title: Immunological data from cancer patients treated with Ad5/3-E2F-Δ24-GMCSF suggests utility for tumor immunotherapy.
abstract: Oncolytic viruses that selectively replicate in tumor cells can be used for treatment of cancer. Accumulating data suggests that virus induced oncolysis can enhance anti-tumor immunity and break immune tolerance. To capitalize on the immunogenic nature of oncolysis, we generated a quadruple modified oncolytic adenovirus expressing granulocyte-macrophage colony-stimulating factor (GMCSF). Ad5/3-E2F-Δ24-GMCSF (CGTG-602) was engineered to contain a tumor specific E2F1 promoter driving an E1 gene deleted at the retinoblastoma protein binding site ("Δ24"). The fiber features a knob from serotype 3 for enhanced gene delivery to tumor cells. The virus was tested preclinically in vitro and in vivo and then 13 patients with solid tumors refractory to standard therapies were treated. Treatments were well tolerated and frequent tumor- and adenovirus-specific T-cell immune responses were seen. Overall, with regard to tumor marker or radiological responses, signs of antitumor efficacy were seen in 9/12 evaluable patients (75%). The radiological disease control rate with positron emission tomography was 83% while the response rate (including minor responses) was 50%. Tumor biopsies indicated accumulation of immunological cells, especially T-cells, to tumors after treatment. RNA expression analyses of tumors indicated immunological activation and metabolic changes secondary to virus replication.
authors.affiliation: Cancer Gene Therapy Group, Transplantation Laboratory & Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Otto
authors.initials: O
authors.lastname: Hemminki
authors.affiliation: Cancer Gene Therapy Group, Transplantation Laboratory & Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Suvi
authors.initials: S
authors.lastname: Parviainen
authors.affiliation: Cancer Gene Therapy Group, Transplantation Laboratory & Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Juuso
authors.initials: J
authors.lastname: Juhila
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.
authors.forename: Riku
authors.initials: R
authors.lastname: Turkki
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.
authors.forename: Nina
authors.initials: N
authors.lastname: Linder
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.|Division of Global Health/IHCAR, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Lundin
authors.affiliation: CSC - IT Center for Science Ltd, Helsinki, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Kankainen
authors.affiliation: Department of Pathology, HUSLAB and Haartman Institute, Helsinki, University Central Hospital and Genome-Scale Biology, Research Programs Unit, University of Helsinki, Helsinki, Finland.
authors.forename: Ari
authors.initials: A
authors.lastname: Ristimäki
authors.affiliation: Cancer Gene Therapy Group, Transplantation Laboratory & Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Anniina
authors.initials: A
authors.lastname: Koski
authors.affiliation: Cancer Gene Therapy Group, Transplantation Laboratory & Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Liikanen
authors.affiliation: Cancer Gene Therapy Group, Transplantation Laboratory & Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Minna
authors.initials: M
authors.lastname: Oksanen
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Nettelbeck
authors.affiliation: Docrates Cancer Center, Helsinki, Finland.
authors.forename: Kalevi
authors.initials: K
authors.lastname: Kairemo
authors.affiliation: Docrates Cancer Center, Helsinki, Finland.
authors.forename: Kaarina
authors.initials: K
authors.lastname: Partanen
authors.affiliation: Docrates Cancer Center, Helsinki, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Joensuu
authors.affiliation: Cancer Gene Therapy Group, Transplantation Laboratory & Haartman Institute, 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, Transplantation Laboratory & Haartman Institute, University of Helsinki, Helsinki, Finland.|Docrates Cancer Center, Helsinki, Finland.|TILT Biotherapeutics Ltd, Helsinki, Finland.
authors.forename: Akseli
authors.initials: A
authors.lastname: Hemminki
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D006224:Cricetinae; D050687:E2F1 Transcription Factor / Q000235:genetics; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D008647:Mesocricetus; D008875:Middle Aged; D009369:Neoplasms / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses; D011401:Promoter Regions, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D016178:Granulocyte-Macrophage Colony-Stimulating Factor