Sex and interleukin-6 are prognostic factors for autoimmune toxicity following treatment with anti-CTLA4 blockade

Background: Ipilimumab is a licensed immunotherapy for metastatic melanoma patients and, in the US, as adjuvant treatment for high risk melanoma radically resected. The use of ipilimumab is associated with a typical but unpredictable pattern of side effects. The purpose of this study was to identify clinical features and blood biomarkers capable of predicting ipilimumab related toxicity. Methods: We performed a prospective study aimed at analyzing potential clinical and biological markers associated with immune-related toxicity in patients treated with ipilimumab (3 mg/kg, q3w). We enrolled 140 consecutive melanoma patients treated with ipilimumab for metastatic disease. The following prospectively collected data were utilized: patient characteristics, previous therapies, level of circulating biomarkers associated with tumour burden or immune-inflammation status (lactic dehydrogenase, C-reactive protein, beta 2-microglobulin, vascular endothelial growth factor, interleukin-2, interleukin-6, S-100, alkaline phosphatase, transaminases) and blood cells subsets (leukocyte and lymphocyte subpopulations). Logistic regression was used for multivariate analysis of data. Results: Out of 140 patients, 36 (26%) experienced a severe adverse event, 33 (24%) discontinued treatment for severe toxicity. Among the immune-profile biomarkers analyzed, only interleukin-6 was associated with the risk of toxicity. Female patients had a further increase of immune-related adverse events. Low baseline interleukin-6 serum levels (OR = 2.84, 95% CI 1.34-6.03, P = 0.007) and sex female (OR = 1.5, 95% CI 1.06-2.16 P = 0.022) and were significant and independent risk factors for immune related adverse events. Conclusions: Baseline IL6 serum levels and female sex were significantly and independently associated with higher risk of severe toxicity and could be exploited in clinical practice to personalize toxicity surveillance in patients treated with ipilimumab.