Evaluation of serum IL-17 levels during ipilimumab therapy: Correlation with colitis.

2505 Background: Ipilimumab is the first agent to demonstrate a survival benefit in patients with metastatic melanoma in a randomized phase III clinical trial. Immune-related adverse events (irAEs) are the most common side effects associated with ipilimumab. Grade III/IV irAEs occur in approximately 10-15% of patients, and colitis is the most common irAE within this group. Ipilimumab-associated colitis has been managed effectively with immunosuppressive medications in clinical trials. IL-17 is an important mediator of autoimmunity and inflammation that has been implicated in colitis. We evaluated serum IL-17 levels in patients treated with ipilimumab, comparing patients who developed colitis to those without irAEs. Methods: Patients with metastatic melanoma received 10 mg/kg of ipilimumab on an expanded access protocol (EAP) (CA184-045). We obtained serum samples from 52 serially accrued EAP patients. Samples were collected pre-treatment and at appointed intervals during treatment. The serum concentration of IL-17 at each time point was quantitated using the Meso Scale Discovery system. Patients were classified into three groups based upon clinical symptoms: (1) colitis, (2) no irAE, or (3) non-colitis irAE. Results: Pairwise comparison of serum IL-17 levels in patients with colitis (n=13) versus no irAEs (n=16) demonstrated significantly higher serum IL-17 levels in patients with colitis at week 7 (p=0.007) and week 12 (p=0.02). In individual patients, development and resolution of colitis symptoms temporally correlated with increases and decreases in serum IL-17, respectively. Upon resolution of clinical symptoms, IL-17 levels in patients with colitis decreased to levels comparable to patients without colitis. Pre-treatment IL-17 levels were not significantly different between patients with or without colitis or between patients and healthy donor controls. This pattern was unique when compared with several additional cytokines tested. Conclusions: We report that the development and resolution of colitis is significantly associated with fluctuations in serum IL-17 in this subset of ipilimumab-treated patients, reinforcing the immune-based mechanism of the most common ipilimumab side effect.