli.hemminki@helsinki.fi.
authors.forename: Akseli
authors.initials: A
authors.lastname: Hemminki
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics* / Q000276:immunology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D023061:Gene Order; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D050504:Oncolytic Viruses / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D000068878:Trastuzumab / Q000235:genetics* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab