Theresa L. Whiteside

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 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.

Cytotoxic Mechanisms of Natural Killer Cells

Publisher Summary This chapter focuses on the two cytotoxic mechanisms in natural killer (NK) cells: secretory/necrotic and nonsecretory/apoptotic killing. NK cells are cytotoxic effector cells of the immune system that have spontaneous ability to selectively kill virus-infected and tumor cells without damaging normal cells. The secretory/necrotic pathway model of killing is based on the hypothesis that NK cells, interacting with susceptible targets, are triggered via specific receptors to actively release cytolytic granules and molecules capable of damaging the target cell membrane. The nonsecretory/apoptotic pathway can kill a large variety of solid tissue-derived tumor cell targets. These pathways are mediated via ligand/receptor initiating signal transduction in either effector or target cells. The novel pathway is mediated by the tumor necrosis factor (TNF) family ligands and is highly promiscuous, which may be potentially important in immune surveillance, antimetastatic/antitumor functions, and immunoregulation.