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

描述(申请人提供)：宫颈癌是全球女性中第二常见的癌症，人类乳头瘤病毒(HPV)与宫颈癌的发展之间的联系是众所周知的。尽管巴氏涂片早期检测的出现，但在欠发达国家，宫颈癌是发病率和死亡率的主要原因。现在有一种预防性HPV疫苗可以防止妇女感染HPV，但一旦确定HPV感染，这种疫苗就不起作用了。我们的长期目标是开发一种治疗性HPV疫苗，该疫苗能够有效预防高危类型HPV感染人群引发的宫颈癌。我们提出了一种新的抗原和佐剂的组合。HPV向恶性表型的转化由两个基因产物E6和E7介导，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)女性治疗性疫苗的候选抗原来源。我们的临床研究检测了CD8T细胞反应和自发的sIL消退，结果表明CD8T细胞对HPV16型(HPV-16)E6蛋白(特别是中央区)的反应与宫颈病变的消退显著相关，而与E7蛋白无关。这种保护似乎在所有高风险但不是低风险的HPV类型中具有交叉反应。需要类似的研究来评估CD4T细胞对E7蛋白的反应是否也在sIL消退中起作用。我们推测HPV-16E6蛋白，可能还有E7蛋白，包含与sIL回归相关的CD4和CD8T细胞表位，是治疗性HPV疫苗的有效抗原(抗原)的来源，而念珠菌抗原具有抗HPV作用，导致皮肤疣消退，是增强疫苗免疫原性的有效佐剂(佐剂)。我们的具体目标是：(1a)确定HPV-16E6和E7蛋白中与宫颈病变消退相关的区域，并确定主要的CD4T细胞表位；(1b)通过检测与模式识别受体的相互作用，确定念珠菌抗原如何作用于增强免疫反应；(2)检测HPV多肽-念珠菌疫苗的剂量和毒性；以及(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为宫颈癌的预防提供一种新型的治疗性HPV疫苗，还将为增强多肽疫苗的免疫原性提供一种新的佐剂，该佐剂可应用于其他癌症和感染性疾病。 公共卫生相关性：该项目的成功完成将导致开发一种新的治疗性HPV疫苗，该疫苗可以降低HPV相关癌症(包括宫颈癌)的发病率和死亡率。此外，该项目有可能开发一种新型佐剂，能够增强多肽疫苗的免疫原性，可应用于其他癌症以及其他感染性病原体。

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.