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

我们的长期目标是开发针对人乳头瘤病毒(HPV)引起的疾病的免疫疗法。 虽然癌症免疫治疗领域已经在人类身上证明了原理，即建立了 恶性肿瘤可以通过肿瘤特异性适应性T细胞反应来识别和根除，而且是可重复的 实现这一效果一直很困难。一个原因可能是迄今为止测试的治疗性疫苗并没有 具有足够的免疫原性，足以消除既定疾病。另一个原因可能是免疫学 通过发展和进展的肿瘤直接介导的抑制，这些肿瘤是在病变中手术的 微环境。该项目将检验HPV特异性适应性T细胞反应可以是 由高度宫颈不典型增生(CIN3)患者的治疗性疫苗接种引起的，以及 局部应用TLR7激动剂咪喹莫特将增强CD8+T细胞的获得性 到损伤处。CIN3病变相对容易，在我们15周的研究中，其中一些确实会消退 窗户。该病为治疗性疫苗接种提供了合理的、非自身抗原性靶点。这个项目 将测试一种基于重组牛痘的异源DNA增强方案以增强免疫力 对HPV16E6和E7的免疫应答，这两种病毒在宫颈中以功能专一性的方式表达 癌症及其前驱病变，高度宫颈不典型增生(CIN3)。该项目还提供了 有机会直接分析目标损伤，以确定我们是否可以确定机制的证据 会减轻免疫效应器反应的功能，即归巢功能障碍和 免疫细胞亚群。事实上，我们发现CD8+T细胞在CIN3病变处积聚，但在CIN3病变的情况下 持续性疾病，不能进入皮损上皮。而免疫细胞的渗透模式一直是 据我们所知，在侵袭性疾病的临床背景下，它们被确定为预测临床结果。 在疾病早期没有被发现，在出现明显的侵袭性表型之前。这项工作是一项 有机会研究对早期肿瘤的局部免疫反应和免疫平衡 可局部解偶联以增强效应器免疫细胞的访问和功能的机制 来消灭疾病。 相关性(见说明)； 宫颈癌是由人类乳头瘤病毒(HPV)感染引起的。这项研究的目标是开发 免疫治疗策略，可以教育免疫反应到靶点，消除既定的 由人乳头瘤病毒引起的疾病。

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.