Gene Therapy and Radiation Therapy for Prostate Cancer

前列腺癌的基因治疗和放射治疗

• 批准号: 8401887
• 负责人: SVEND O FREYTAG
• 金额: $ 28.57万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8401887
• 关键词: Adenoviruses; Androgen Suppression; Animals; Antigen Presentation; Biochemical; Biopsy; Blood Cell Count; Blood Chemical Analysis; C57BL/6 Mouse; Cell Survival; Cells; Clinic; Clinical; Clinical Trials; Control Groups; Cyclophosphamide; Development; Diagnostic Neoplasm Staging; Disease; Dose; Effectiveness; Exhibits; Failure; Flucytosine; Freedom; Ganciclovir; Generations; Goals; Histopathology; Human Adenoviruses; Immune; Immunotherapy; Injection of therapeutic agent; Intensity-Modulated Radiotherapy; Interferons; Interleukin-10; Interleukin-12; Interleukin-12 Gene; Interleukin-6; Investigational Therapies; Lead; Malignant neoplasm of prostate; Mediating; Mesocricetus auratus; Modality; Modeling; Mus; Natural Immunity; Neoplasm Metastasis; Newly Diagnosed; Organ; Patients; Pelvis; Play; Prodrugs; Prostate; Radiation; Radiation therapy; Regulatory T-Lymphocyte; Research; Role; Saline; Serum; Staging; Suicide; Suicide Gene Therapy; T-Cell Activation; TNF gene; Testing; Toxic effect; Translational Research; Transrectal Ultrasound; Tumor Angiogenesis; Tumor Immunity; Valganciclovir; adaptive immunity; arm; base; cancer therapy; chemotherapy; cohort; cytokine; gene therapy; high risk; improved; in vivo; male; men; preclinical study; programs; prostate cancer model; stem; suicide gene; tumor

DESCRIPTION (provided by applicant): For the past 15 years our translational research program has been developing a multi-modal, gene therapy- based approach for the treatment of cancer. We have evaluated the toxicity and preliminary efficacy of our investigational approach in five clinical trials of non-metastatic prostate cancer. Our early stage results indicate that our approach is safe and has the potential to improve local tumor control. Although local tumor control is important, new therapies for high-risk prostate cancer must also target metastatic disease if they are to have an impact on survival. Hence, we have added a fourth modality to our investigational approach by generating a third-generation adenovirus armed with interleukin 12 (IL-12) that has the potential to eradicate both local and metastatic disease. This new adenovirus has generated encouraging preliminary results in preclinical studies, and we plan to move it into the clinic targeting high-risk prostate cancer. In specific aim 1, we will test the hypothesis that IL-12 will improve the efficacy of replication-competent adenovirus-mediated suicide gene therapy and radiation in an immune-competent, orthotopic model of prostate cancer. C57BL/6 male mice bearing intraprostatic TRAMP-C2 tumors will receive an intratumoral injection of Ad5-yCD/mutTKSR39rep-mIL12 followed by 2 weeks of 5-fluorocytosine (5-FC) + ganciclovir (GCV) prodrug therapy and pelvic radiation. Primary endpoints are local and metastatic tumor control. Secondary endpoints include T cell activation, NK and CTL activity, serum and tumor cytokine levels, and development of anti-tumor immunity. In specific aim 2, we will test the hypothesis that cyclophosphamide (CP) can be combined safely with replication-competent adenovirus-mediated suicide and IL-12 gene therapy and that the combined therapies exhibit synergy in vivo. Efficacy will be examined in the immune-competent, orthotopic TRAMP-C2 tumor model without and with CP. Efficacy endpoints are identical to those in specific aim 1. Toxicity will be examined in C57BL/6 male mice and Syrian hamsters, the latter of which are permissive for human adenovirus replication. In specific aim 3, we will test the hypothesis that replication-competent adenovirus-mediated suicide and IL-12 gene therapy can be combined safely with intensity modulated radiation therapy (IMRT) and androgen suppression therapy (AST) in men with newly-diagnosed, high-risk prostate cancer. Fifteen men (5 cohorts, 3 patients each) with high-risk prostate cancer (Stage e T3 or Gleason e 8 or PSA > 20 ng/mL) will receive a single injection of Ad5- yCD/mutTKSR39rep-hIL12 at five dose levels (1 x 1010 vp to 1 x 1012 vp in half-log increments). The adenovirus will be injected intraprostatically under transrectal ultrasound-guidance. Two days later, men will receive 2 weeks of 5-FC + valganciclovir (vGCV) prodrug therapy concomitant with 80 Gy IMRT and e 2 years of AST. The primary endpoint is toxicity through day 90. Secondary endpoints are: 1) prostate biopsy at 2 years, 2) freedom from biochemical/clinical failure (FFF), 3) disease-specific survival, 4) overall survival, and 5) serum cytokine levels. We believe this research will have high impact because it may lead to better treatments for aggressive forms of prostate cancer.

