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IL-21 induces in vivo immune activation of NK cells and CD8 T cells in patients with metastatic melanoma and renal cell carcinoma

Cancer Immunology, Immunotherapy, ISSN: 0340-7004, Vol: 57, Issue: 10, Page: 1439-1449
2008
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Article Description

Purpose: Human interleukin-21 (IL-21) is a class I cytokine previously reported in clinical studies on immune responsive cancers. Here we report the effects of systemic IL-21 therapy on the immune system in two phase 1 trials with this novel cytokine. Experimental design: Recombinant IL-21 was administered by intravenous bolus injection at dose levels from 1 to 100 μg/kg using two planned treatment regimens: thrice weekly for 6 weeks (3/week); or once daily for five consecutive days followed by nine dose-free days (5 + 9). The following biomarkers were studied in peripheral blood mononuclear cells (PBMC) during treatment: phosphorylation of STAT3, alterations in the composition of leukocyte subsets, ex vivo cytotoxicity, expression of effector molecules in enriched CD8 T cells and CD56 NK cells by quantitative RT-PCR, and gene array profiling of CD8 T cells. Results: Effects of IL-21 were observed at all dose levels. In the 5 + 9 regimen IL-21 induced a dose dependent decrease in circulating NK cells and T cells followed by a return to baseline in resting periods. In both CD8 T cells and CD56 NK cells we found up-regulation of perforin and granzyme B mRNA. In addition, full transcriptome analysis of CD8 T cells displayed changes in several transcripts associated with increased cell cycle progression, cellular motility, and immune activation. Finally, cytotoxicity assays showed that IL-21 enhanced the ability of NK cells to kill sensitive targets ex vivo. Conclusions: IL-21 was biologically active at all dose levels administered with evidence of in vivo NK cell and CD8 T cell activation. © 2008 The Author(s).

Bibliographic Details

Frederiksen, Klaus Stensgaard; Lundsgaard, Dorthe; Freeman, Jeremy A; Hughes, Steven D; Holm, Thomas L; Skrumsager, Birte K; Petri, Andreas; Hansen, Lasse T; McArthur, Grant A; Davis, Ian D; Skak, Kresten

Springer Science and Business Media LLC

Medicine; Immunology and Microbiology; Biochemistry, Genetics and Molecular Biology

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