Rapid Cytokine Release in Cancer Patients Treated with Interleukin-2

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Summary:Serum concentrations of interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-α ), interferon-gamma (IFN-γ), interleukin-6 (IL-6), interleukin-1 (IL-1) and interferon-alpha (IFN-α) were determined by commercially available enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA) in cancer patients treated with recombinant IL-2 (rIL-2) either as 1-h infusion (3 or 5 x 106/m2) or continuous intravenous infusion for 5 days (3 x 106/m2/day). A significant increase of TNF-α and IL-6 serum levels was observed in each patient. One-hour infusion of IL-2 induced a very rapid secretion of TNF-α, IL-6 and IFN-γ with considerably higher peak levels than during IL-2 continuous intravenous infusion. IFN-γ was released into the blood of all patients receiving IL-2 1-h infusion, but only occasionally during or after IL-2 continuous intravenous infusion. Neither IFN-α nor IL-1 were detectable in the serum before, during, or following IL-2 treatment in all patients studied. The kinetics of IL-2 after 1-h infusion fitted to a two-compartment model, suggesting the synthesis of considerable amounts of endogenous IL-2. Following IL-2 1-h infusion, rising TNF-α serum levels preceded the increase of serum IFN-γ or IL-6. The serum peak levels of IFN-γ and IL-6 decreased rapidly with a half-life of 0.29 to 2.5 h. The concentration time profiles of TNF following 1-h infusion of IL-2 demonstrated a considerably longer half-life than that of intravenously administered recombinant TNF as done in other studies. The prolonged TNF-α synthesis seems to be the result of sustained activation of TNF-α producing cells by IL-2 and/or the endogenously released IFN-γ. An attempt was made to estimate the total amount of TNF-α released into the intravascular space. The calculated total amount of TNF-α (median 37 µg, range 18-119 µg) released in patients in the present study was close to the dosages of TNF-α administered in previously described phase I studies for therapeutic purposes in cancer patients.

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