Chemotherapy-refractory epithelial ovarian cancer (EOC) will kill 14,500 women in the United States in 1996 by progressive dissemination limited to the peritoneal cavity, but producing profound inanition, abdominal distention, and then death. The applicant's phase I clinical study of intraperitoneal interleukin 2 (IPIL-2) has suggested that IL-2 induced immune activation may clear ovarian cancer by the recruitment of new immune effector mechanisms, including cytotoxic immunocytes which produce cytokines locally. IL-2 induced tumor clearance has led to a degree of long term survival not previously seen with second line chemotherapy in ovarian cancer patients. A phase II study is being conducted over the next 24 months to determine if 16 weekly outpatient infusions of 6 x 10(5) IU/m2 IPIL-2 produces a significant therapeutic response and survival benefit in EOC. The applicant has proposed as an adjunct to this clinical trial that measurement of peritoneal immunocytes and cytokine levels over the 16 weekly IPIL-2 infusions will demonstrate prognostic changes that will correlate and predict a developing clinical response. The applicant proposes to: 1) analyze the T cell CD4+, T cell CD8+, NK cell, B cell, eosinophil, and antigen presenting cell ratios in the peritoneal and circulating compartments following sequential weekly pulses of IPIL-2, 2) determine the pattern of IL-10, IL-5, IL-6 versus IFN-gamma, TNF-alpha, and GM-CSF levels in sequential peritoneal samples of patients receiving the 16 weekly IPIL-2 infusions, and 3) select five patients for intensive monitoring of the kinetics of cytokine induction for 7 days after the first, fourth, eight and sixteenth course of IPIL-2 infusion. Preliminary data suggest that both Th1 and Th2-type cytokines are induced in response to IPIL-2 infusions, and elevated levels of these cytokines at 8-16 weeks of therapy, together with an eosinophilic exudate, may predict a future clinical response.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA074105-02
Application #
2683707
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Xie, Heng
Project Start
1997-04-01
Project End
2000-03-31
Budget Start
1998-04-01
Budget End
2000-03-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Magee-Women's Hospital of Upmc
Department
Type
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Vlad, Anda M; Budiu, Raluca A; Lenzner, Diana E et al. (2010) A phase II trial of intraperitoneal interleukin-2 in patients with platinum-resistant or platinum-refractory ovarian cancer. Cancer Immunol Immunother 59:293-301
Wei, Shuang; Kryczek, Ilona; Edwards, Robert P et al. (2007) Interleukin-2 administration alters the CD4+FOXP3+ T-cell pool and tumor trafficking in patients with ovarian carcinoma. Cancer Res 67:7487-94
Black, C A; Rohan, L C; Cost, M et al. (2000) Vaginal mucosa serves as an inductive site for tolerance. J Immunol 165:5077-83