Therapeutic DNA-MVA prime boost vaccination for HPV disease

描述（由申请人提供）：宫颈鳞状癌（SCCx）是由人乳头瘤病毒（HPV）致瘤毒株持续感染引起的。HPV16与60%以上的恶性疾病有关。HPV E6和E7蛋白在功能上需要维持转化状态，在SCCx及其前体病变，高级别宫颈发育不良（CIN2/3）中一致表达，并且代表宿主的外来抗原。因此，它们提供了潜在的令人信服的免疫治疗靶点。我们与NCI RAID合作，研制了一种靶向hpv16e7的治疗性DNA疫苗。我们与Transgene公司的合作将提供gmp级疫苗，该疫苗由修饰的安卡拉牛苗（MVA）组成，包含E6、E7和IL2 （MVA- e6e7 -IL2）。这两种疫苗已在该患者群体中单独进行了临床试验。我们建议在HPV16相关的高级别宫颈发育不良的健康女性中，评估在病变部位局部使用或不使用toll样受体（TLR）激动剂的异源DNA - mva增强疫苗接种。该患者队列可能具有信息性，因为在研究治疗窗口（15周）中，该队列的自发消退率预计为25%。在健康志愿者中测试其他抗原靶点的临床试验中，DNA-MVA初级增强疫苗已被证明是安全和免疫原性的。我们将验证DNA-MVA预增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反应，使它们能够克服存在于发育不良病变粘膜微环境中的免疫抑制机制。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在“揭露”慢性病毒感染中是否重要，并研究局部，效应和抑制性免疫反应的分区措施。研究设计的目标是一个独特的临床资源和理想适合的患者群体，其中证明的原则。我们在这一患者群体的临床试验设计和执行方面有良好的记录，这些患者群体不成比例地由少数民族妇女组成，她们无法有效地获得医疗保健系统。

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.