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

描述（由申请人提供）：宫颈癌是全球女性中第二常见的癌症，人乳头瘤病毒（HPV）与宫颈癌发生之间的联系众所周知。尽管巴氏涂片检查可以早期发现宫颈癌，但宫颈癌仍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，但一旦确定感染HPV，这种疫苗就无效了。我们的长期目标是开发一种治疗性HPV疫苗，有效预防HPV暴露个体中高危型HPV引起的宫颈癌。我们提出了一种新的抗原和佐剂的组合。HPV相关的恶性表型转化是由两种基因产物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蛋白是用于患有HPV感染和/或鳞状上皮内病变（SIL）的女性的治疗性疫苗的候选抗原来源。我们的临床研究检查了CD8 T细胞应答和自发性SIL消退，结果表明，CD8 T细胞对HPV 16型（HPV-16）E6蛋白（特别是中心区域）的应答，而不是E7蛋白，与宫颈病变的消退显著相关。这种保护似乎在所有高风险但不是低风险HPV类型之间具有交叉反应性。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消退中起作用。我们假设，HPV-16 E6蛋白，可能还有E7蛋白的区域，含有与SIL消退相关的CD4和CD8 T细胞表位，是治疗性HPV疫苗的有效抗原（抗原）的来源，而念珠菌抗原具有诱导皮肤疣消退的抗HPV作用，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）鉴定HPV-16 E6和E7蛋白内与宫颈病变消退相关的区域，并表征占优势的CD4 T细胞表位;（1b）通过检查与模式识别受体的相互作用来确定念珠菌抗原如何增强免疫应答;（2）检查HPV肽-念珠菌疫苗的剂量和毒性;和（3）在剂量递增的I期临床试验中确保安全性并检查候选疫苗的免疫原性和临床应答。该项目的成功完成不仅将导致开发用于预防宫颈癌的新型治疗性HPV疫苗，还将导致开发用于增强肽疫苗免疫原性的新型佐剂，该佐剂可应用于其他癌症和感染因子。 公共卫生相关性：该项目的成功完成将导致一种新型治疗性HPV疫苗的开发，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，该项目具有开发能够增强肽疫苗免疫原性的新型佐剂的潜力，其可应用于其他癌症以及其他感染因子。

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.