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

新辅助原位细胞毒基因治疗可潜在地触发全身免疫反应，从而可能影响隐匿性微转移疾病。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)治疗局限性高危前列腺癌的新辅助前列腺癌治疗。这项研究评估了基因治疗后的全身T细胞反应。在这项I、II期试验中，我们招募了5名临床上有局限性前列腺癌但复发风险高的男性患者(Kitan Norgraph Score&gt；115)。前列腺腔内注射病毒2周后行GCV治疗，4周后行前列腺切除术。所有患者在注射载体和GCV治疗后血清PSA立即降低。平均下降31.1%，降幅在24.8%~38.9%之间。治疗前CD8+T细胞的平均阳性百分率为10.6%。在治疗后第2天、第7天、第14天、第16天和第56天，CD8+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%，差异有统计学意义(第14天；p=0.0431；第16天；p=0.0431)。在载体注射后，外周血中激活的CD8+T细胞增加，这表明在这种新的佐剂环境中，细胞介导的免疫反应的组成部分可能被激活。

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.