Understanding and Enhancing T-Cell Responses to high Risk Human Papillomaviruses

简介（由申请人提供）：子宫颈癌是全球妇女中第二常见的癌症，人类乳头瘤病毒（HPV）与子宫颈癌的发展之间的联系是众所周知的。尽管出现了巴氏涂片早期检测，但宫颈癌是欠发达国家发病率和死亡率的主要原因。现在有一种预防性HPV疫苗可以预防女性感染HPV，但是一旦HPV感染就没有效果了。我们的长期目标是开发一种治疗性HPV疫苗，有效预防HPV暴露人群中由高危型HPV引起的宫颈癌。我们提出一种抗原和佐剂的新组合。hpv相关转化为恶性表型是由两个基因产物E6和E7介导的，它们的表达是维持转化表型所必需的。因此，E6和E7蛋白是HPV感染和/或鳞状上皮内病变（SILs）妇女治疗性疫苗的候选抗原来源。我们的临床研究检查了CD8 t细胞反应和自发SIL消退，结果表明CD8 t细胞对HPV 16型（HPV-16） E6蛋白（特别是中部区域）的反应，而不是对E7蛋白的反应，与宫颈病变的消退显著相关。这种保护似乎在所有高危型HPV中都有交叉反应，但在低危型HPV中没有。需要类似的研究来评估CD4 t细胞对E7蛋白的反应是否也在SIL回归中起作用。我们假设HPV-16 E6蛋白和E7蛋白中含有与SIL消退相关的CD4和CD8 t细胞表位的区域是治疗性HPV疫苗（抗原）的有效抗原来源，而念珠菌抗原具有诱导皮肤疣消退的抗HPV作用，是增强疫苗免疫原性（佐剂）的有效佐剂。我们的具体目标是：（1a）确定HPV-16 E6和E7蛋白中与宫颈病变消退相关的区域，并表征显性CD4 t细胞表位；（1b）确定念珠菌抗原如何通过检测与模式识别受体的相互作用来增强免疫反应；(2)检测HPV肽-念珠菌疫苗的剂量和毒性；(3)确保安全性，并在剂量递增的I期临床试验中检查候选疫苗的免疫原性和临床反应。该项目的成功完成不仅将开发出一种用于预防宫颈癌的新型治疗性HPV疫苗，而且还将开发出一种增强肽疫苗免疫原性的新型佐剂，可应用于其他癌症和传染病。

DESCRIPTION (provided by applicant): Cervical cancer is the second most common cancer among women worldwide, and the link between human papillomavirus (HPV) and the development of cervical cancer is well known. Despite the advent of early detection with Papanicolaou smears, cervical cancer is a major cause of morbidity and mortality in less developed nations. A prophylactic HPV vaccine is now available to prevent women from acquiring HPV infection, but it is not effective once HPV infection is established. Our long-term goal is to develop a therapeutic HPV vaccine that is effective in preventing cervical cancer caused by high-risk types of HPV in HPV-exposed individuals. We propose a novel combination of antigens and adjuvant. HPV-related transformation to a malignant phenotype is mediated by two gene products, E6 and E7, and their expression is required for maintenance of a transformed phenotype. Therefore, E6 and E7 proteins are candidate antigen sources for a therapeutic vaccine for women with HPV infection and/or squamous intraepithelial lesions (SILs). Our clinical study examining CD8 T-cell responses and spontaneous SIL regression showed that CD8 T-cell responses to HPV type 16 (HPV-16) E6 protein (particularly the central regions), but not the E7 protein, are significantly associated with regression of cervical lesions. Such protection appears to be crossreactive among all high-risk but not low-risk HPV types. Analogous studies are needed to assess whether CD4 T-cell responses to the E7 protein also have a role in SIL regression. We hypothesize that regions of HPV-16 E6 protein, and perhaps E7 protein, containing CD4 and CD8 T-cell epitopes associated with SIL regression are sources of effective antigens for a therapeutic HPV vaccine (antigens), and that Candida antigen, with anti-HPV effects inducing skin wart regression, is an effective adjuvant in enhancing vaccine immunogenicity (adjuvant). Our specific aims are to: (1a) identify regions within HPV-16 E6 and E7 proteins associated with cervical lesion regression and characterize the dominant CD4 T-cell epitopes; (1b) determine how Candida antigen may work to enhance immune response by examining interactions with pattern recognition receptors; (2) examine dosage and toxicity of the HPV peptide-Candida vaccine; and (3) assure safety and examine immunogenicity and clinical responses to the candidate vaccine in a dose-escalation Phase I clinical trial. Successful completion of this project would lead to not only development of a novel therapeutic HPV vaccine for cervical cancer prevention, but also a novel adjuvant to enhance peptide vaccine immunogenicity, which can be applied to other cancers and infectious agents. PUBLIC HEALTH RELEVANCE: Successful completion of this project would lead to the development of a novel therapeutic HPV vaccine that can reduce morbidity and mortality due to HPV-associated cancers, including cervical cancer. In addition, this project has the potential for developing a novel adjuvant capable of enhancing peptide vaccine immunogenicity, which can be applied to other cancers as well as other infectious agents.