Frontiers in Immunology (Apr 2017)

Association of CTLA-4 Gene Variants with Response to Therapy and Long-term Survival in Metastatic Melanoma Patients Treated with Ipilimumab: An Italian Melanoma Intergroup Study

  • Paola Queirolo,
  • Beatrice Dozin,
  • Anna Morabito,
  • Barbara Banelli,
  • Barbara Banelli,
  • Patrizia Piccioli,
  • Cristiana Fava,
  • Claudio Leo,
  • Roberta Carosio,
  • Stefania Laurent,
  • Vincenzo Fontana,
  • Pier Francesco Ferrucci,
  • Chiara Martinoli,
  • Emilia Cocorocchio,
  • Angelo Battaglia,
  • Paolo A. Ascierto,
  • Mariaelena Capone,
  • Ester Simeone,
  • Federica De Galitiis,
  • Elena Pagani,
  • Gian Carlo Antonini Cappellini,
  • Paolo Marchetti,
  • Paolo Marchetti,
  • Michele Guida,
  • Stefania Tommasi,
  • Mario Mandalà,
  • Barbara Merelli,
  • Pietro Quaglino,
  • Paolo Fava,
  • Massimo Guidoboni,
  • Massimo Romani,
  • Francesco Spagnolo,
  • Maria Pia Pistillo

DOI
https://doi.org/10.3389/fimmu.2017.00386
Journal volume & issue
Vol. 8

Abstract

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Ipilimumab (IPI) blocks CTLA-4 immune checkpoint resulting in T cell activation and enhanced antitumor immunity. IPI improves overall survival (OS) in 22% of patients with metastatic melanoma (MM). We investigated the association of CTLA-4 single nucleotide variants (SNVs) with best overall response (BOR) to IPI and OS in a cohort of 173 MM patients. Patients were genotyped for six CTLA-4 SNVs (−1661A>G, −1577G>A, −658C>T, −319C>T, +49A>G, and CT60G>A). We assessed the association between SNVs and BOR through multinomial logistic regression (MLR) and the prognostic effect of SNVs on OS through Kaplan–Meier method. Both −1577G>A and CT60G>A SNVs were found significantly associated with BOR. In particular, the proportion of responders was higher in G/G genotype while that of stable patients was higher in A/A genotype. The frequency of patients experiencing progression was similar in all genotypes. MLR evidenced a strong downward trend in the probability of responsiveness/progression, in comparison to disease stability, as a function of the allele A “dose” (0, 1, or 2) in both SNVs with reductions of about 70% (G/A vs G/G) and about 95% (A/A vs G/G). Moreover, −1577G/G and CT60G/G genotypes were associated with long-term OS, the surviving patients being at 3 years 29.8 and 30.8%, respectively, as compared to 12.9 and 14.4% of surviving patients carrying −1577G/A and CT60G/A, respectively. MM patients carrying −1577G/G or CT60G/G genotypes may benefit from IPI treatment in terms of BOR and long-term OS. These CTLA-4 SNVs may serve as potential biomarkers predictive of favorable outcome in this subset of patients.

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