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


METHODS
Recombinant IL-21 was administered by intravenous bolus injection at dose levels from 1 to 100 microg/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.
Frederiksen
Klaus Stensgaard
KS
Novo Nordisk A/S, Novo Nordisk Park, Maalov, Denmark.
Lundsgaard
Dorthe
D
Freeman
Jeremy A
JA
Hughes
Steven D
SD
Holm
Thomas L
TL
Skrumsager
Birte K
BK
Petri
Andreas
A
Hansen
Lasse T
LT
McArthur
Grant A
GA
Davis
Ian D
ID
Skak
Kresten
K
D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007378:Interleukins / Q000008:administration & dosage* / Q000009:adverse effects; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000008:administration & dosage; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D000098546:Interleukin-21
D007378:Interleukins; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000098546:Interleukin-21