Baseline circulating IL-17 predicts toxicity while TGF-β1 and IL-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma

Abstract

BackgroundWe evaluated candidate circulating serum cytokines, chemokines and growth factors in patients with locally/regionally advanced melanoma receiving neoadjuvant ipilimumab with toxicity and clinical outcome.MethodsPatients 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.ResultsThirty-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.ConclusionsBaseline 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.Trial registrationClinicalTrials.gov Identifier NCT00972933.

Future perspectives in melanoma research

“…Biomarker and mechanistic data nested within this study have supported the immunotherapeutic predictive value of the proinflammatory tumor microenvironment as measured by mRNA expression and CD8 T cell density at the tumor invasive margin [88]. Other studies have supported a role for the TH17 pathway in mediating immune related colitis after treatment with ipilimumab [89]. Ongoing studies are testing the neoadjuvant therapeutic value ipilimumab in combination with IFNα (NCT01608594), pembrolizumab in combination with IFNα (NCT02339324) and the combination of ipilimumab-nivolumab as compared to nivolumab alone (NCT02736123).…”

Enterocolitis due to immune checkpoint inhibitors: a systematic review

“…In contrast, there was little association with Anti-Saccharomyces Cerevisiae Antibody, anti-CBir1 or anti-I2 antibodies 17. Higher baseline serum interleukin (IL)-17 levels have also been shown to correlate significantly with the incidence of grade 3 diarrhoea and colitis (p=0.02) 18. In addition, increasing eosinophil blood count during treatment with ipilimumab was associated with increasing rate of irAE 19.…”

IL‐17 and its role in inflammatory, autoimmune, and oncological skin diseases: state of art

“…In patients with advanced inoperable melanoma, a better understanding of the regulation of cytokine and cellular immune activity in response to melanoma may be important in order to predict therapeutic response to immunotherapy, including treatment with ipilimumab. A recent study showed that in patients with regionally advanced melanoma enrolled in a trial of neoadjuvant therapy with ipilimumab at 10 mg/kg, baseline IL‐17 level was significantly associated with the risk of subsequent development of severe immune‐mediated diarrhea/colitis . Further investigation and confirmation in larger trials is necessary in order to confirm these findings.…”