THERAPEUTIC VACCINES FOR HPV DISEASES

描述：（申请人描述）本项目的总体目标是 评估新的、治疗性的、抗原特异性的疫苗策略， 人乳头瘤病毒（HPV）16型的E7抗原， 在宫颈癌及其直接前驱病变中发现的类型， 鳞状上皮内病变（锡尔斯）。 分子、生物化学和细胞 研究已经明确表明，两种HPV基因产物，E6和E7， 在锡尔斯和宫颈癌中一致表达，此外， 上皮细胞的恶性转化。 E6结合、失活和 促进p53的降解，而E7结合并灭活pRb。 因为 HPV 16是宫颈癌中最常见的HPV类型， 前病变，因为E7是一致表达的转化 上皮细胞，我们集中精力诱导免疫反应， 针对这种特殊的抗原。 经典测量之间的相关性 免疫反应和疾病临床消退的情况并不好 表征了 因此，识别临床相关的免疫学 用于监测疫苗试验的检测方法是最重要的科学方法之一， 在现代癌症疫苗开发方面的努力。 该项目将提供不 只有新的见解，这种相关性，但也作为一个潜在的模型， 用于开发其他治疗性癌症疫苗。 我们的假设是：1）疫苗接种将增强细胞介导的免疫力 针对表达E7的上皮细胞，以及2）这种应答将反映在 通过病变大小、组织病理学、病毒活性的定量变化， 免疫反应的局部组织和外周测量。 我们的具体目标是：1）评价的安全性和毒性 内体/溶酶体靶向E7疫苗在中试翻译试验中的应用 HPV 16+高级别、浸润前宫颈病变的女性，2）评估 病理学、病毒学和临床测量，以确定这些 针对HPV 16+高度宫颈病变的疫苗。 为此我们将 HPV病变的相关阴道镜特征，组织病理学 HPV 16 E7特异性体液免疫血清学检测结果和病毒载量， 和细胞免疫反应。 该提案协调了约翰霍普金斯大学的广泛资源 医疗机构 这些设施将用于开发特林布尔博士的 设计和执行临床试验评估肿瘤前病变的能力 女性下生殖道HPV相关病变

DESCRIPTION: (Applicant's Description) The overall goal of this project is to evaluate new, therapeutic, antigen-specific vaccine strategies targeted at the E7 antigen of human papillomavirus (HPV) type 16, the most prevalent HPV type found in both cervical cancer and its immediate precursor lesions, squamous intraepithelial lesions (SILs). Molecular, biochemical, and cellular studies have unequivocally demonstrated that two HPV gene products, E6 and E7, are consistently expressed in SILs and cervical cancers, and furthermore, lead to malignant transformation of epithelial cells. E6 binds, inactivates, and promotes the degradation of p53 while E7 binds and inactivates pRb. Because HPV 16 is the most commonly found HPV type in cervical cancer and its precursor lesions, and because E7 is consistently expressed in transformed epithelial cells, we have focused our efforts inducing an immune response directed at this particular antigen. The correlation between classic measures of immune response and clinical regression of disease is not well characterized. As such, the identification of clinically relevant immunologic assays to monitor vaccine trials is one of the most important scientific endeavors in modern cancer vaccine development. This project will provide not only new insight into this correlation, but also serve as a potential model for the development of other therapeutic cancer vaccines. Our hypotheses are: 1) vaccination will enhance cell-mediated immunity against epithelial cells expressing E7, and 2) this response will be reflected by quantitative changes in lesion size, histopathology, viral activity, and in local tissue and peripheral measures of immune response. Our specific aims are: 1) to evaluate the safety and toxicity of endosomal/lysosomal targeted E7 vaccines in pilot translational trials in women with HPV16+ high grade, preinvasive cervical lesions, 2) to evaluate pathologic, virologic, and clinical measures to determine efficacy of these vaccines against HPV16+ high grade cervical lesions. To this end, we will correlate colposcopic characteristics of HPV lesions, histopathologic findings, and viral load, with serologic assays of HPV16 E7-specific humoral and cellular immune response. This proposal coordinates extensive resources available at the Johns Hopkins Medical Institutions. These facilities will be used to develop Dr. Trimble's ability to design and execute clinical trials evaluating preneoplastic HPV-associated lesions of the female lower genital tract.