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Low-dose IL-2 induces cytokine cascade, eosinophilia, and a transient Th2 shift in melanoma patients

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Abstract

Purpose: To assess changes in serum cytokine levels in patients treated concomitantly with or without systemic low-dose IL-2. Vaccination targeted CTL responses to peptide antigens, and IL-2 was coadministered to expand activated CTL. Paradoxically, CTL responses were diminished in patients after 2 weeks of IL-2. We hypothesized that changes in the cytokine milieu may have contributed to this result. Experimental design: Serum samples were studied from 37 patients enrolled in two clinical trials of a melanoma peptide vaccine administered with or without low-dose IL-2 therapy. Twenty-two patients enrolled in the MEL36 trial received six weekly vaccinations with the four-peptide mixture and were randomized to receive subcutaneous IL-2 (3×106 IU/m2/day) daily for 6 weeks beginning either at week 1 (upfront group) or at week 4 (delayed group) of vaccine therapy. Fifteen patients on the MEL39 trial were treated with the same vaccine without concurrent IL-2 administration. Results: Circulating levels of IL-5 peaked 1 week after starting IL-2, followed 2 weeks later by a marked eosinophilia, correlating in magnitude with peak IL-5 serum levels. Levels of IFNγ, GM-CSF, IL-4, IL-10, and IL-12 had no observed relationship to IL-2 administration. At the time of the IL-5 serum peak, PBL responses to mitogen suggested a transient shift to Th2-dominance. Conclusions: Low-dose IL-2 appears to have induced a transient Th2-dominant secondary cytokine cascade at the time of vaccination, for which eosinophilia is a surrogate marker. For future vaccine therapies targeting cytotoxic T-cell responses, delaying IL-2 until after initiation of immune responses may be more effective.

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Acknowledgements

We thank Melanie Mayer for her assistance with the manuscript preparation and submission. This research was supported in part by NIH/NCI grant R01 CA57653 (to CLS), by Chiron Corporation, by an American Cancer Society Virginia Summer Student Fellowship Grant (to WCC), the University of Virginia Cancer Center Support Grant (NIH/NCI P30 CA44579, Clinical Trials Office, Tissue Procurement Facility, Biomolecular Core Facility); the UVA General Clinical Research Center (NIH M01 RR00847); and the Pratt Fund at the University of Virginia. Cancer Research Institute supported infrastructure of the UVA Human Immune Therapy Center.

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Authors and Affiliations

  1. School of Medicine, University of Virginia Health System, Charlottesville, VA, USA

    William Chad Cragun

  2. Department of Surgery/Division of Surgical Oncology, University of Virginia Health System, Charlottesville, VA, USA

    Galina V. Yamshchikov, Shannon Eastham, Randy S. Schrecengost, Elizabeth M. H. Woodson & Craig L. Slingluff Jr

  3. Department of Health Evaluation Sciences, University of Virginia Health System, Charlottesville, VA, USA

    Eric A. Bissonette, Mark E. Smolkin & Gina R. Petroni

  4. Human Immune Therapy Center, University of Virginia Health System, Box 801457, Charlottesville, VA, 22908, USA

    Craig L. Slingluff Jr

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  1. William Chad Cragun
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  2. Galina V. Yamshchikov
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Correspondence to Craig L. Slingluff Jr.

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William Chad Cragun and Galina V. Yamshchikov contributed equally to this paper.

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Cragun, W.C., Yamshchikov, G.V., Bissonette, E.A. et al. Low-dose IL-2 induces cytokine cascade, eosinophilia, and a transient Th2 shift in melanoma patients. Cancer Immunol Immunother 54, 1095–1105 (2005). https://doi.org/10.1007/s00262-005-0701-6

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