Therapeutic DNA-MVA prime boost vaccination for HPV disease

针对 HPV 疾病的治疗性 DNA-MVA 初免加强疫苗接种

• 批准号: 7158947
• 负责人: Cornelia L Trimble
• 金额: $ 22.12万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7158947
• 关键词: DNA; active immunization; clinical research; clinical trials; immune response; infection; inflammation; toll like receptor; transfection

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.

描述(申请人提供)：宫颈鳞癌(SCCx)是由人乳头瘤病毒(HPV)致癌毒株持续感染引起的。HPV16是一种与超过60%的恶性疾病有关的菌株。HPVE6和E7蛋白在功能上是维持转化状态所必需的，在SCCx及其前驱病变高度宫颈不典型增生(CIN2/3)中持续表达，并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。与NCI Raid合作，我们制造了一种针对HPV16E7的治疗性DNA疫苗。我们与Transgene SA的合作将提供GMP级疫苗，该疫苗由包含E6、E7和IL2(MVA-E6E7-IL2)的改良安卡拉牛痘(MVA)组成。这两种疫苗都在这一患者群体的临床试验中进行了单独测试。我们建议评估异种DNA PRIME-MVA加强接种，在病变部位应用和不应用局部Toll样受体(TLR)激动剂，在其他情况下，对患有HPV16相关的高度宫颈发育不良的健康女性。这个患者队列可能会提供信息，因为在研究治疗窗口中，15周的自然消退率在这个队列中预计为25%。在对健康志愿者进行的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的和免疫原性的。我们将检验这样的假设，即DNA-MVA初级增强疫苗具有免疫原性和安全性，局部应用TLR激动剂可以增强宫颈免疫反应，使其能够克服异常增生性病变粘膜微环境中存在的免疫抑制机制。这项拟议的分析是新颖的，因为我们将能够研究局部炎症的产生是否对“揭露”慢性病毒感染很重要，并能够研究局部的、区分的效应性和抑制性免疫反应的措施。这项研究设计的目标是独特的临床资源和理想的适合患者群体，在其中证明原则。在这些患者群体中，我们在临床试验设计和执行方面有着良好的记录，这些患者群体中不成比例地由无法有效获得医疗保健系统的少数族裔妇女组成。