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（由申请人提供）：子宫颈（SCCX）的鳞状癌是由人乳头瘤病毒（HPV）的致癌菌株持续感染引起的。 HPV16是与超过60％的恶性病有关的菌株。 HPV E6和E7蛋白在功能上需要维持转化状态，在SCCX及其前体病变中始终表达，高级颈椎发育不良（CIN2/3），并代表宿主的异物。因此，它们提出了潜在的吸引人的免疫治疗靶标。与NCI RAID合作，我们制作了靶向HPV16E7的治疗DNA疫苗。我们与Transgene SA的合作将提供GMP级疫苗，该疫苗由修改的vaccinia ankara（MVA），住房E6，E7和IL2（MVA-E6E7-IL2）组成。这两种疫苗在该患者人群的临床试验中已经单独进行了测试。我们建议评估在病变部位应用的异源DNA Prime-MVA促进疫苗接种，有或没有局部收费的受体（TLR）激动剂，在与HPV16相关的高级颈椎发育不良的其他健康女性中。该患者队列可能会提供信息，因为在研究治疗窗口中自发回归的速率预计在该队列中为25％。在健康志愿者中，DNA-MVA促进疫苗接种已被证明是安全且免疫原性的，该试验测试了其他抗原靶标。我们将检验以下假设：DNA-MVA素促进疫苗是免疫原性和安全的，并且局部应用的TLR激动剂可以增强宫颈免疫反应，从而使它们能够克服粘膜损伤中存在的免疫抑制机制，使其具有多个脱发性疾病的粘膜微环境。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”慢性病毒感染并研究局部，分隔的效应子和抑制性免疫反应的测量中是否重要。该研究设计针对独特的临床资源，并且非常适合证明原则证明的患者人群。我们在该患者人群中有一个记录在临床试验设计和执行方面的记录，这是不成比例的，这些妇女由少数族裔妇女组成，这些妇女无法有效地获得医疗系统。