Molecular Attributes of Tissue Immune Response in HPV Disease

免疫疗法的临床成功受到对免疫细胞归巢、功能和在靶组织中保留的机制的不完全理解的阻碍。我们的研究团队利用我们独特的临床资源开发新的方法，数据和见解来解决这些基本问题。人乳头瘤病毒（HPV）引起的上皮内病变（CIN 2/3）提供了一个机会，以确定如何在非无菌屏障上皮组织中产生和维持免疫反应。CIN 2/3病变可直接触及，临床惰性，并与病毒癌蛋白E6和E7的功能性专性表达相关。虽然一个子集经历完全消退，外周血T细胞对病毒抗原的反应是弱的，并不与疾病的结果。我们提出的研究，以确定在该网站的抗原，在CIN 2/3隔离的免疫反应的机制。我们有一个针对癌前HPV疾病的主动免疫治疗计划，测试增强T细胞对病毒抗原反应的策略，并使归巢和进入女性生殖道粘膜。我们开发了一系列技术，对研究干预前后获得的人体样本进行定量、基于组织的分析。该提案基于我们前两个资助周期的成熟数据，包括由三个制药商赞助的IND管理的免疫治疗试验，每个IND都是与NCI RAID计划合作生成的。我们最近的初步数据表明，全身性治疗性疫苗接种可以诱导靶病变中的显著效应免疫应答，尽管外周血中对疫苗抗原的T细胞应答可检测到。我们的短期目标是识别这些组织反应的分子特征;确定其免疫治疗相关性;并开发组织特征以预测对治疗性疫苗接种或直接操纵病变微环境的反应的可能性。我们的长期目标是开发基于组织的生物标志物的分析算法，为新的治疗策略的开发提供客观的指导，并指导治疗决策。

Clinical success of immunotherapies has been hampered by an incomplete understanding of mechanisms of immune cell homing, function, and retention in the target tissue. Our research team has taken advantage of our unique clinical resources to develop new methods, data, and insights to address these basic questions. Intraepithelial lesions (CIN2/3) caused by human papillomavirus (HPV) present an opportunity to determine how immune responses are generated and maintained in a non-sterile barrier epithelial tissue. CIN2/3 lesions are directly accessible, clinically indolent, and are associated with functionally obligate expression of viral oncoproteins E6 and E7. Although a subset undergo complete regression, peripheral blood T cell responses to viral antigens are weak, and do not correlate with disease outcome. We propose studies to identify mechanisms of immune response sequestered at the site of antigen, in CIN2/3. We have an active immunotherapy program for premalignant HPV disease, testing strategies to enhance T cell responses to viral antigens, and to enable homing and access to the female reproductive tract mucosa. We have developed a constellation of technologies to perform quantitative, tissue-based analyses of human samples obtained before and after study interventions. This proposal is based on maturing data from our two previous funding cycles, including immune therapeutic trials governed by three investigator-sponsored INDs, each of which was generated in collaboration with the NCI RAID program. Our recent preliminary data indicate that systemic therapeutic vaccination can induce a striking effector immune response in the target lesion, despite modest detectable T cell responses to vaccine antigen in the peripheral blood. Our short-term Aims are to identify the molecular signature of these tissue responses; to determine their immune therapeutic relevance; and to develop tissue signatures to predict likelihood of response either to therapeutic vaccination or to direct manipulation of the lesion microenvironment. Our long-term goal is to develop analytic algorithms for tissue-based biomarkers that will provide objective guidelines to inform development of new therapeutic strategies and to guide treatment decisions.