CTLA-4 gene variant -1661A>G may predict the onset of endocrine adverse events in metastatic melanoma patients treated with ipilimumab

The anti-CTLA-4 monoclonal antibody ipilimumab (IPI) was the first immune-checkpoint inhibitor approved for the treatment of metastatic melanoma (MM). Despite the current availability of more effective and less toxic anti-PD-1 agents, IPI remains used in monotherapy as adjuvant or second/third line setting and in combination with anti-PD-1 or other agents [1]. Immune-related adverse events (irAEs) likely associated with IPI treatment include endocrinopathies, mostly pituitary and, to a less extent, thyroid dysfunctions [2], [3]. Nowadays, no predictive biomarkers identify patients at risk of developing endocrine irAEs (endo-irAEs). Functional CTLA-4 single nucleotide variants (SNVs) are associated with susceptibility to autoimmune diseases including endocrinopathies [4]. These variants may influence the host immune response through alteration of CTLA-4 expression levels and inhibitory function in T cells [4]. We here report an observational and exploratory study showing, for the first time to our knowledge, the significant association of the CTLA-4 -1661A>G SNV (rs4553808) with the onset of endo-irAEs in MM patients treated with IPI. This SNV was the only one, out of the six we analysed (-1661A>G, -1577G>A, -658C>T, -319C>T, +49A>G, and CT60G>A) that showed a possible effect on endo-irAE occurrence.