Details

Autor(en) / Beteiligte

• van der Linden, R.R.M.
• Haagmans, B.L.
• Mongiat-Artus, P.
• van Doornum, G.J.
• Kraaij, R.
• Kadmon, D.
• Aguilar-Cordova, E.
• Osterhaus, A.D.M.E.
• van der Kwast, T.H.
• Bangma, C.H.

Titel

Virus Specific Immune Responses after Human Neoadjuvant Adenovirus-mediated Suicide Gene Therapy for Prostate Cancer

Ist Teil von

• European urology, 2005-07, Vol.48 (1), p.153-161

Ort / Verlag

Oxford: Elsevier B.V

Erscheinungsjahr

2005

Quelle

Elsevier ScienceDirect Journals

Beschreibungen/Notizen

• 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. The Adv-HSV-tk vector was injected into the prostate in two doses (2 × 10 10 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. 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. 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 × 10 11 viral particles. Activation of the immune system was observed. Application of higher vector doses may be considered.