title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Medical Oncology, Erasmus MC - Daniel den Hoed, 3075 EA Rotterdam, the Netherlands.
authors.forename: Johanna E A
authors.initials: JE
authors.lastname: Portielje
authors.forename: Cor H J
authors.initials: CH
authors.lastname: Lamers
authors.forename: Wim H J
authors.initials: WH
authors.lastname: Kruit
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
authors.forename: Reinder L H
authors.initials: RL
authors.lastname: Bolhuis
authors.forename: Gerrit
authors.initials: G
authors.lastname: Stoter
authors.forename: Christoph
authors.initials: C
authors.lastname: Huber
authors.forename: Jan W
authors.initials: JW
authors.lastname: Gratama
mesh_terms: D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy*; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D018664:Interleukin-12 / Q000008:administration & dosage*; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D007694:Killer Cells, Natural / Q000378:metabolism; D008875:Middle Aged; D011994:Recombinant Proteins / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D016209:Interleukin-8; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma