The long-term objectives of this interactive R01 proposal are to develop new and effective treatment approaches for epithelial ovarian cancer (EOC) based upon the activation in vivo of tumor infiltrating lymphocytes (TIL) specific for autologous tumor. Notwithstanding recent advances in the chemotherapy of EOC the survival of these patients leaves much to be desired. The hypotheses to be tested in this grant application are that ovarian TIL-derived T-cell lines can be developed from peritoneal exudate cells (PEC) of EOC patients after intraperitoneal (IP) priming with interferon-lambda (rLFN-lambda) followed by low doses of IL-2. In particular, we will address the issues whether IP priming with these cytokines is correlated with (a) increased proportions of tumor cells that express MHC Class I and/or Class II surface antigens in vivo; (b) recovery of large numbers of CD3+TCRalphabeta+ lymphocytes from the peritoneal cavity (P.c.) that express either CD8+ or CD4+ phenotypes; (c) an ability to expand either CD8+ or CD4+ T-cell lines from PEC utilizing a T cell purification procedure and (d) that the T-cell lines obtained after IP priming with rIFN-lambda exhibit specificity in terms of (i_ autologous tumor cell cytolytic activity and/or (ii) cytokine production. All these hypotheses are focused on elucidating the mechanisms of action, in vivo, of these TILs and can be addressed only in conjunction with a clinical trial in which patients with EOC are treated with a strategy of adoptively transferred TIL developed from (PEC) obtained after in vivo priming with rIFN-lambda and IL-2. The clinical trial follows a basic design that we have used in IP adoptive immunotherapy trials of EOC patients. IP priming with rIFN-lambda is a novel feature of our trial design. (e) We will also test the hypothesis in a separate protocol that: ovarian TIL-derived T-cell lines concentrate at tumor sites after IP injection.
Our specific aims are to: Determine whether IP priming of EOC patients with rIFN-lambda followed by low dose rIL-2 correlates with (1) Increased expression of MHC Class I or Class II surface antigens on EOC cells in vivo, and (2) Production of ovarian TIL-derived T-cell lines from PEC that (a) express either the CD8+TCRalphabeta+ or CD4+TCRalphabeta+ phenotype, and (b) exhibit tumor specific activity in terms of (i) Autologous tumor cell cytotoxicity and/or (ii) cytokine production.
Other specific aims are to (3) Determine the frequency and intensity of toxic events and/or clinical responses that result from a treatment strategy that includes IP priming with cytokines and IP treatment with rIFN-lambda followed by cytokine primed T-cell lines and low dose rIL-2, and (4) Determine the ability of purified ovarian T-cell lines to concentrate at tumor sites.
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