Immunopharmacology and cytokine production of a low-dose schedule of intraperitoneally administered human recombinant interleukin-2 in patients with advanced epithelial ovarian carcinoma

We determined in the peritoneal cavity (p.c.) of epithelial ovarian carcinoma patients during a 4-day treatment cycle of low-dose recombinant human interleukin-2 (rlL-2): (a) pharmacokinetics of IL-2, (b) endogenous cytokine production. and (c) numbers and percentages of peritoneal exudate lymphocytes. We administered 6 x 10 5 IU/m 2 of rIL-2 (0.03 mg/m 2 Proleukin rIL-2) intraperitoneally (i.p.) over 30 min on each of 4 days. One and one-half liters of D5 0.25 NS was injected i.p. before each rIL-2 infusion. Multiple peritoneal fluid samples were obtained from each of four patients on day I and day 4 for detection of IL-2, endogenous cytokines, and soluble IL-2 receptor (IL-2R-α). IL-2 concentrations in the peritoneal fluid were determined by bioassay and interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL- 10, transforming growth factor (TGF)-β2, and sIL-2R-α by enzyme-linked immunosorbent assay. Numbers of cells per microliter and lymphocyte subpopulation percentages after staining with a panel of monoclonal antibodies were determined on day I, day 4, and subsequent off-treatment days. IL-2 disappearance in the p.c. was well described by a pharmacokinetic model having constant-rate infusion and biexponential disposition. About 90% of the IL-2 disappearance occurred during the β-phase, during which IL-2 concentrations were sustained at ∼10-30 ng/ml (day 1 and day 4) and the median t 1/2β was 21.5 and 9.2 h on days 1 and 4, respectively. In four of four patients, p.c. production of IL-10 was observed on day 1 and day 4 (maximum 387 pg/ml). Maximum levels of IFN-γ and sIL-2R-α were observed on day 4. (IFN-γ 217 pg/ml; sIL2-R-α: 3486 U/ml.) No increases in TNF-α or TGF-β2 were observed. Large increases in p.c. CD3 + , CD4 + , CD8 + , CD16 + , and CD56 + cells were observed. We conclude that biologically active levels of IL-2 are generated in p.c. fluids after i.p. administration of rIL-2 at 0.03 mg/m 2 .