Antigen-specific immunotherapy of cervical and ovarian cancer

Abstract

We contrast the efforts to treat ovarian cancer and cervical cancer through vaccination because of their different pathobiology. A plethora of approaches have been developed for therapeutic vaccination against cancer, many of which target defined tumor-associated antigens (TAAs). Persistent infection with oncogenic human papillomavirus (HPV) types causes cervical cancer. Furthermore, cervical cancer patients frequently mount both humoral and T-cell immune responses to the HPV E6 and E7 oncoproteins, whose expression is required for the transformed phenotype. Numerous vaccine studies target these viral TAAs, including recent trials that may enhance clearance of pre-malignant disease. By contrast, little is known about the etiology of epithelial ovarian cancer. Although it is clear that p53 mutation or loss is a critical early event in the development of epithelial ovarian cancer, no precursor lesion has been described for the most common serous histotype, and even the location of its origin is debated. These issues have complicated the selection of appropriate ovarian TAAs and the design of vaccines. Here we focus on mesothelin as a promising ovarian TAA, because it is overexpressed and immunogenic at high frequency in patients, is displayed on the cell surface, and potentially contributes to ovarian cancer biology.

Figure 1. Morphological progression of squamous cell carcinoma of the cervix and high grade serous carcinoma of the ovary

A. Cervical carcinogenesis is initiated by infection of the normal cervical squamous epithelium with an oncogenic type HPV and its persistance. Productive lesions produce mild dysplasia and are termed CIN1 or LSIL. These lesions become progressively less differentiated resulting in a severe displasia termed CIN2/3 or HSIL. Progression is associated with integration of the viral genome, loss of E2 expression and consequent upregulation of E6 and E7 expression, and genomic instability. Microinvasive carcinoma in situ metastasizes. B. Ovarian carcinogenesis. In contrast to cervical cancer, the timing of carcinogenesis, the cell types from which it arises, the critical molecular events and precursor lesions of high grade ovarian serous carcinoma are far less clear. It is believed to arise from the ovarian surface epithelium, or from the mesothelium or the fallopian tube. Certain hereditary genetic conditions, notably BRCA 1or 2 mutation, predispose women to ovarian carcinoma. Both the hereditary and sporadic forms exhibit p53 mutations and genomic instability (16,219).