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

Karlijn De Joode, Alfonso Rojas Mora, Ron H.N. Van Schaik, Alfred Zippelius, Astrid Van Der Veldt, Camille Léa Gerard, Heinz Läubli, Olivier Michielin, Roger Von Moos, Markus Joerger, Mitchell P. Levesque, Stefanie Aeppli, Johanna Mangana, Cristina Mangas, Nadine Trost, Stefan Meyer, Sandra Leoni Parvex, Ron Mathijssen, Yannis Metaxas*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)190-194
Number of pages5
JournalJournal of Immunotherapy
Issue number5
Publication statusPublished - Jun 2024

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