Ovarian carcinoma is the leading cause of death from gynecologic malignancies in the United States, responsible for an estimated 14,000 deaths per year. Despite improvements in therapy, 5-year survival for advanced ovarian cancer remains approximately 20-30%. Ovarian cancers differentially express certain proteins normally present on other tissues only during embryonal development. Among these onco fetal proteins are the WT1 protein, the glycosylated mucin Ca125 (MUC16) and HER2/neu. Recently, we and others have identified potentially immunogenic peptides derived from WT1 and MUC16 which bind the common HLA allele, HLA A0201. Our initial studies with immunogenic WT1 peptides and with candidate MUC16 peptides suggest that these peptides can be used to sensitize T cells from normal individuals and from ovarian cancer patients, which can be expanded in vitro. The T cells sensitized with WT1 and MUC16 generate IFNy and other cytokines in response to peptide and specifically lyse primary HLA A2+ WT1+ or MUC16+ leukemias and selected carcinomas, including ovarian cancer cells in vitro. In a SCID mouse, human tumor xenograft model, we have found that adoptively transferred WT1 specific HLA A2+ T cells home to and specifically induce regressions of certain HLA A2+ WT1+ leukemia and selected carcinomas including ovarian cancer. In this grant, we propose first, to identify and characterize peptides of WT-1 and MUC16 which have moderate to high affinity for HLA A2, and thereafter, other HLA alleles. We will then use EBV BLCL either loaded with WT1, MUC16 or HER2/neu peptides or transduced to express these proteins, for their capacity to sensitize and stimulate the expansion of peptide-specific T cells capable of lysing primary ovarian cancer cells and established cell lines in vitro. We will also explore a novel pentadecapeptide approach to identify novel antigens in WT1 and MUC16. We will then identify features of these tumors which can potentiate or inhibit the tumoricidal activity of these T cells in vitro. We will also comparatively evaluate T cell populations generated from patients and from normal individuals against these peptides to determine whether disparities in phenotypic or functional features of those T cells affect tumor cell interactions in vitro. Third, we will test these peptide-specific cells for their capacity to home to, using a novel in vivo imaging approach, and induce regressions of human ovarian carcinoma xenografts in a SCID mouse model. Lastly, we propose to conduct a phase I/II trial of WT1 or MUC16 peptide-specific T cells in the treatment of women with advanced ovarian carcinoma. These studies may provide important new information regarding the potential of T cells generated ex vivo against these immunogenic peptides for adoptive cell therapy of ovarian cancer.
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