LABORATORY STUDIES WITH INTRAPERITONEAL RHIL-12 THERAPY

这些研究的长期目标是开发有效的

The long-term goal of these studies is to develop effective immunotherapy with recombinant human interleukin-12 (rhIL-12) for the treatment of patients with peritoneal carcinomatosis. Peritoneal carcinomatosis due to either Mullerian or Gastrointestinal tract (GIT) malignancies is a major cause of morbidity and death. Despite recent advances, the results of presently available therapy leave much to be desired. There has been renewed interest in intraperitoneal (IP) therapies for malignancies that affect the peritoneal cavity. Recently rhIL-12 has been introduced into clinical trials. This cytokine is of particular interest since in animal studies it has been shown to be a powerful inducer of cytotoxic antitumor activity and of the differentiation of activation of T-helper 1 (TH1) lymphocytes, and because of its potential for synergy with other biotherapeutic agents. The hypothesis that rhIL-12 will enhance antitumor immunity in patients with peritoneal carcinomatosis caused by either Mullerian or GIT malignancies will be tested by elucidating mechanisms of action of rhIL-12 in patients participating in a phase I clinical study of IP rhIL-12. Therefore the specific aims are: (1) To determine, (a) whether interferon-g (IFN-gamma) levels are increased in the peritoneal cavity of patients treated with IP rHIL-12, (b) whether CD3+ (TH1) and CD3-(NK) lymphocytes are responsible for IFN-gamma production, and (c) whether MHC Class I and Class II expression on tumor calls is augmented by IP rhIL-12. (2) To determine whether IP rhIL-12 increases expression of activation markers on peritoneal NK and T-cells and expression of costimulatory and accessory molecules on antigen presenting cells. (3) To determine whether IP rhIL-12 treatment results in (a) the in vivo development of cytotoxic lymphocytes (CTL) and NK calls that exhibit augmented cytolytic activity against autologous tumor cells, and (b) to determine whether T-cell lines and clones with augmented cytotoxic activity against autologous tumor cells can be developed from peritoneal lymphocytes of patients treated with rhIL-12. (4) To determine whether IP rhIL-12 results in (a) increased production of tumor growth inhibitory molecules in the peritoneal cavity, specifically inducible nitric oxide synthetase (INOS), (b) decreased production of immunosuppressive molecules, specifically transforming growth factor beta and interleukin-10 and (c) increased levels of interferon inducible protein-10 (IP-10), a chemokine with antiangiogenesis activity.