B7.1 COSTIMULATION IN OVARIAN CANCER

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DESCRIPTION: (Applicant's Abstract) The long-term goal of this study is to develop immunotherapy for patients with ovarian carcinomatosis that involves intraperitoneal (IP) injections of (a) x-irradiated autologous tumor cells that have the transgene for the human costimulatory molecule hB7.1, and (b) rlFN-gamma (g). Ovarian carcinomatosis is a significant cause of morbidity and mortality and cure rates have improved little. Results from experimental tumor models suggest that costimulation through the B7/CD28 pathway and immunogenicity (MHC expression) of the tumor are required for the induction of effective tumor specific immunity in vivo. To determine whether costimulation with hB7.1 facilitates tumor-specific immune responses in patients with ovarian carcinomatosis, a novel tumor-vaccine strategy has been developed. This strategy consists of autologous tumor cells transduced with hB7.1 following infection with the B7.1 encoded canarypox vector, ALVAC-hB7.1 (Pasteur Merieux Connaught). HLA Class I and HLA Class II expression on ovarian carcinoma cells is often reduced, and this effect can be reversed by injecting rlFN-g intraperitoneally. Therefore, rlFN-g will be used both in the preparation of the vaccine and in vivo to facilitate tumor specific immune responses. The applicant's specific aims are: (1) To determine whether IP injections of a tumor vaccine consisting of B7.1-modified autologous tumor cells and rlFN-g, results in development in vivo of T lymphocytes that exhibit (a) cytotoxicity primarily restricted to autologous tumor cells, (b) TH1 or TH2 cytokine production in response to autologous tumor but not to normal cells, and (c) early intermediate and late activation antigens on T-cells. (2) To determine whether the tumor-cell vaccine facilitates production of T-cell lines (or clones) that are derived from peritoneal tumor infiltrating lymphocytes (TIL), and whether these T-cell lines (or clones) exhibit increased cytotoxic activity or cytokine production against autologous tumor cells. (3) To determine (a) whether T-cell responses to the tumor vaccine are associated with maturation of peritoneal antigen-presenting cells in vivo, and (b) whether the T-cell responses are inhibited in vitro by peritoneal cavity DR+ monocytes that secrete IL-10 and TGF-beta, and whether these effects can be reversed by monoclonal antibodies against TGF-beta and the IL-10 receptor. Significance: The studies proposed will advance knowledge about: (a) treatment for ovarian cancer, (b) development of TIL-derived T-cell lines that might be used for adoptive immunotherapy, and (c) the in vivo role of certain factors that interfere with T-cell activation, and (d) directions for future clinical trials with these agents.