A phase I trial to assess the immunogenicity, safety, tolerability and efficacy o

我们的长期目标是为人类乳头瘤病毒（HPV）引起的疾病开发免疫疗法。 虽然癌症免疫疗法领域已经在人类中显示出原理证明，即， 恶性肿瘤可以通过肿瘤特异性适应性T细胞应答识别和根除， 实现这种效果是困难的。一个原因可能是迄今为止测试的治疗性疫苗没有 免疫原性足以消除已建立的疾病。另一个原因可能是免疫 抑制直接介导的发展和进展的肿瘤，这是有效的病变 微环境该项目将测试HPV特异性适应性T细胞反应可以被免疫抑制的假设。 在高度宫颈发育不良（CIN 3）受试者中通过治疗性疫苗接种引起， 局部应用TLR 7激动剂咪喹莫特，直接作用于病变，将增强CD 8 + T细胞的进入， 到病变。CIN 3病变相对容易，其中一些在我们的15周研究中确实消退 窗口该疾病为治疗性疫苗接种提供了合理的、非自身抗原性的靶点。这个项目 将测试一种异源DNA初免，重组牛痘为基础的加强方案，以增强免疫力， 针对HPV 16 E6和E7的应答，其在宫颈中以功能性专性方式表达。 癌及其前驱病变，高度宫颈不典型增生（CIN 3）。该项目还提供了 有机会直接分析靶病变，以确定我们是否可以确定机制的证据， 将减轻免疫效应子应答的功能，即归巢和免疫应答功能的损害。 免疫细胞亚群事实上，我们发现CD 8 + T细胞在CIN 3病变处积聚，但在CIN 3病变的情况下， 持续性疾病，无法进入病变上皮。虽然免疫细胞浸润的模式已经被 在侵袭性疾病的临床环境中，它们被鉴定为预测临床结果，据我们所知，它们 在疾病的早期，在明显的侵袭性表型发展之前没有被识别。这项工作是一个 有机会研究免疫反应是本地化的初期肿瘤，免疫稳态 可以局部解偶联以增强效应免疫细胞的接近和功能的机制 来消除疾病。 相关性（参见说明）; 宫颈癌是由人乳头瘤病毒（HPV）感染引起的。这项研究的目的是开发 免疫治疗策略，可以训练免疫应答，以靶向和消除已建立的 HPV引起的疾病

Our long term goal is to develop immune therapies for disease caused by Human Papillomavirus (HPV). While the field of cancer immunotherapy has shown proof of principle in humans, namely, that established malignancies can be recognized and eradicated by a tumor-specific adaptive T cell response, reproducibly achieving this effect has been difficult. One reason may be that therapeutic vaccines tested to date have not been immunogenic enough to eliminate established disease. Another reason may be immunologic suppression directly mediated by developing and progressing tumors, which are operative in the lesion microenvironment. This project will test the hypothesis that HPV-specific adaptive T cell responses can be elicited by therapeutic vaccination in subjects with high grade cervical dysplasia (CIN3), and that the application of a topical TLR7 agonist, imiquimod, directly on the lesion, will enhance access of CD8+ T cells to the lesions. CIN3 lesions are relatively accessible, and some of them do regress within our 15-week study window. The disease provides rational, non-self antigenic targets for therapeutic vaccination. This project will test a heterologous DNA prime, recombinant vaccinia-based boost regimen to enhance the immune response against HPV16 E6 and E7, which are expressed in a functionally obligate manner in cervical cancer and its precursor lesion, high grade cervical dysplasia (CIN3). This project also provides the opportunity to analyze target lesions directly to determine if we can identify evidence of mechanisms that would mitigate the function of immune effector responses, namely, impairment of homing and function of immune cell subsets. In fact, we found that CD8+ T cells accumulate at CIN3 lesions, but in the case of persistent disease, fail to access lesional epithelium. While patterns of immune cell infiltration have been identified to predict clinical outcome in the clinical setting of invasive disease, to our knowledge, they have not been identified early in disease, before development of an overtly invasive phenotype. This work is an opportunity to study immune responses that are localized to incipient neoplasia, and immune homeostatic mechanisms which could be locally uncoupled to enhance both access and function of effector immune cells to eliminate disease. RELEVANCE (See instructions); Cervical cancer is caused by human papillomavirus (HPV) infection. The goal of this research is to develop immune therapeutic strategies which could educate the immune response to target and eliminate established disease caused by HPV.