) 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.
|Trimble, Cornelia L; Clark, Rachael A; Thoburn, Christopher et al. (2010) Human papillomavirus 16-associated cervical intraepithelial neoplasia in humans excludes CD8 T cells from dysplastic epithelium. J Immunol 185:7107-14|
|Trimble, Cornelia L; Peng, Shiwen; Thoburn, Christopher et al. (2010) Naturally occurring systemic immune responses to HPV antigens do not predict regression of CIN2/3. Cancer Immunol Immunother 59:799-803|
|Trimble, Cornelia L; Peng, Shiwen; Kos, Ferdynand et al. (2009) A phase I trial of a human papillomavirus DNA vaccine for HPV16+ cervical intraepithelial neoplasia 2/3. Clin Cancer Res 15:361-7|
|Zhai, Yali; Kuick, Rork; Nan, Bin et al. (2007) Gene expression analysis of preinvasive and invasive cervical squamous cell carcinomas identifies HOXC10 as a key mediator of invasion. Cancer Res 67:10163-72|
|Trimble, Cornelia L; Genkinger, Jeanine M; Burke, Alyce E et al. (2005) Active and passive cigarette smoking and the risk of cervical neoplasia. Obstet Gynecol 105:174-81|
|Trimble, Cornelia L; Piantadosi, Steven; Gravitt, Patti et al. (2005) Spontaneous regression of high-grade cervical dysplasia: effects of human papillomavirus type and HLA phenotype. Clin Cancer Res 11:4717-23|
|Trimble, Cornelia L; Richards, Lynn A; Wilgus-Wegweiser, Barbara et al. (2004) Effectiveness of screening for cervical cancer in an inpatient hospital setting. Obstet Gynecol 103:310-6|