This study shows that subcutaneous administration of increasing doses of IL‐12, once a week, in 21 cancer patients increased the expression of cytokine genes (interferon‐gamma (IFN‐γ), tumour necrosis factor‐alpha (TNF‐α), IP‐10, MIG, IL‐10, IL‐4) in peripheral blood mononuclear cells even at very low doses (30 ng/kg). Surprisingly, no circulating TNF‐α or IL‐4 could be detected in the plasma of patients treated with IL‐12. However, a marked increase of soluble IL‐4 receptor was demonstrated in the plasma of five of the six patients studied, which may represent an additional mechanism by which IL‐12 inhibits the development of the Th2 response in vivo. A marked decline of IFN‐γ and IP10 induction was recorded after repeated cycles of IL‐12. In contrast, in most patients IL‐12 increased IL‐10 expression with no subsequent decrease during the course of therapy, and even an earlier peak of IL‐10 induction at the 6th cycle. In addition, a constant up‐regulation of serum soluble IFN‐γ receptor levels was observed after each cycle of IL‐12 treatment with a delayed peak compared with the IFN‐γ peak. The constant rise of IL‐10 and soluble IFN‐γ receptor during IL‐12 therapy may therefore contribute to the inhibition of IFN‐γ activity detected after repeated cycles of IL‐12. Lastly, a marked heterogeneity of cytokine induction was observed from one patient to another, which appeared to be independent of the dose of IL‐12 administered. These data may lead to a better understanding of the biological activity of IL‐12 and the in vivo mechanisms of its regulation.

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