Originally published as JCO Early Release 10.1200/JCO.2004.10.005 on March 29 2004

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Virus-Directed Enzyme Prodrug Therapy: Intratumoral Administration of a Replication-Deficient Adenovirus Encoding Nitroreductase to Patients With Resectable Liver Cancer

From the Cancer Research UK Institute for Cancer Studies, Department of Pathology and Liver Research Laboratories, University of Birmingham; University Hospital Birmingham NHS Trust, Queen Elizabeth Hospital, Edgbaston, Birmingham; ML Laboratories, Keele, Staffs; Department of Clinical Pharmacology, University of Oxford, Oxford, UK; Vrije Universiteit, Department of Medical Oncology, Amsterdam, the Netherlands.

Address reprint requests to Vivien Mautner, PhD, Cancer Research UK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; e-mail: v.mautner{at}bham.ac.uk

PURPOSE: Virus-directed enzyme prodrug therapy depends on selective delivery of virus encoding a prodrug-activating enzyme to tumor, followed by systemic treatment with prodrug to achieve high levels of the activated cytotoxic at the intended site of action. The use of the bacterial enzyme nitroreductase to activate CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) to a short lived, highly toxic DNA cross-linking agent has been demonstrated in tumor xenografts. In this study, we report the first clinical trial investigating the feasibility, safety, and transgene expression of a replication-defective adenovirus encoding nitroreductase (CTL102) in patients with liver tumors.

PATIENTS AND METHODS: Patients with resectable primary or secondary (colorectal) liver cancer received a single dose of CTL102 delivered by direct intratumoral inoculation 3 to 8 days before surgical resection.

RESULTS: Eighteen patients were treated with escalating doses of CTL102 (range, 10⁸–5 x 10¹¹ virus particles). The vector was well tolerated with minimal side effects, had a short half-life in the circulation, and stimulated a robust antibody response. Dose-related increases in tumoral nitroreductase expression measured by immunohistochemical analysis have been observed.

CONCLUSION: Direct intratumoral inoculation of CTL102 to patients with primary and secondary liver cancer is feasible and well tolerated. The high level of nitroreductase expression observed at 1 to 5 x 10¹¹ virus particles mandates further studies in patients with inoperable tumors who will receive CTL102 and CB1954.

Supported by Cancer Research UK and the Medical Research Council UK.

Presented in part at the 5th Annual Meeting of the American Society of Gene Therapy, Boston, MA, June 5-9, 2002, and the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 29-June 1, 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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