Induction of CA125-specific cytotoxic T lymphocytes in human leukocyte antigen-A*0201 positive healthy donors and patients with advanced ovarian cancer Free

5098

CA125/MUC16 represents the best known human ovarian tumor-associated antigen. However, although CA125 secreted form has long been recognized as the gold standard for monitoring patients with ovarian carcinoma, its therapeutic potential as target for vaccination remains largely unknown. Few years ago our research group reported the cloning of the CA125 tumor antigen (O’Brien T, et al., Tumor Biol. 22:348-366:2001). In this study, using a bioinformatics approach (i.e., BIMAS algorithm of the Center for Information Technology, NIH, http://bimas.dcrt.nih.gov/molbio/hla_bind) we report the identification of multiple immunogenic peptides derived from CA125/MUC16 that bind to human leukocyte antigen-A*0201 and elicit strong peptide-specific human cytotoxic T lymphocytes (CTL) responses in healthy individuals as well as advanced stage ovarian carcinoma patients. Some CTL cell lines generated against these peptides specifically lysed HLA-A2-matched epithelial ovarian tumor cells expressing CA125/MUC16 but not HLA-identical CA125/MUC16-negative control cells. Cytotoxicity was significantly inhibited by anti-HLA class I (W6/32) and anti-CD11a/LFA 1 monoclonal antibodies and high levels of perforin were detected in the most cytotoxic CA125/MUC16 peptide-specific CTL populations. Importantly, at least one CA125/MUC16-peptide-specific CD8+ CTL population was found to effectively kill autologous ovarian cancer cells naturally expressing CA125 in patients harboring advanced stage disease. These data may pave the way for CA125 peptide derived cell-based-therapy, including dendritic cell (DC) immunotherapy, for the vaccination of ovarian cancer patients harboring chemotherapy resistant/residual disease.