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Eur Urol ; 48(1): 153-61, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15967266

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 (2x10(10) to 2x10(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-gamma 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-gamma 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 2x10(11) viral particles. Activation of the immune system was observed. Application of higher vector doses may be considered.


Subject(s)
Adenocarcinoma/immunology , Adenoviridae/genetics , Genes, Transgenic, Suicide , Genetic Vectors/therapeutic use , Immunity, Cellular/immunology , Neoadjuvant Therapy/methods , Prostatic Neoplasms/immunology , Adenocarcinoma/pathology , Adenocarcinoma/therapy , Adenoviridae/immunology , Aged , Antibodies, Anti-Idiotypic/immunology , Antibodies, Viral/immunology , Antiviral Agents/therapeutic use , B-Lymphocytes/immunology , Follow-Up Studies , Ganciclovir/therapeutic use , Genetic Vectors/administration & dosage , Humans , Immunity, Cellular/drug effects , Immunoglobulin A/immunology , Immunoglobulin G/immunology , Injections, Intralesional , Lymphocyte Activation , Lymphocyte Count , Male , Middle Aged , Neoplasm Staging , Prostatectomy , Prostatic Neoplasms/pathology , Prostatic Neoplasms/therapy , Safety , T-Lymphocytes/immunology , Treatment Outcome
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