title: Integrin targeted oncolytic adenoviruses Ad5-D24-RGD and Ad5-RGD-D24-GMCSF for treatment of patients with advanced chemotherapy refractory solid tumors.
abstract: The safety of oncolytic viruses for treatment of cancer has been shown in clinical trials while antitumor efficacy has often remained modest. As expression of the coxsackie-adenovirus receptor may be variable in advanced tumors, we developed Ad5-D24-RGD, a p16/Rb pathway selective oncolytic adenovirus featuring RGD-4C modification of the fiber. This allows viral entry through alpha-v-beta integrins frequently highly expressed in advanced tumors. Advanced tumors are often immunosuppressive which results in lack of tumor eradication despite abnormal epitopes being present. Granulocyte-macrophage colony stimulating factor (GMCSF) is a potent activator of immune system with established antitumor properties. To stimulate antitumor immunity and break tumor associated immunotolerance, we constructed Ad5-RGD-D24-GMCSF, featuring GMCSF controlled by the adenoviral E3 promoter. Preliminary safety of Ad5-D24-RGD and Ad5-RGD-D24-GMCSF for treatment of human cancer was established. Treatments with Ad5-D24-RGD (N = 9) and Ad5-RGD-D24-GMCSF (N = 7) were well tolerated. Typical side effects were grade 1-2 fatigue, fever and injection site pain. 77% (10/13) of evaluable patients showed virus in circulation for at least 2 weeks. In 3 out of 6 evaluable patients, disease previously progressing stabilized after a single treatment with Ad5-RGD-D24-GMCSF. In addition, 2/3 patients had stabilization or reduction in tumor marker levels. All patients treated with Ad5-D24-RGD showed disease progression in radiological analysis, although 3/6 had temporary reduction or stabilization of marker levels. Induction of tumor and adenovirus specific immunity was demonstrated with ELISPOT in Ad5-RGD-D24-GMCSF treated patients. RGD modified oncolytic adenoviruses with or without GMCSF seem safe for further clinical development.
authors.affiliation: Cancer Gene Therapy Group, Transplantation Laboratory, Haartman Institute and Finnish Institute of Molecular Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Sari
authors.initials: S
authors.lastname: Pesonen
authors.forename: Iulia
authors.initials: I
authors.lastname: Diaconu
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerullo
authors.forename: Sophie
authors.initials: S
authors.lastname: Escutenaire
authors.forename: Mari
authors.initials: M
authors.lastname: Raki
authors.forename: Lotta
authors.initials: L
authors.lastname: Kangasniemi
authors.forename: Petri
authors.initials: P
authors.lastname: Nokisalmi
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
authors.forename: Kilian
authors.initials: K
authors.lastname: Guse
authors.forename: Leena
authors.initials: L
authors.lastname: Laasonen
authors.forename: Kaarina
authors.initials: K
authors.lastname: Partanen
authors.forename: Eerika
authors.initials: E
authors.lastname: Karli
authors.forename: Elina
authors.initials: E
authors.lastname: Haavisto
authors.forename: Minna
authors.initials: M
authors.lastname: Oksanen
authors.forename: Aila
authors.initials: A
authors.lastname: Karioja-Kallio
authors.forename: Päivi
authors.initials: P
authors.lastname: Hannuksela
authors.forename: Sirkka-Liisa
authors.initials: SL
authors.lastname: Holm
authors.forename: Satu
authors.initials: S
authors.lastname: Kauppinen
authors.forename: Timo
authors.initials: T
authors.lastname: Joensuu
authors.forename: Anna
authors.initials: A
authors.lastname: Kanerva
authors.forename: Akseli
authors.initials: A
authors.lastname: Hemminki
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004279:DNA, Viral / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005221:Fatigue / Q000209:etiology; D005260:Female; D005334:Fever / Q000209:etiology; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism*; D050130:Oncolytic Virotherapy / Q000009:adverse effects / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D016896:Treatment Outcome; D019562:Viral Load; D014779:Virus Replication / Q000235:genetics
chemical_list: D004279:DNA, Viral; D016023:Integrins; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D016178:Granulocyte-Macrophage Colony-Stimulating Factor