DEVELOPMENT OF TAILORED-MADE TYPE PROSTATE CANCER GENE THERAPY AIMING AT SYSTEMIC IMMUNE-ACTIVATION

这项研究的目的是开发量身定制的前列腺癌基因疗法，激活肿瘤特异性全身免疫。1)前列腺癌基因治疗的临床试验我们采用前列腺内注射表达HSV-tk基因的腺病毒载体和全身给药更昔洛韦进行前列腺癌基因治疗，并分析每位患者的免疫学特征以及临床安全性和有效性。9例临床证实安全性和有效性。基因治疗前后血清细胞因子水平无明显变化。有趣的是，治疗后外周血CD8+/HLA-DR+增加，表明细胞介导的免疫系统激活。2)前列腺癌肿瘤相关抗原的表达分析分析NY-ESO-1、SSX在前列腺癌中的表达，并检测其基于组织表达的宿主免疫反应。提示NY-ESO-1，SSX可作为前列腺癌免疫治疗的靶点。3)免疫治疗的临床试验：进行肽脉冲树突状细胞治疗和NY-ESO-1蛋白免疫治疗。临床安全性和临床活性得到证实。在一些病例中还观察到肿瘤特异性免疫反应。4)白细胞介素-12免疫基因治疗（广泛研究）IL- 12基因治疗的辅助和新辅助应用的有效性被确认为贝勒医学院的广泛合作。

This research has been conducted for the purpose of developing the tailored-made type of prostate cancer gene therapy activating tumor specific systemic immunity. We achieved following resuts1)Clinical trial of prostate cancer gene therapyWe performed prostate cancer gene therapy using intraprostatic injection of adenoviral vector expressing HSV-tk gene and systemic administration of Ganciclovir and analyzed immunological profile of each patient in addition to clinical safety and efficacy. Clinical safety and efficacy were confirmed in 9 cases. Serum cytokine level did not change significantly before and after gene therapy. Interestingly peripheral blood CD8+/HLA-DR+ increased after treatment indicating systemic activation of cell mediated immunity.2)Expression analysis of tumor associated antigen in prostate cancerExpression of NY-ESO-1,SSX in prostate cancer were analyzed and its host immune reaction based of tissue expression were also checked. As a result it was suggested that NY-ESO-1,SSX can be a target for the prostate cancer immunotherapy.3)Clinical trial of immunotherapyPeptid pulsed dendritic cell therapy and NY-ESO-1 protein immuno-therapy were conducted. Clinical safety and clinical activity were confirmed. Tumor specific immune response were also observed in some cases.4)Interleukin-12 immuno gene therapy(extensive research)Usefulness of adjuvant and neo-adjuvant application of IL- 12 gene therapy was confirmed as a extensive collaboration Baylor College of Medicine.