IMMUNOMODULATORY FUNCTION OF INTERFERON-GAMMA IN PATIENTS WITH METASTATIC MELANOMA - RESULTS OF A PHASE II-B TRIAL IN SUBJECTS WITH METASTATIC MELANOMA, ECOG STUDY E-4987

Interferon-gamma (IFN-gamma) has the most potent immunomodulatory acti vity of all the interferons. This phase II-B study was performed to de fine time- and dose-dependent immunomodulatory effects mediated by IFN -gamma in a subset of patients with melanoma treated in the dose-seeki ng therapeutic trial conducted by the Eastern Cooperative Oncology Gro up E4687 (13). The effects of IFN-gamma (Genentech, San Francisco, CA) were evaluated for phenotype and function of peripheral blood lymphoc ytes obtained twice prestudy, and on days 2, 9, and 29 of IFN-gamma th erapy for 50 patients. Early significant increases in CD4/CD8 ratio (p = 0.001) were noted, largely due to a rise in CD4(+) and fall in CD8( +) T-cell populations sustained through day 29 at only the lowest dosa ge. Increased natural killer cell (NK) activity (p = 0.001 on day 9; p = 0.01 on day 29) was accompanied by durable increases in circulating activated NK cells (CD56(+)DR(+)% p = 0.001, day 9; p = 0.001, day 29 ). After initial depression of CD56(+) and CD16(+) cells on day 2, the total percent of CD56(+) and CD16(+) cells increased significantly by day 29. Increases in NK cell activity were maximal at doses greater t han or equal to 0.1 mg. Monocyte CD14(+) expression of DQ(+) rose earl y (p = 0.011 and 0.001 on days 2 and 9), accompanied by elevation in C D14(+)DR(+) cells that was less significant. Immunomodulatory effects of IFN-gamma reported in this trial have major implications for interp retation of past and current clinical trials, and the design of future trials. This is the first trial in which IFN-gamma has been shown to have significant effects on the T-cell compartment of the immune syste m.