BIOLOGIC RESPONSE MODULATION BY TUMOR-NECROSIS-FACTOR-ALPHA (TNF-ALPHA) IN A PHASE IB TRIAL IN CANCER-PATIENTS

During a phase I study of recombinant human tumor necrosis factor (TNF ) in cancer patients, serial immune studies were performed and analyze d for effects of TNF. The TNF (specific activity 9.6 x 10(6) U/mg prot ein, <5.0 endotoxin units/mg protein) was given over 2 h intravenously on days 1, 8-12, 29-33, 50-54. and 71-75 at doses of 40, 80, 160, 200 , and 230 mu g/m(2). Immunologic testing was performed before therapy three times and subsequently on days 2, 8, 10, 12, 29, 33, 50, 54, 71, 75, and off-study two times. Immune parameters evaluated included cyt otoxicity [natural killer (NK), spontaneous lymphokine activated kille r cells (LAK), LAK, and monocyte], cytokine production [spontaneous an d stimulated interferon (IFN)-gamma and interleukin (IL)-2], superoxid e production [resting and stimulated polymorphonuclear leukocytes (PMN ) and mononuclear cells (MNC)], and phenotype of peripheral blood lymp hocyte subsets (CD3, CD4, CD8, CD16, CD56, CD19). Data were analyzed f or long-term effects, the effect after 1 day of treatment (day 1), and for weekly effect (change from day 1 to day 5 of a given treatment we ek). Significant decreases were seen in the spontaneous cytotoxicity o f peripheral blood NK cells and IL-2-inducible LAK cells, whereas incr eases in spontaneous peripheral blood LAK activity were seen with TNF treatment. Consistent increases in superoxide production of resting PM N and MNC were demonstrated, with late increases in superoxide product ion by opsonized, zymosan-treated PMN. No spontaneous IFN-gamma or IL- 2 were noted in sera with treatment, but production of IL-2 by MNCs ro se with TNF treatment. During 5 days of TNF treatment, the percentages of circulating CD8(+) and CD56(+) cells decreased, whereas that of CD 4(-) and CD19(+) cells increased significantly and consistently, as de termined by a multivariate analysis. Significant changes in several in dependently measured parameters were observed, including a dose-relate d diminished production of IFN-gamma by MNC stimulated by phytohemaggl utinin and increased in vitro-generated LAK activity. Because there wa s no clinical response in this trial, no association of immunologic ch ange with clinical response can be made. No biologically optimal dose of TNF was evident. The data suggest that TNF may act as a trigger cyt okine, initiating a broad immune/inflammatory response.