title: Immunological effects of a tumor necrosis factor alpha-armed oncolytic adenovirus.
abstract: For long it has been recognized that tumor necrosis factor alpha (TNFa) has anticancer characteristics, and its use as a cancer therapeutic was proposed already in the 1980s. However, its systemic toxicity has limited its usability. Oncolytic viruses, selectively cancer-killing viruses, have shown great potency, and one of their most useful aspects is their ability to produce high amounts of transgene products locally, resulting in high local versus systemic concentrations. Therefore, the overall magnitude of tumor cell killing results from the combination of oncolysis, transgene-mediated direct effect such as TNFa-mediated apoptosis, and, perhaps most significantly, from activation of the host immune system against the tumor. We generated a novel chimeric oncolytic adenovirus expressing human TNFa, Ad5/3-D24-hTNFa, whose efficacy and immunogenicity were tested in vitro and in vivo. The hTNFa-expressing adenovirus showed increased cancer-eradicating potency, which was shown to be because of elevated apoptosis and necrosis rates and induction of various immune responses. Interestingly, we saw increase in immunogenic cell death markers in Ad5/3-d24-hTNFa-treated cells. Moreover, tumors treated with Ad5/3-D24-hTNFa displayed enhanced presence of OVA-specific cytotoxic T cells. We thus can conclude that tumor eradication and antitumor immune responses mediated by Ad5/3-d24-hTNFa offer a new potential drug candidate for cancer therapy.
authors.affiliation: 1 Laboratory of Immunovirotherapy, Division of Pharmaceutical Biosciences and Centre for Drug Research, Faculty of Pharmacy, University of Helsinki , 00790 Helsinki, Finland .
authors.forename: Mari
authors.initials: M
authors.lastname: Hirvinen
authors.forename: Maria
authors.initials: M
authors.lastname: Rajecki
authors.forename: Mika
authors.initials: M
authors.lastname: Kapanen
authors.forename: Suvi
authors.initials: S
authors.lastname: Parviainen
authors.forename: Noora
authors.initials: N
authors.lastname: Rouvinen-Lagerström
authors.forename: Iulia
authors.initials: I
authors.lastname: Diaconu
authors.forename: Petri
authors.initials: P
authors.lastname: Nokisalmi
authors.forename: Mikko
authors.initials: M
authors.lastname: Tenhunen
authors.forename: Akseli
authors.initials: A
authors.lastname: Hemminki
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerullo
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D017209:Apoptosis / Q000276:immunology; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000276:immunology / Q000627:therapeutic use*; D057809:HEK293 Cells; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D018709:Statistics, Nonparametric; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha