1. ¹CR UK Institute for Cancer Studies, University of Birmingham, Birmingham, UK
2. ²University Hospital Birmingham NHS Trust, Queen Elizabeth Hospital, Birmingham, UK
3. ³Innovata plc, 1 Mere Way, Nottingham, UK
4. ⁴Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, UK
5. ⁵University of Newcastle Upon Tyne Medical School, Newcastle Upon Tyne, UK

Correspondence: Vivien Mautner, CR UK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. E-mail: v.mautner@bham.ac.uk

The first two authors contributed equally to this work.

Current address: Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.

Received 1 February 2008; Accepted 25 March 2009; Published online 14 April 2009.

Abstract

We report a phase I/II clinical trial in prostate cancer (PCa) using direct intraprostatic injection of a replication defective adenovirus vector (CTL102) encoding bacterial nitroreductase (NTR) in conjunction with systemic prodrug CB1954. One group of patients with localized PCa scheduled for radical prostatectomy received virus alone, prior to surgery, in a dose escalation to establish safety, tolerability, and NTR expression. A second group with local failure following primary treatment received virus plus prodrug to establish safety and tolerability. Based on acceptable safety data and indications of prostate-specific antigen (PSA) responses, an extended cohort received virus at a single dose level plus prodrug. The vector was well tolerated with minimal side effects, had a short half-life in the circulation, and stimulated a robust antibody response. Immunohistochemistry of resected prostate demonstrated NTR staining in tumor and glandular epithelium at all dose levels [5 10¹⁰–1 10¹² virus particles (vp)]. A total of 19 patients received virus plus prodrug and 14 of these had a repeat treatment; minimal toxicity was observed and there was preliminary evidence of change in PSA kinetics, with an increase in the time to 10% PSA progression in 6 out of 18 patients at 6 months.