CTLA4 promoter methylation predicts response and progression-free survival in stage IV melanoma treated with anti-CTLA-4 immunotherapy (ipilimumab)

Simon Fietz,Christian Posch,Torsten Pietsch,Romina Zarbl,Dimo Dietrich,Gerrit H Gielen,Friedrich Bootz,Dennis Niebel,Jennifer Landsberg,Sebastian Strieth,Peter Brossart,Glen Kristiansen

doi:10.1007/s00262-020-02777-4

Abstract

Anti-CTLA-4-antibodies can induce long-lasting tumor remissions. However, only a few patients respond, necessitating the development of predictive companion biomarkers. Increasing evidence suggests a major role of epigenetics, including DNA methylation, in immunology and resistance to immune checkpoint blockade. Here, we tested CTLA4 promoter methylation and CTLA-4 protein expression as predictive biomarkers for response to anti-CTLA-4 immunotherapy. We identified retrospectively N = 30 stage IV melanoma patients treated with single-agent anti-CTLA-4 immunotherapy (ipilimumab). We used quantitative methylation-specific PCR and immunohistochemistry to quantify CTLA4 methylation and protein expression in pre-treatment samples. CTLA4 methylation was significantly higher in progressive as compared to responding tumors and significantly associated with progression-free survival. A subset of infiltrating lymphocytes and tumor cells highly expressed CTLA-4. However, CTLA-4 protein expression did not predict response to treatment. We conclude that CTLA4 methylation is a predictive biomarker for response to anti-CTLA-4 immunotherapy.

Highlights

Therapeutic monoclonal antibodies targeting the immune checkpoints cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) have revolutionized the treatment of various cancers
To test the utility of CTLA4 methylation as a predictive biomarker for response to anti-CTLA-4 immune checkpoint blockade in stage IV melanoma patients, we identified retrospectively 30 patients diagnosed with advanced melanoma and treated with anti-CTLA-4 antibody ipilimumab monotherapy
We have previously reported the utility of CTLA4 promoter methylation as a predictive biomarker for response to immunotherapy and survival in a heterogeneous cohort comprised of N = 50 melanoma patients who received anti-progressive disease (PD)-1 and anti-CTLA-4 single-agent or combination immunotherapy [16]

Summary

Introduction

Therapeutic monoclonal antibodies (mAbs) targeting the immune checkpoints cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) have revolutionized the treatment of various cancers. Only a subgroup of patients responds to treatment due to primary resistance to ICB. This is true for ipilimumab, the first in class CTLA-4-directed immune checkpoint inhibitor, which has shown efficacy in 19% of patients [2]. Robust biomarkers indicating patients, who benefit from anti-CTLA-4 first-line monotherapy, are needed in the field of personalized medicine. Such biomarkers are of considerable interest since next-generation

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