Therapeutic DNA-MVA prime boost vaccination for HPV disease

描述（由申请方提供）：宫颈鳞状细胞癌（SCCx）是由人乳头瘤病毒（HPV）致癌株持续感染引起的。HPV 16是与超过60%的恶性疾病相关的毒株。HPV E6和E7蛋白在功能上是维持转化状态所必需的，在SCCx及其前体病变、高度宫颈不典型增生（CIN 2/3）中一致表达，并代表宿主的外源抗原。因此，它们提供了潜在的令人信服的免疫靶点。与NCI RAID合作，我们已经制备了HPV 16 E7靶向治疗性DNA疫苗。我们与Transgene，SA的合作将提供GMP级疫苗，该疫苗由改良的安卡拉牛痘（MVA）组成，包含E6，E7和IL 2（MVA-E6 E7-IL 2）。这两种疫苗已在该患者人群的临床试验中单独进行了测试。我们建议评估异源DNA引物-MVA加强疫苗接种，局部Toll样受体（TLR）激动剂应用于病变部位，在其他健康的妇女与HPV 16相关的高度宫颈发育不良。该患者队列可能提供信息，因为该队列中研究治疗窗（15周）的自发消退率预计为25%。DNA-MVA初免-加强疫苗接种在健康志愿者中测试其他抗原靶标的临床试验中已显示出安全性和免疫原性。我们将检验DNA-MVA初免-加强疫苗接种具有免疫原性和安全性的假设，以及局部应用TLR激动剂可以增强宫颈免疫应答，使其能够克服发育异常病变粘膜微环境中存在的免疫抑制机制。所提出的分析是新颖的，因为我们将能够研究局部炎症的产生是否在“揭露”慢性病毒感染中是重要的，并研究效应和抑制性免疫反应的局部、区室化措施。研究设计针对独特的临床资源和理想的患者人群，以证明原理的证据。我们在这一患者人群的临床试验设计和执行方面有着良好的记录，这一人群中不成比例地包括无法有效获得医疗保健系统的少数民族妇女。

DESCRIPTION (provided by applicant): Squamous cancers of the cervix (SCCx) are caused by persistent infection with oncogenic strains of human papillomavirus (HPV). HPV16 is the strain associated with over 60% of malignant disease. The HPV E6 and E7 proteins are functionally required to maintain the transformed state, are consistently expressed in SCCx and in its precursor lesion, high grade cervical dysplasia (CIN2/3), and represent foreign antigens to the host. Therefore, they present potentially compelling immunotherapeutic targets. In collaboration with NCI RAID, we have made an HPV16E7-targeted therapeutic DNA vaccine. Our collaboration with Transgene, SA, will provide GMP-grade vaccine which consists of Modified Vaccinia Ankara (MVA), housing E6, E7, and IL2 (MVA-E6E7-IL2). Both of these vaccines have been tested singly in clinical trials in this patient population. We propose to evaluate heterologous DNA prime-MVA boost vaccination, with and without a topical Toll-like receptor (TLR) agonist applied at the lesion site, in otherwise healthy women with high grade cervical dysplasia associated with HPV16. This patient cohort is likely to be informative, as the rate of spontaneous regression in the study treatment window, 15 weeks, is expected to be 25% in this cohort. DNA-MVA prime-boost vaccination has been shown to be safe and immunogenic in clinical trials testing other antigenic targets, in healthy volunteers. We will test the hypothesis that DNA-MVA prime-boost vaccination is immunogenic and safe, and that locally applied TLR agonist can enhance cervical immune responses, allowing them to overcome immunologic inhibitory mechanisms present in the mucosal microenvironment of dysplastic lesions. The proposed analysis is novel because we will be able to study whether the generation of local inflammation is important in "unmasking" a chronic viral infection, and to study local, compartmentalized measures of effector and inhibitory immune responses. The study design targets a unique clinical resource and ideally suited patient population in which to demonstrate proof of principle. We have a demonstrated record in clinical trial design and execution in this patient population, which is disproportionately comprised of minority women who do not access the medical care system effectively.