title: Treatment of melanoma with a serotype 5/3 chimeric oncolytic adenovirus coding for GM-CSF: Results in vitro, in rodents and in humans.
abstract: Metastatic melanoma is refractory to irradiation and chemotherapy, but amenable to immunological approaches such as immune-checkpoint-inhibiting antibodies or adoptive cell therapies. Oncolytic virus replication is an immunogenic phenomenon, and viruses can be armed with immunostimulatory molecules. Therefore, oncolytic immuno-virotherapy of malignant melanoma is an appealing approach, which was recently validated by a positive phase 3 trial. We investigated the potency of oncolytic adenovirus Ad5/3-D24-GMCSF on a panel of melanoma cell lines and animal models, and summarized the melanoma-specific human data from the Advanced Therapy Access Program (ATAP). The virus effectively eradicated human melanoma cells in vitro and subcutaneous SK-MEL-28 melanoma xenografts in nude mice when combined with low-dose cyclophosphamide. Furthermore, virally-expressed granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulated the differentiation of human monocytes into macrophages. In contrast to human cells, RPMI 1846 hamster melanoma cells exhibited no response to oncolytic viruses and the chimeric 5/3 fiber failed to increase the efficacy of transduction, suggesting limited utility of the hamster model in the context of viruses with this capsid. In ATAP, treatments appeared safe and well-tolerated. Four out of nine melanoma patients treated were evaluable for possible therapy benefit with modified RECIST criteria: one patient had minor response, two had stable disease, and one had progressive disease. Two patients were alive at 559 and 2,149 days after treatment. Ad5/3-D24-GMCSF showed promising efficacy in preclinical studies and possible antitumor activity in melanoma patients refractory to other forms of therapy. This data supports continuing the clinical development of oncolytic adenoviruses for treatment of malignant melanoma.
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory and Haartman Institute, University of Helsinki, Finland.
authors.forename: Simona
authors.initials: S
authors.lastname: Bramante
authors.affiliation: Oncolytic Adenovirus Group, German Cancer Research Center (Deutsches Krebsforschungszentrum [DKFZ]), Heidelberg, Germany.
authors.forename: Johanna K
authors.initials: JK
authors.lastname: Kaufmann
authors.affiliation: Unit of Systems Toxicology, Finnish Institute of Occupational Health, Topeliuksenkatu 41 a, Helsinki, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Veckman
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory and Haartman Institute, University of Helsinki, Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Liikanen
authors.affiliation: Oncolytic Adenovirus Group, German Cancer Research Center (Deutsches Krebsforschungszentrum [DKFZ]), Heidelberg, Germany.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Nettelbeck
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory and Haartman Institute, University of Helsinki, Finland.
authors.forename: Otto
authors.initials: O
authors.lastname: Hemminki
authors.affiliation: Oncos Therapeutics Ltd., Helsinki, Finland.
authors.forename: Lotta
authors.initials: L
authors.lastname: Vassilev
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory and Haartman Institute, University of Helsinki, Finland.|Laboratory of Immunovirotherapy, Division of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Helsinki, Finland.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerullo
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory and Haartman Institute, University of Helsinki, Finland.
authors.forename: Minna
authors.initials: M
authors.lastname: Oksanen
authors.affiliation: Oncos Therapeutics Ltd., Helsinki, Finland.
authors.forename: Raita
authors.initials: R
authors.lastname: Heiskanen
authors.affiliation: Docrates Cancer Center, Helsinki, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Joensuu
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory and Haartman Institute, University of 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 and Transplantation Laboratory and Haartman Institute, University of Helsinki, Finland.
authors.forename: Sari
authors.initials: S
authors.lastname: Pesonen
authors.affiliation: Unit of Systems Toxicology, Finnish Institute of Occupational Health, Topeliuksenkatu 41 a, Helsinki, Finland.
authors.forename: Sampsa
authors.initials: S
authors.lastname: Matikainen
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory and Haartman Institute, University of Helsinki, Finland.
authors.forename: Markus
authors.initials: M
authors.lastname: Vähä-Koskela
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory and Haartman Institute, University of Helsinki, Finland.
authors.forename: Anniina
authors.initials: A
authors.lastname: Koski
authors.affiliation: Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory and Haartman Institute, University of Helsinki, Finland.|TILT Biotherapeutics Ltd., Helsinki, Finland.
authors.forename: Akseli
authors.initials: A
authors.lastname: Hemminki
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D006224:Cricetinae; D003520:Cyclophosphamide / Q000494:pharmacology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008264:Macrophages / Q000473:pathology / Q000821:virology; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000628:therapy* / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D009000:Monocytes / Q000473:pathology / Q000821:virology; D050130:Oncolytic Virotherapy / Q000379:methods*; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide
keywords: GM-CSF; combination treatment; cyclophosphamide; immunotherapy; melanoma; oncolytic adenovirus