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. Eastern Cooperative Oncology Group.
Interferon-gamma (IFN-gamma) has the most potent immunomodulatory activity of all the interferons. This phase II-B study was performed to define time- and dose-dependent immunomodulatory effects mediated by IFN-gamma in a subset of patients with melanoma treated in the dose-seeking therapeutic trial conducted by the Eastern Cooperative Oncology Group E4687 (13). The effects of IFN-gamma (Genentech, San Francisco, CA) were evaluated for phenotype and function of peripheral blood lymphocytes obtained twice prestudy, and on days 2, 9, and 29 of IFN-gamma therapy 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 dosage. 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 > or =0.1 mg. Monocyte CD14+ expression of DQ+ rose early (p = 0.011 and 0.001 on days 2 and 9), accompanied by elevation in CD14+DR+ cells that was less significant. Immunomodulatory effects of IFN-gamma reported in this trial have major implications for interpretation 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 system.
Kirkwood
J M
JM
Division of Medical Oncology, University of Pittsburgh and Pittsburgh Cancer Institute, Pennsylvania, 15213-2582, U.S.A.
Bryant
J
J
Schiller
J H
JH
Oken
M M
MM
Borden
E C
EC
Whiteside
T L
TL
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007371:Interferon-gamma / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000187:drug effects*; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary; D009000:Monocytes / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects*
D000276:Adjuvants, Immunologic; D007371:Interferon-gamma