Neoadjuvant in situ gene therapy with adenoviral delivery of HSV-tK gene for patients with high-risk prostate cancer

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Neoadjuvant in situ cytotoxic gene therapy can potentially trigger a systemic immune response, which could impact occult micro-metastatic disease. We are currently conducting adenoviral vector mediated Herpes Simplex Virus-thymidine kinese(HSV-tk) gene plus ganciclovir(GCV) therapy as neoadjuvant intraprostatic injection for localized high-risk prostate cancer. This study evaluates the systemic T-cell response following gene therapy.We enrolled 5 men with clinically localized prostate cancer but high risk for recurrence(Kattan nomogram score> 115) in this Phase I. II trial. Intraprostatic viral injections(two) were followed by 2 weeks of GCV and prostatectomy 4 weeks later.A reduction in serum PSA was observed immediately after vector injection and GCV therapy in all patients. The mean reduction was 31.1% and ranged from 24.8 to 38.9%.The pretreatment mean percentage of CD8+T cells positive for the HLA-DR marker of activation was 10.6%. For day 2, day 7, day 14, day 16 and day 56 post treatment, the mean percent of CD8+DR+T cells increased by 14.0%, 12.3%, 19.7%, 25.4% and 14.9%, which were statistically significant(day 14 ; p=0.0431, day 16 ; p=0.0431).We present evidence of systemic T-cell responses following HSV-tk+GCV gene therapy under clinical trial condition. There was an increase in activated CD8+T cells in the peripheral blood following vector injection suggesting the potential for activation of components of cell-mediated immune response in this neoadjuvant setting.