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

doi:10.3389/fimmu.2017.00386

Abstract

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.

Highlights

Ipilimumab (IPI) is a human monoclonal antibody targeting the immune-checkpoint molecule cytotoxic T lymphocyte antigen-4 (CTLA-4), which is expressed on activated effector T cells (Teff cells) and regulatory T cells (Tregs)
The present study assessed the potential role of defined CTLA-4 gene variants in predicting clinical outcome in patients with advanced melanoma treated with IPI
The rationale for this study was based on the assumption that, since CTLA-4 represents a key negative regulator of T cell activation, genetic variants which alter its expression and/or function could affect the interaction of CTLA-4 with IPI and its therapeutic efficacy in MM patients

Summary

Introduction

Ipilimumab (IPI) is a human monoclonal antibody targeting the immune-checkpoint molecule CTLA-4 (cytotoxic T lymphocyte antigen-4), which is expressed on activated effector T cells (Teff cells) and regulatory T cells (Tregs). CTLA-4 negatively regulates Teff cell activation through inhibition of cell proliferation, IL2 production, and cell-cycle progression [1, 2] upon binding to B7 ligands (CD80/CD86) expressed by the antigen-presenting cells. IPI may achieve clinical benefit in terms of long-lasting disease control and long-term survival in ≈20% of patients [5, 7]. The increasing number of treatment options available (including targeted therapies and other immune-checkpoint inhibitors) and the evidence that IPI may achieve a relevant clinical benefit (i.e., durable response to treatment and long-term survival) in a small subset of patients highlight the need to investigate predictive biomarkers that identify this subset of patients

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Conclusion