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

新辅助原位细胞毒性基因治疗可能会引发全身免疫反应，这可能会影响隐匿性微转移性疾病。我们目前正在进行腺病毒载体介导的单纯疱疹病毒胸苷激酶（HSV-tk）基因联合更昔洛韦（GCV）治疗作为新辅助前列腺内注射局部高危前列腺癌。本研究评估了基因治疗后的全身性T细胞反应。我们在I期研究中纳入了5名临床局限性前列腺癌但复发风险高（Kynomogram评分> 115）的男性。II试验。两次前列腺内病毒注射后2周进行GCV治疗，4周后行前列腺切除术，所有患者在载体注射和GCV治疗后血清PSA立即下降。平均下降31.1%，范围为24.8%至38.9%。治疗前HLA-DR活化标志物阳性的CD 8 +T细胞平均百分比为10.6%。治疗后第2、7、14、16和56天，CD 8 +DR+T细胞的平均百分比分别增加了14.0%、12.3%、19.7%、25.4%和14.9%，具有统计学意义（第14天; p=0.0431，第16天; p=0.0431）。我们提供了在临床试验条件下HSV-tk+GCV基因治疗后全身性T细胞应答的证据。载体注射后外周血中活化的CD 8 +T细胞增加，表明在这种新辅助治疗环境中细胞介导的免疫应答组分活化的潜力。

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.