Autoantibodies as potential biomarkers of immune-related adverse events in patients with advanced cutaneous melanoma treated with immune checkpoint inhibitors.

9536 Background: The majority of patients treated with immune checkpoint inhibitors (ICIs) develop immune-related adverse events (irAE). It is currently not possible to predict the development of irAEs using biomarkers. Here we evaluated the IgG autoantibodies (AAbs) profile in pre-treatment sera of cutaneous metastatic melanoma patients treated with ICIs to identify AAbs that are associated with irAEs. Methods: Clinical data of patients with metastatic melanoma treated with pembrolizumab or nivolumab monotherapy (n = 48) or combination ipilimumab and nivolumab (n = 37) was retrospectively evaluated. irAEs were graded using CTCAE v5.0. Sera from the 85 patients were evaluated for IgG AAbs using the HuProt™ microarray v4.0 covering 23,059 proteins ( > 81% of the human proteome). AAb profiles were compared between groups (any irAEs vs no irAEs), using the no irAEs group as control group. Results were inputted into the Advaita Bio’s iPathwayGuide software to find significantly differentially expressed AAbs using p < 0.05 and Log2FC > 0.6, and identify relevant biological pathways. Results: Out of 85 patients, 60 experienced any grade irAEs, 29 of 48 (60.4%) in the PD-1 group and 31 of 37 (83.8%) in the combination group. We found 758 proteins were differentially elevated, 102 in the in the PD-1 group and 666 in the combination treatment group. A comparison of these groups identified 10 AAbs that were elevated in patients experiencing irAEs independent of ICI regimen. These targeted proteins are highly expressed in tissues that are commonly affected by irAEs. Previous studies have shown their links to autoimmune and inflammatory conditions such as dermatitis and thyroiditis. Pathway analysis shows the RIG like receptor signalling pathway, which has been associated with autoinflammatory conditions, was significantly affected in the PD-1 group (p = 0.011), but not in the combination group (p = 0.442). Other pathways involved included the NOD-like receptor, purine and D-amino acid metabolism which play a role in innate immune system and assembly of inflammasomes and maturation, pro-inflammatory cytokines and mediators that contribute to inflammatory response. Conclusions: Further analyses are being conducted to identify the correlation of irAE type and severity to specific autoantibodies which will be presented. Prospective studies are required for validation of these AAbs specificities. This approach could be used to identify patients at high risk of irAEs, for treatment monitoring to maintain an effective stimulation of the patient’s anti-cancer immune response, to determine if treatment cessation is required and prevent hospitalisation or lengthy immunosuppression to treat irAEs.