Two-thirds of ovarian cancer patients have advanced disease at the time of diagnosis, and ovarian cancer has the highest mortality rate among gynecological malignancies. Immunotherapy based on induction of tumor-specific cytotoxic T lymphocyte (CTL) responses may represent an attractive option for these patients. We have identified a series of novel ovarian tumor antigens, including the tumor-associated differentially expressed gene 14 (TADG-14) product, TADG-15, hepsin, stratum corneum chymotryptic enzyme (SCCE), all of which are serine proteases, and the matrix metalloprotease, pump-l. These antigens are highly expressed in ovarian cancer but not in normal ovaries or the majority of other normal adult tissues, suggesting that they may be excellent target antigens for dendritic cell (DC) immunotherapy. This proposal will test the hypothesis that antigen or peptide-loaded DC can be used to induce specific T lymphocyte responses from patients with ovarian cancer, and that tumor antigen-specific CTL will lyse ovarian tumor cells. We have shown that peptide-loaded DC stimulate HLA class I-restricted CDS+ CTL that lyse antigen-expressing targets, including HLA-matched ovarian tumor cells. The 1st Specific Aim will identify further CTL epitopes and determine whether DC-stimulated peptide-specific CD8+ CTL from ovarian cancer patients lyse ovarian tumor cells. We will also test whether DC transfected with novel HLA class I single chain trimers induce peptide-specific CD8+ CTL responses. In the 2nd Specific Aim, we will construct peptides that encompass defined CTL epitopes and candidate CD4+ helper T cell epitopes with degenerate HLA class II binding potential. DC loaded with multi-epitope peptides will be tested for their ability to induce antigen-specific CD8+ CTL responses and CD4+ helper T cell responses. The rationale for this strategy is that antigen-specific CD4+ T cells provide essential help for the induction and maintenance of effective CD8+ T cell responses in vivo. We will also test the immunogenicity of peptides translated from recently discovered intron sequences expressed in variant hepsin and TADG-14. The 3rd Specific Aim will determine whether DC loaded with full-length recombinant tumor antigen or transfected with linear DNA constructs induce CD8+ CTL and CD4+ T cell responses from ovarian cancer patients. This proposal is targeted at the development of clinical trial protocols for therapeutic DC vaccination for prevention of progression of ovarian cancer.

R01CA098927

2004-08-09

2009-05-31