Effects of CTLA-4 Single Nucleotide Polymorphisms on Toxicity of Ipilimumab-Containing Regimens in Patients With Advanced Stage Melanoma

Abstract

Single nucleotide polymorphisms (SNPs) in the cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) gene, an inhibitor of T-cell priming, are associated with auto and alloimmunity. Studies implied a role for these SNPs as surrogate markers for immunotherapy-outcome in patients with melanoma. However, no predictive SNPs are defined to date. We analyzed different CTLA-4 SNPs in a large multicenter cohort of patients with ipilimumab-treated melanoma and investigated possible correlations with treatment-related outcomes. Archival blood and/or tumor tissue samples were collected from 361 patients with advanced-stage ipilimumab-treated (±nivolumab) in 6 Swiss and Dutch hospitals. Matrix-assisted laser desorption/ionization–time of flight mass spectrometry based DNA genotyping was performed for 10 different CTLA-4 SNPs: 49A>G, CT60G>A, Jo27T>C, Jo30G>A, Jo31G>T, −658C>T, −1722T>C, −1661A>G, 318C>T, and C>T rs1863800. Associations between different allele genotypes and occurrence of grade ≥3 adverse events (AEs) and survival were tested using univariable logistic regressions or Cox proportional hazard models. 262/361 (73%) patients could be analyzed; 65% of those were males, the median age was 58 years, 39% showed a partial or complete response, and 65% had ≥1 AEs. A TT-genotype of −1722T>C SNP was significantly associated with a lower incidence of grade ≥3 AEs (P = 0.049), whereas the GG-genotype of CT60G>A correlated with a higher incidence of grade ≥3 AEs (P = 0.026). The TT-genotype of Jo27T>C SNP (P = 0.056) and GG-genotype of Jo31G>T (P = 0.046) were associated with overall survival. CTLA-4 SNPs might predict treatment-related outcomes in patients with melanoma receiving ipilimumab. Confirmatory studies are needed to fully exploit those findings as predictive biomarkers for ipilimumab AEs.