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


METHODS
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 x 10(6) 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 IFNgamma, 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.
Cragun
William Chad
WC
School of Medicine, University of Virginia Health System, Charlottesville, VA, USA.
Yamshchikov
Galina V
GV
Bissonette
Eric A
EA
Smolkin
Mark E
ME
Eastham
Shannon
S
Petroni
Gina R
GR
Schrecengost
Randy S
RS
Woodson
Elizabeth M H
EM
Slingluff
Craig L
CL
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D016207:Cytokines / Q000097:blood*; D004802:Eosinophilia / Q000209:etiology*; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000627:therapeutic use*; D015848:Interleukin-5 / Q000097:blood; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D008875:Middle Aged; D008969:Molecular Sequence Data; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
D016207:Cytokines; D007376:Interleukin-2; D015848:Interleukin-5