title: Baseline circulating IL-17 predicts toxicity while TGF-β1 and IL-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma.
abstract: BACKGROUND
  We evaluated candidate circulating serum cytokines, chemokines and growth factors in patients with locally/regionally advanced melanoma receiving neoadjuvant ipilimumab with toxicity and clinical outcome.
  
  
  METHODS
  Patients were treated with ipilimumab (10 mg/kg IV every 3 weeks, 2 doses) before and after surgery. xMAP multiplex serum testing for 36 functionally selected cytokines and chemokines was performed at baseline and at six weeks (following ipilimumab). Based on our prior data, the association of IL-17 and immune related colitis was tested. Serum cytokines were divided into functional groups (Th1, Th2, Regulatory, Proinflammatory) and were assessed at baseline and week 6 using sparse-group Lasso modeling to assess the association of various cytokine groups with progression free survival (PFS). The linear combination of the cytokines/chemokines in this model was then used as a risk score and a Kaplan-Meier curve was generated to examine the association of the dichotomized score and PFS.
  
  
  RESULTS
  Thirty-five patients were enrolled whose staging was: IIIB (3; N2b), IIIC (30; N2c, N3), IV (2). Median follow-up was 18 months. Among 33 evaluable patients, median PFS was 11 months (95 % CI = 6.2-19.2). IL-17 was found to correlate significantly with the incidence of grade 3 diarrhea/colitis when measured at baseline (p = 0.02) with a trend towards significance at 6 weeks (p = 0.06). In the modeling analysis, at baseline, the linear combination of 2 regulatory cytokines [TGF- β1 (ρ = 0.19) and IL-10 (ρ = -0.34)] was significantly associated with PFS (HR 2.66; p = 0.035). No significant correlations with clinical outcomes were found in examining the week 6 cytokines.
  
  
  CONCLUSIONS
  Baseline IL-17 level was significantly associated with the later development of severe diarrhea/colitis while the combination of baseline TGF- β1 and IL-10 levels were associated with therapeutic clinical outcome after neoadjuvant ipilimumab. These findings warrant further investigation and validation.
  
  
  BACKGROUND
  ClinicalTrials.gov Identifier NCT00972933.
authors.affiliation: University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, 5150 Centre Avenue (555), Pittsburgh, PA 15232 USA.
authors.forename: Ahmad A
authors.initials: AA
authors.lastname: Tarhini
authors.affiliation: University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, 5150 Centre Avenue (555), Pittsburgh, PA 15232 USA.
authors.forename: Haris
authors.initials: H
authors.lastname: Zahoor
authors.affiliation: University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, 5150 Centre Avenue (555), Pittsburgh, PA 15232 USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, 5150 Centre Avenue (555), Pittsburgh, PA 15232 USA.
authors.forename: Usha
authors.initials: U
authors.lastname: Malhotra
authors.affiliation: University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, 5150 Centre Avenue (555), Pittsburgh, PA 15232 USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Sander
authors.affiliation: University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, 5150 Centre Avenue (555), Pittsburgh, PA 15232 USA.
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Butterfield
authors.affiliation: University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, 5150 Centre Avenue (555), Pittsburgh, PA 15232 USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
keywords: CTLA4; Cytokines; Ipilimumab; Melanoma; Neoadjuvant