Phase ii intraperitoneal rhIL 12

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DESCRIPTION (Provided by applicant): Our long-term goal is to develop an effective bioimmunotherapy approach to improve the survival of patients with epithelial ovarian carcinoma (EOC). EOC involves the abdominopelvic peritoneum and serosal surfaces, and provide an appropriate target for intraperitoneal (IP) therapy trials. Recombinant human interleukin- 12 (rhIL- 12) stimulates natural killer cell activity and enhances adaptive immunity through activation of TH1 lymphocytes in vitro. rhIL-12 mediated antitumor effects in preclinical animal models primarily involve tumor specific T cells and antiangiogenic mechanisms. The large size of the IL-12 molecule and its immunobiologic potency in preclinical studies suggest that rhIL-12 could have useful clinical, pharmacologic and pharmacodynamic effects as an immunobiological agent in the IP treatment of patients with EOC. We have determined the dose limiting toxicity (DLT) of IP rhIL-12 (Genetics Institute) in a phase I clinical trial in a once weekly IP injection schedule. Pharmacokinetic studies from the phase I clinical trial demonstrated persistence of IL-12 in peritoneal fluid (pf) after IP injection. Increased pf levels of IFN-gamma and in some instances TNF-a, were detected after IP injection of rhIL- 12. Furthermore, decreased expression of the proangiogenic molecules FGF2 and VEGF on peritoneal cavity tumor was detected at higher dosing levels of IP rhIL- 12. The specific aims of this proposal in response to PA00-047 are: (1) To conduct a phase II clinical trial in patients with minimal residual disease after one prior chemotherapy, with IP rhIL-12 at a weekly dose of 300 ng/kg, and determine (a) response rate, (b) progression-free survival, (c) clinical toxicity, (d) quality of life profiles, (e) therapy effects on peritoneal tumor cells (DNA flow & apoptosis), & (f) pharmacokinetics. (2) Determine pharmacodynamics of IP rhIL-12 and whether it facilitates adaptive or innate immunity in vivo evidenced by (a) change in posttreatment cytokine profiles indicating a TH1 type response (tIL2, (up arrow) IFN-g (up arrow) TNF-a) or TH2 type response ((up arrow) IL-5,(up arrow) IL-10) or NK cell response ((up arrow) IFN-g) & whether patient responses correlate with a specific cytokine profile; (b) Determine whether IP rhIL- 12 results in increased production of IFN-g by peripheral blood lymphocytes or peritoneal exudate T cells or NK cells at the cellular level; (3) Determine whether IL-12 facilitates serum antibody responses to tumor associated antigens on EOC cells utilizing immunoblotting analysis. (4) Determine whether expression of proangiogenic factors VEGF, FGF2 and IL-8 are decreased following IF rhIL- 12.