title: Immunomodulatory effects of high-dose and low-dose interferon alpha2b in patients with high-risk resected melanoma: the E2690 laboratory corollary of intergroup adjuvant trial E1690.
abstract: BACKGROUND
  The clinical antitumor activity of recombinant interferon alpha2b (IFNalpha2b) has been well documented in patients with advanced and high-risk melanoma; however, its mechanism of action remains conjectural. Trial E2690 evaluated the immunomodulatory effects of IFNalpha2b in vivo during treatment at high doses (the HDI arm; n = 51 patients) and at low doses (the LDI arm; n = 54 patients) in relation to standard observation (OBS; n = 43 patients).
  
  
  METHODS
  This study evaluated peripheral blood lymphocytes (PBLs) for phenotypic markers and cytotoxic functions at 1 month, 3 months, and 12 months in the HDI arm, the LDI arm, and the OBS arm and examined correlations between changes observed in PBLs or in tumors with regard to treatment dosage and disease outcome. Tumor biopsy samples were studied for response to IFNalpha2b at a range of concentrations in vitro.
  
  
  RESULTS
  Baseline blood phenotypic and functional assays did not predict disease outcome; however, modulation of these immunologic assays by IFNalpha2b treatment was observed and was associated with IFNalpha2b dosage. Tumor cell class II major histocompatibility antigen expression (human leukocyte/lymphocyte antigen DR) and adhesion molecule expression (ICAM-1) were modulated by exposure to IFNalpha2b in a dose dependent manner. Blood natural killer (NK) cell function, T-cell function, and subset distribution were modulated early by patients in the HDI arm and later by patients in the LDI arm. None of the variables tested in these studies predicted recurrence free survival. The numbers of patients studied were smaller than may be needed to detect potentially clinically significant changes.
  
  
  CONCLUSIONS
  These data demonstrate changes in immunologic parameters associated with IFNalpha2b treatment and dosage that may account for some of the differences in the clinical efficacy of this modality. The current results also suggest the need for further study of newer molecular intermediates of IFNalpha2b and T-cell response to specific antigens of melanoma.
authors.affiliation: Department of Medicine, University of Pittsburgh, Pennsylvania, USA. jmk@jimmy.harvard.edu
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: Thomas
authors.initials: T
authors.lastname: Richards
authors.forename: Hassane M
authors.initials: HM
authors.lastname: Zarour
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Sosman
authors.forename: Marc
authors.initials: M
authors.lastname: Ernstoff
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Whiteside
authors.forename: Joseph
authors.initials: J
authors.lastname: Ibrahim
authors.forename: Ronald
authors.initials: R
authors.lastname: Blum
authors.forename: Samuel
authors.initials: S
authors.lastname: Wieand
authors.forename: Ruth
authors.initials: R
authors.lastname: Mascari
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D017024:Chemotherapy, Adjuvant; D005260:Female; D006680:HLA Antigens / Q000032:analysis* / Q000096:biosynthesis; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis* / Q000096:biosynthesis; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000502:physiology; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000601:surgery; D008875:Middle Aged; D010641:Phenotype; D011237:Predictive Value of Tests; D011994:Recombinant Proteins; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000601:surgery; D013601:T-Lymphocytes / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D006680:HLA Antigens; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D018799:Intercellular Adhesion Molecule-1