PURPOSE: Repeated administrations of recombinant human interleukin-12 (rHuIL-12) to cancer patients are characterized by a reduction of side effects during treatment. Induction of IFN-gamma, considered a key mediator of antitumor effects of IL-12, is known to decline on repeated administrations. We studied whether other immunological effects of rHuIL-12 are tapered in the course of treatment. EXPERIMENTAL DESIGN: In a Phase I study of 26 patients with advanced renal cell cancer, rHuIL-12 was administered s.c. on day 1, followed by 7 days rest and six injections administered over a 2-week time period. Plasma concentrations of various cytokines were monitored, as well as absolute counts of circulating leukocyte and lymphocyte subsets. RESULTS: The first injection of IL-12 was accompanied by rapid, transient, and dose-dependent increments of plasma levels IFN-gamma, tumor necrosis factor-alpha, IL-10, IL-6, IL-8, but not IL-4, as well as rapid, transient, and dose-dependent reductions of lymphocyte, monocyte, and neutrophil counts. The major lymphocyte subsets, i.e., CD4+ and CD8+ T cells, B cells, and natural killer cells, followed this pattern. On repeated rHuIL-12 injections, IL-10 concentrations increased further, whereas the transient increments of IFN-gamma, tumor necrosis factor-alpha, IL-6, and IL-8 concentrations, as well as the fluctuations of the leukocyte subset counts, were tapered. Dose escalation of IL-12 within clinically tolerable margins did not reduce the decline of these immunological effects. CONCLUSIONS: Induction of pro-inflammatory cytokines and associated fluctuations in leukocyte subset counts decrease on repeated administrations of rHuIL-12. The steady increment of IL-10 plasma levels may mediate the observed down-regulation of clinical and immunological effects.

Adult, Aged, B-Lymphocytes/metabolism, CD4-Positive T-Lymphocytes/metabolism, CD8-Positive T-Lymphocytes/metabolism, Carcinoma, Renal Cell/blood/*drug therapy, Cytokines/metabolism, Humans, Immunophenotyping, Interferon Type II/blood, Interleukin-10/blood, Interleukin-12/*administration & dosage, Interleukin-6/blood, Interleukin-8/blood, Killer Cells, Natural/metabolism, Middle aged, Recombinant Proteins/pharmacology, Time Factors, Tumor Necrosis Factor-alpha/biosynthesis
Clinical Cancer Research
Erasmus MC: University Medical Center Rotterdam

Portielje, J.E, Lamers, C.H.J, Kruit, W.H.J, Sparreboom, A, Bolhuis, R.L.H, Stoter, G, … Gratama, J.W. (2003). Repeated administrations of interleukin (IL)-12 are associated with persistently elevated plasma levels of IL-10 and declining IFN-gamma, tumor necrosis factor-alpha, IL-6, and IL-8 responses. Clinical Cancer Research. Retrieved from http://hdl.handle.net/1765/10059