描述（由申请人提供）：在过去的15年里，我们的转化研究项目一直在开发一种多模式、基于基因治疗的癌症治疗方法。我们已经在五项非转移性前列腺癌临床试验中评估了我们的研究方法的毒性和初步疗效。我们的早期结果表明，我们的方法是安全的，并有可能改善局部肿瘤控制。虽然局部肿瘤控制很重要，但高危前列腺癌的新疗法如果要对生存产生影响，还必须针对转移性疾病。因此，我们通过产生具有根除局部和转移性疾病的潜力的装备有白细胞介素12（IL-12）的第三代腺病毒，在我们的研究方法中增加了第四种方式。这种新的腺病毒在临床前研究中已经产生了令人鼓舞的初步结果，我们计划将其转移到针对高危前列腺癌的临床中。在具体的目标1中，我们将测试IL-12将提高复制型腺病毒介导的自杀基因治疗和放射在免疫活性的原位前列腺癌模型中的功效的假设。携带前列腺内TRAMP-C2肿瘤的C57 BL/6雄性小鼠将接受Ad 5-yCD/mutTKSR 39 rep-mIL 12的肿瘤内注射，随后接受2周的5-氟胞嘧啶（5-FC）+更昔洛韦（GCV）前药治疗和盆腔放射。主要终点是局部和转移性肿瘤控制。次要终点包括T细胞活化、NK和CTL活性、血清和肿瘤细胞因子水平以及抗肿瘤免疫的发展。在具体目标2中，我们将检验以下假设：环磷酰胺（CP）可以安全地与复制型腺病毒介导的自杀和IL-12基因疗法组合，并且组合疗法在体内表现出协同作用。将在无CP和有CP的免疫活性原位TRAMP-C2肿瘤模型中检查疗效。疗效终点与具体目标1中的终点相同。将在C57 BL/6雄性小鼠和叙利亚仓鼠中检查毒性，后者允许人腺病毒复制。在具体目标3中，我们将检验以下假设：在新诊断的高危前列腺癌患者中，复制型腺病毒介导的自杀和IL-12基因治疗可以安全地与调强放射治疗（IMRT）和雄激素抑制治疗（AST）联合使用。患有高风险前列腺癌（eT 3期或Gleason e8期或PSA > 20 ng/mL）的15名男性（5个群组，各3名患者）将接受五个剂量水平（以半对数增量为1 × 1010 vp至1 × 1012 vp）的Ad 5- yCD/mutTKSR 39 rep-hIL 12的单次注射。腺病毒将在经直肠超声引导下经前列腺内注射。两天后，男性将接受2周的5-FC +缬更昔洛韦（vGCV）前药治疗，同时接受80戈伊IMRT和2年AST治疗。主要终点是第90天的毒性。次要终点为：1）2年时的前列腺活检，2）无生化/临床失败（FFF），3）疾病特异性生存期，4）总生存期和5）血清细胞因子水平。我们相信这项研究将产生很大的影响，因为它可能会导致更好的治疗侵袭性前列腺癌。