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: 8599755
• 负责人: SVEND O FREYTAG
• 金额: $ 29.49万
• 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/8599755
• 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，我们的翻译研究计划一直在开发一种基于基因治疗的多模式癌症治疗方法。我们已经在五个非转移性前列腺癌的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，并具有改善局部肿瘤控制的潜力。尽管局部肿瘤控制很重要，但高危前列腺癌的新疗法也必须针对转移性疾病，才能对生存产生影响。因此，我们在我们的研究方法中增加了第四种方法，通过产生携带白介素12(IL-12)的第三代腺病毒，具有根除局部和转移疾病的潜力。这种新腺病毒已经在临床前研究中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。在特定的目标1中，我们将检验这样的假设，即IL-12将在免疫活性的前列腺癌原位模型中提高复制型腺病毒介导的自杀基因治疗和放射治疗的有效性。携带TRAMP-C2肿瘤的C57BL/6雄性小鼠将接受瘤内注射Ad5-yCD/muTKSR39rep-mIL12，然后接受为期2周的5-氟胞嘧啶(5-FC)+更昔洛韦(GCV)前体药物治疗和盆腔放疗。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。在特定的目标2中，我们将检验环磷酰胺(CP)可以安全地与增殖型腺病毒介导的自杀和IL-12基因治疗相结合的假设，以及联合治疗在体内表现出协同作用的假设。疗效将在无CP和有CP的原位TRAMP-C2肿瘤模型中进行检测。药效终点与特定目的1相同。毒性将在C57BL/6雄性小鼠和叙利亚仓鼠身上进行检测，后者允许人腺病毒复制。在具体目标3中，我们将检验这样一种假设，即在新诊断的高危前列腺癌患者中，可以安全地将增殖型腺病毒介导的自杀和IL-12基因治疗与调强放射治疗(IMRT)和雄激素抑制治疗(AST)相结合。15名患有高危前列腺癌(e期T3或Gleason e 8期或PSA&GT；20 ng/ml)的男性(5个队列，每组3名患者)将接受一次Ad5-yCD/muTKSR39rep-hIL12注射，剂量水平为5个剂量水平(1×1010 VP至1×1012 VP，半对数增量)。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+valganciclovir(VGCV)前体药物治疗，同时接受80GyIMRT和2年的AST。主要终点是90天内的毒性。次要终点是：1)2年时的前列腺活检，2)免于生化/临床失败(FFF)，3)特定疾病的存活率，4)总存活率，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，因为它可能会导致对侵袭性前列腺癌的更好治疗。