THERAPEUTIC VACCINES FOR HPV DISEASES

描述：(申请者描述)这个项目的总体目标是 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，最流行的HPV 在宫颈癌及其直接的前驱病变中发现的类型， 鳞状上皮内病变(SILS)。分子、生化和细胞 研究已经明确地证明，两种HPV基因产物E6和E7， 在系统性红斑狼疮和宫颈癌中持续表达，此外，铅 上皮细胞的恶性转化。E6绑定、停用和 促进P53的降解，而E7结合并失活pRb。因为 HPV16是宫颈癌中最常见的HPV型，其 前驱病变，而且因为E7在转化中持续表达 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。经典度量之间的相关性 免疫反应和疾病的临床消退情况不佳 特色化的。因此，临床相关免疫学的鉴定 监测疫苗试验的化验是最重要的科学方法之一 致力于现代癌症疫苗的开发。该项目将提供备注 不仅对这种相关性有新的见解，而且还可以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)接种疫苗会增强细胞免疫。 针对表达E7的上皮细胞，以及2)这种反应将被反映出来 通过病变大小、组织病理学、病毒活性和 局部组织和外周免疫反应的测量。 我们的具体目标是：1)评估阿司匹林的安全性和毒性 内噬菌体/溶酶体靶向E7疫苗在试点翻译试验中 HPV16+高级别、侵袭前宫颈病变2)评估 病理学、病毒学和临床措施以确定这些药物的疗效 针对HPV16+高度宫颈病变的疫苗。为此，我们将 HPV病变镜检查特征与组织病理学的关系 HPV16E7特异性体液的血清学检测结果和病毒载量 和细胞免疫反应。 这项建议协调了约翰霍普金斯大学的大量可用资源。 医疗机构。这些设施将被用来开发特林布尔博士的 设计和执行评估癌前病变的临床试验的能力 女性下生殖道的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.