title: Combined HSV-TK/IL-2 gene therapy in patients with recurrent glioblastoma multiforme: biological and clinical results.
abstract: Following our pilot clinical study of combined IL-2/HSV-TK gene therapy for recurrent glioblastoma multiforme (GBM), we extended the protocol to a larger population of patients and evaluated safety, feasibility, and biological activity of treatment. A total of 12 patients received intratumor injection of retroviral vector-producing cells (RVPCs), followed by intravenous ganciclovir (GCV). Treatment was well tolerated with only minor adverse events. Transduction of tumor cells was demonstrated in tumor biopsies. A marked and persistent increase of intratumor and plasma Th1 cytokine levels was demonstrated after RVPC injection. At magnetic resonance imaging evaluation, two patients had a partial response (including a patient showing disappearance of a distant noninjected tumor mass), four had a minor response, four had stable disease, and two had progressive disease. The 6- and 12-month progression-free survival rates were 47 and 14%, respectively. The 6- and 12-month overall survival rates were 58 and 25%, respectively. In conclusion, the results of our clinical protocol of gene therapy for recurrent GBM, based on combined delivery of a suicide and a cytokine gene, demonstrate that intratumor injection of RVPCs was safe, provided effective transduction of the therapeutic genes to target tumor cells, and activated a systemic cytokine cascade, with tumor responses in 50% of cases.
authors.affiliation: Division of Neurosurgery, San Bortolo Hospital, Vicenza, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Colombo
authors.forename: Luisa
authors.initials: L
authors.lastname: Barzon
authors.forename: Elisa
authors.initials: E
authors.lastname: Franchin
authors.forename: Monia
authors.initials: M
authors.lastname: Pacenti
authors.forename: Vittore
authors.initials: V
authors.lastname: Pinna
authors.forename: Daniela
authors.initials: D
authors.lastname: Danieli
authors.forename: Mariano
authors.initials: M
authors.lastname: Zanusso
authors.forename: Giorgio
authors.initials: G
authors.lastname: Palù
mesh_terms: D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000628:therapy*; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D017931:DNA Primers; D005260:Female; D041722:Genes, Transgenic, Suicide / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use; D005909:Glioblastoma / Q000628:therapy*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008979:Moloney murine leukemia virus; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018139:Simplexvirus; D015996:Survival Rate; D013937:Thymidine Kinase / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D016207:Cytokines; D017931:DNA Primers; D007376:Interleukin-2; D013937:Thymidine Kinase