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


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.


CONCLUSIONS
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.
van der Linden
R R M
RR
Department of Urology, Erasmus MC, Rotterdam, The Netherlands.
Haagmans
B L
BL
Mongiat-Artus
P
P
van Doornum
G J
GJ
Kraaij
R
R
Kadmon
D
D
Aguilar-Cordova
E
E
Osterhaus
A D M E
AD
van der Kwast
T H
TH
Bangma
C H
CH
D000230:Adenocarcinoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000368:Aged; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D000998:Antiviral Agents / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000276:immunology; D005500:Follow-Up Studies; D015774:Ganciclovir / Q000627:therapeutic use; D041722:Genes, Transgenic, Suicide; D005822:Genetic Vectors / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology*; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D015552:Injections, Intralesional; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D009367:Neoplasm Staging; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D012449:Safety; D013601:T-Lymphocytes / Q000276:immunology; D016896:Treatment Outcome
D000888:Antibodies, Anti-Idiotypic; D000914:Antibodies, Viral; D000998:Antiviral Agents; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D015774:Ganciclovir