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- Title
IL-21 induces in vivo immune activation of NK cells and CD8<sup>+</sup> T cells in patients with metastatic melanoma and renal cell carcinoma.
- Authors
Frederiksen, Klaus; 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
- Abstract
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. 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. 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. IL-21 was biologically active at all dose levels administered with evidence of in vivo NK cell and CD8+ T cell activation.
- Subjects
IMMUNE system; IMMUNOTHERAPY; MELANOMA treatment; RENAL cell carcinoma; CANCER treatment; INTERLEUKINS; T cells; BIOMARKERS; THERAPEUTICS
- Publication
Cancer Immunology, Immunotherapy, 2008, Vol 57, Issue 10, p1439
- ISSN
0340-7004
- Publication type
Article
- DOI
10.1007/s00262-008-0479-4