Production of tumor necrosis factor α and interferon γ in interleukin-2-treated melanoma patients: Correlation with clinical toxicity

Interleukin-2 (IL-2)-based immunotherapy regimens are accompanied by dose-limiting toxicity consisting of fever, tachycardia, chills and capillary leak syndrome. We hypothesized that the toxicity was caused by the induction and release of endogenous cytokines such as tumor necrosis factor α (TNFα) and interferon γ (IFNγ). We measured the serum levels of TNFα and IFNγ in IL-2-treated melanoma patients and attempted a correlation with clinical toxicity. A total of 23 patients received either 6 × 10⁶ IU or 12 × 10⁶ IU Cetus IL-2/m² by i. v. bolus daily for 5 consecutive days on weeks 1, 3 and 5. Serum TNFα and IFNγ levels were measured by enzyme-linked immunosorbent assay. Clinical toxicity was scored each day by objective measurements of hypotension, tachycardia, fever and chills/rigors. Clinical toxicity and IFNγ levels correlated nicely, peaking on the 5th day of each treatment cycle. The kinetics and magnitude of TNFα production, however, were not predictable and did not correlate with either IFNγ or toxicity. Some patients had modest increases in TNFα production while others had markedly increased levels during the second and third treatment weeks. Remarkably, these high levels persisted during nontreatment weeks and after completion of therapy. This clinical study demonstrates novel kinetics for immunoreactive TNFα in IL-2 cancer patients, which do not correlate well with toxicity.