title: A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma.
abstract: The aim of this phase I clinical trial was to assess the feasibility and safety of intratumoral administration of a first-generation adenoviral vector encoding herpes simplex virus thymidine kinase (HSV-TK) gene (Ad.TK) followed by systemic ganciclovir to patients with advanced hepatocellular carcinoma (HCC). Secondarily, we have analyzed its antitumor effect. Ten patients were enrolled in five dose-level cohorts that received from 10¹⁰ to 2 × 10¹² viral particles (vp). Ad.TK was injected intratumorally and patients received up to three doses at 30-day intervals. Positron emission tomography was used to monitor TK gene expression. Ad.TK injection was feasible in 100% of cases. Treatment was well tolerated and dose-limiting toxicity was not achieved. Cumulative toxicity was not observed. Hepatic toxicity was absent even in cirrhotic patients. Fever, flu-like syndrome, pain at the injection site and pancytopenia were the most common side effects. No partial responses were observed and 60% of patients showed tumor stabilization of the injected lesion. Importantly, two patients who received the highest dose showed signs of intratumoral necrosis by imaging procedures. One of them achieved a sustained stabilization and survived for 26 months. In conclusion, Ad.TK can be safely administered by intratumoral injection to patients with HCC up to 2 × 10¹² vp per patient.
authors.affiliation: Liver Unit, Clínica Universitaria, Pamplona, Spain. bsangro@unav.es
authors.forename: B
authors.initials: B
authors.lastname: Sangro
authors.forename: G
authors.initials: G
authors.lastname: Mazzolini
authors.forename: M
authors.initials: M
authors.lastname: Ruiz
authors.forename: J
authors.initials: J
authors.lastname: Ruiz
authors.forename: J
authors.initials: J
authors.lastname: Quiroga
authors.forename: I
authors.initials: I
authors.lastname: Herrero
authors.forename: C
authors.initials: C
authors.lastname: Qian
authors.forename: A
authors.initials: A
authors.lastname: Benito
authors.forename: J
authors.initials: J
authors.lastname: Larrache
authors.forename: C
authors.initials: C
authors.lastname: Olagüe
authors.forename: J
authors.initials: J
authors.lastname: Boan
authors.forename: I
authors.initials: I
authors.lastname: Peñuelas
authors.forename: B
authors.initials: B
authors.lastname: Sádaba
authors.forename: J
authors.initials: J
authors.lastname: Prieto
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000628:therapy*; D005260:Female; D015774:Ganciclovir / Q000008:administration & dosage; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D013937:Thymidine Kinase / Q000235:genetics*
chemical_list: D013937:Thymidine Kinase; D015774:Ganciclovir