title: CD40 ligand and tdTomato-armed vaccinia virus for induction of antitumor immune response and tumor imaging.
abstract: Oncolytic vaccinia virus is an attractive platform for immunotherapy. Oncolysis releases tumor antigens and provides co-stimulatory danger signals. However, arming the virus can improve efficacy further. CD40 ligand (CD40L, CD154) can induce apoptosis of tumor cells and it also triggers several immune mechanisms. One of these is a T-helper type 1 (Th1) response that leads to activation of cytotoxic T-cells and reduction of immune suppression. Therefore, we constructed an oncolytic vaccinia virus expressing hCD40L (vvdd-hCD40L-tdTomato), which in addition features a cDNA expressing the tdTomato fluorochrome for detection of virus, potentially important for biosafety evaluation. We show effective expression of functional CD40L both in vitro and in vivo. In a xenograft model of bladder carcinoma sensitive to CD40L treatment, we show that growth of tumors was significantly inhibited by the oncolysis and apoptosis following both intravenous and intratumoral administration. In a CD40-negative model, CD40L expression did not add potency to vaccinia oncolysis. Tumors treated with vvdd-mCD40L-tdtomato showed enhanced efficacy in a syngenic mouse model and induced recruitment of antigen-presenting cells and lymphocytes at the tumor site. In summary, oncolytic vaccinia virus coding for CD40L mediates multiple antitumor effects including oncolysis, apoptosis and induction of Th1 type T-cell responses.
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Parviainen
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Ahonen
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: I
authors.initials: I
authors.lastname: Diaconu
authors.affiliation: Laboratory of Immunovirotherapy, Faculty of Pharmacy, Division of Biopharmaceutics and Pharmacokinetics, University of Helsinki, Helsinki Finland.
authors.forename: M
authors.initials: M
authors.lastname: Hirvinen
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Å
authors.initials: Å
authors.lastname: Karttunen
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Vähä-Koskela
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Hemminki
authors.affiliation: Laboratory of Immunovirotherapy, Faculty of Pharmacy, Division of Biopharmaceutics and Pharmacokinetics, University of Helsinki, Helsinki Finland.
authors.forename: V
authors.initials: V
authors.lastname: Cerullo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D023201:CD40 Ligand / Q000235:genetics* / Q000276:immunology; D045744:Cell Line, Tumor; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics; D018417:Th1 Cells / Q000276:immunology*; D059016:Tumor Microenvironment; D001749:Urinary Bladder Neoplasms / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D023201:CD40 Ligand