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01-06-2009 | Original Article

Immune activation in advanced cancer patients treated with recombinant IL-21: multianalyte profiling of serum proteins

Authors: Michael G. Dodds, Klaus Stensgaard Frederiksen, Kresten Skak, Lasse Tengbjerg Hansen, Dorthe Lundsgaard, John A. Thompson, Steven D. Hughes

Published in: Cancer Immunology, Immunotherapy | Issue 6/2009

Abstract

Purpose

Recombinant interleukin-21 (rIL-21) is an immune stimulating cytokine recently tested in two Phase 1 trials for immune responsive cancers. A secondary objective of these trials was to characterize pharmacodynamic responses to rIL-21 in patients. Here, we report the effects of systemic rIL-21 on serum markers of immune stimulation.

Experimental design

Recombinant IL-21 was administered by intravenous bolus injection at dose levels from 1 to 100 μg/kg using two distinct treatment regimens: thrice weekly (‘3/w’) for 6 weeks; or once daily for five consecutive days followed by nine dose-free days (‘5 + 9’). In the absence of dose limiting toxicity, additional cycles of dosing were initiated immediately following the nine dose-free days. An array of 70 different proteins was profiled in subject serum samples from several time points during the course of the study. Hierarchical clustering analysis was performed on a normalized subset of these data.

Results

Systemic administration of rIL-21 affected the serum levels of several cytokines, chemokines, acute-phase proteins and cell adhesion proteins. The magnitude and duration of response were dose dependent for a subset of these biomarkers. The 5 + 9 dosing regimen generally produced cyclic changes that were of greater magnitude, as compared to a more chronic stimulation with the 3/w dosing regimen. Despite these differences, rIL-21 effects on many analytes were similar between regimens when averaged over the time of treatment. Based on similar temporal, between-subject and dose response changes, groups of analytes were identified that exhibited distinct components of the rIL-21-mediated immune activation. Biomarkers indicative of lymphocyte activation (increased IL-16, decreased RANTES), acute phase response (increased CRP, ferritin), myeloid activation (increased MDC, MIP-1 alpha), and leukocyte chemotaxis/trafficking (increased sCAMs, MCP-1) were strongly modulated in subjects treated with rIL-21.

Conclusions

Administration of rIL-21 resulted in activation of multiple cell types and immune response pathways. The changes observed in serum proteins were consistent with coincident processes of lymphoid and myeloid cell activation and trafficking, and acute phase response.

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Title: Immune activation in advanced cancer patients treated with recombinant IL-21: multianalyte profiling of serum proteins
Authors: Michael G. Dodds
Klaus Stensgaard Frederiksen
Kresten Skak
Lasse Tengbjerg Hansen
Dorthe Lundsgaard
John A. Thompson
Steven D. Hughes
Publication date: 01-06-2009
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 6/2009
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-008-0600-8

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Abstract

Purpose

Experimental design

Results

Conclusions

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