Virus specific immune responses after human neoadjuvant adenovirus-mediated suicide gene therapy for prostate cancer

Abstract

Purpose: Neoadjuvant gene therapy potentially improves the outcome of primary treatment of prostate cancer by radical prostatectomy in patients with high risk of recurrence. We conducted a Phase I escalating dose study with a replication-defective adenovirus expressing the herpes simplex virus-thymidine kinase gene (Adv-HSV-tk vector). The primary end point was toxicity, while the evaluation of the patients' cellular and humoral immune responses served as a secondary endpoint. Material and methods: The Adv-HSV-tk vector was injected into the prostate in two doses (2 × 1010 to 2 × 10 11 viral particles), followed by ganciclovir twice daily for 14 days and retropubic radical prostatectomy on day 21. Adenovirus-specific neutralizing, IgG and IgA antibodies were evaluated. Peripheral blood mononuclear cells (PBMC) were stimulated by Adv-HSV-tk and analysed for IFN-γ production and 3H-thymidine incorporation. Prostate specimens were immunostained for B (CD20+) and for T (CD3 +) lymphocytes. Results: Toxicity was minor in all 8 patients treated. In the prostate, no virus related cytopathic effect could be observed. Dose-dependent infiltration of T and B lymphocytes in the whole prostate and in tumor areas was observed. Boosting of adenovirus-specific antibody responses was observed in 7 patients, and an increased adenovirus-specific PBMC proliferation and IFN-γ production was seen after Adv-HSV-tk stimulation. Conclusion: Neo-adjuvant adenovirus-mediated cytotoxic gene therapy prior to prostatectomy for prostate cancer is feasible and safe in an outpatient setting for intraprostatic vector doses up to 2 × 1011 viral particles. Activation of the immune system was observed. Application of higher vector doses may be considered. © 2005 Elsevier B.V. All rights reserved.