PT  - JOURNAL ARTICLE
AU  - Portielje, Johanna E. A.
AU  - Lamers, Cor H. J.
AU  - Kruit, Wim H. J.
AU  - Sparreboom, Alex
AU  - Bolhuis, Reinder L. H.
AU  - Stoter, Gerrit
AU  - Huber, Christoph
AU  - Gratama, Jan W.
TI  - Repeated Administrations of Interleukin (IL)-12 Are Associated with Persistently Elevated Plasma Levels of IL-10 and Declining IFN-γ, Tumor Necrosis Factor-α, IL-6, and IL-8 Responses
DP  - 2003 Jan 01
TA  - Clinical Cancer Research
PG  - 76--83
VI  - 9
IP  - 1
4099  - http://clincancerres.aacrjournals.org/content/9/1/76.short
4100  - http://clincancerres.aacrjournals.org/content/9/1/76.full
SO  - Clin Cancer Res2003 Jan 01; 9
AB  - 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-γ, 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-γ, tumor necrosis factor-α, 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-γ, tumor necrosis factor-α, 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.