A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma

• Published in: Cancer gene therapy Vol. 17; no. 12; pp. 837 - 843
• Main Authors: Sangro, B, Mazzolini, G, Ruiz, M, Ruiz, J, Quiroga, J, Herrero, I, Qian, C, Benito, A, Larrache, J, Olagüe, C, Boan, J, Peñuelas, I, Sádaba, B, Prieto, J
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-12-2010; Nature Publishing Group
• Subjects: 631/326/596/2561; 692/699/67/1504/1610; 692/700/565/201; Adolescent; Adult; Aged; Aged, 80 and over; Antitumor activity; Biomedical and Life Sciences; Biomedicine; Carcinoma, Hepatocellular - therapy; Care and treatment; Clinical trials; Dosage and administration; Female; Fever; Ganciclovir; Ganciclovir - administration & dosage; Gene Expression; Gene Therapy; Genetic aspects; Genetic Therapy; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Hepatocellular carcinoma; Hepatoma; Herpes simplex; Herpes simplex virus; Humans; Injection; Kinases; Liver cancer; Liver Neoplasms - therapy; Male; Middle Aged; original-article; Pancytopenia; Patients; Positron emission tomography; Product development; Risk factors; Thymidine; Thymidine kinase; Thymidine Kinase - genetics; TK gene; Toxicity; Tumors; Spain; HCC; liver tumors; adenovirus; TK; suicide genes
• ISSN: 0929-1903; 1476-5500
• DOI: 10.1038/cgt.2010.40

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 10
10
to 2 × 10
12
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 × 10
12
 vp per patient.