title: Ad3-hTERT-E1A, a fully serotype 3 oncolytic adenovirus, in patients with chemotherapy refractory cancer.
abstract: Twenty-five patients with chemotherapy refractory cancer were treated with a fully serotype 3-based oncolytic adenovirus Ad3-hTERT-E1A. In mice, Ad3 induced higher amounts of cytokines but less liver damage than Ad5 or Ad5/3. In humans, the only grade 3 adverse reactions were self-limiting cytopenias and generally the safety profile resembled Ad5-based oncolytic viruses. Patients that had been previously treated with Ad5 viruses presented longer lasting lymphocytopenia but no median increase in Ad3-specific T-cells in blood, suggesting immunological activity against antigens other than Ad3 hexon. Frequent alterations in antitumor T-cells in blood were seen regardless of previous virus exposure. Neutralizing antibodies against Ad3 increased in all patients, whereas Ad5 neutralizing antibodies remained stable. Treatment with Ad3-hTERT-E1A resulted in re-emergence of Ad5 viruses from previous treatments into blood and vice versa. Signs of possible efficacy were seen in 11/15 (73%) patients evaluable for tumor markers, four of which were treated only intravenously. Particularly promising results were seen in breast cancer patients and especially those receiving concomitant trastuzumab. Taken together, Ad3-hTERT-E1A seems safe for further clinical testing or development of armed versions. It offers an immunologically attractive alternative, with possible pharmacodynamic differences and a different receptor compared to Ad5.
authors.affiliation: Cancer Gene Therapy Group, Haartman Institute and Transplantation Laboratory, University of Helsinki, Helsinki, Finland.
authors.forename: Otto
authors.initials: O
authors.lastname: Hemminki
authors.affiliation: Cancer Gene Therapy Group, Haartman Institute and Transplantation Laboratory, University of Helsinki, Helsinki, Finland.
authors.forename: Iulia
authors.initials: I
authors.lastname: Diaconu
authors.affiliation: Cancer Gene Therapy Group, Haartman Institute and Transplantation Laboratory, University of Helsinki, Helsinki, Finland.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerullo
authors.affiliation: Cancer Gene Therapy Group, Haartman Institute and Transplantation Laboratory, University of Helsinki, Helsinki, Finland.
authors.forename: Saila K
authors.initials: SK
authors.lastname: Pesonen
authors.affiliation: Cancer Gene Therapy Group, Haartman Institute and Transplantation Laboratory, University of Helsinki, Helsinki, Finland; Department of OB/GYN, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kanerva
authors.affiliation: International Comprehensive Cancer Center Docrates, Helsinki, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Joensuu
authors.affiliation: International Comprehensive Cancer Center Docrates, Helsinki, Finland.
authors.forename: Kalevi
authors.initials: K
authors.lastname: Kairemo
authors.affiliation: International Comprehensive Cancer Center Docrates, Helsinki, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Laasonen
authors.affiliation: International Comprehensive Cancer Center Docrates, Helsinki, Finland.
authors.forename: Kaarina
authors.initials: K
authors.lastname: Partanen
authors.affiliation: Oncos Therapeutics Ltd., Helsinki, Finland.
authors.forename: Lotta
authors.initials: L
authors.lastname: Kangasniemi
authors.affiliation: University of Washington, Division of Medical Genetics, Seattle, Washington, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: Lieber
authors.affiliation: Cancer Gene Therapy Group, Haartman Institute and Transplantation Laboratory, University of Helsinki, Helsinki, Finland.
authors.forename: Sari
authors.initials: S
authors.lastname: Pesonen
authors.affiliation: Cancer Gene Therapy Group, Haartman Institute and Transplantation Laboratory, University of Helsinki, Helsinki, Finland; International Comprehensive Cancer Center Docrates, Helsinki, Finland; Oncos Therapeutics Ltd., Helsinki, Finland. Electronic address: akseli.hemminki@helsinki.fi.
authors.forename: Akseli
authors.initials: A
authors.lastname: Hemminki
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000328:Adult; D000368:Aged; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000276:immunology; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000628:therapy; D019008:Drug Resistance, Neoplasm; D005260:Female; D005814:Genes, Viral; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics / Q000276:immunology*; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology; D000068878:Trastuzumab; D014779:Virus Replication
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000914:Antibodies, Viral; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000068878:Trastuzumab