Abstract
BackgroundLong-term survival of stage IV melanoma patients has improved significantly with the development of immune checkpoint inhibitors (CIs). Reliable biomarkers to predict response and clinical outcome are needed.MethodsWe investigated the role of melanoma-associated antibodies as predictive markers for CI therapy in two independent cohorts. In cohort 1, a prospective study, we measured specific antibodies before treatment, after one week and after six to nine weeks of treatment. Cohort 2 consisted of serum samples prior to CI therapy initiation. ELISA assays were performed to quantify specific IgG directed against melanocyte differentiation antigens tyrosinase-related proteins 1 and 2 (TRP1/TYRP1 and TRP2/TYRP2), glycoprotein 100 (gp100), MelanA/MART1, and the cancer-testis antigen NY-ESO-1. Response was defined as either complete or partial remission on CT scan according to RECIST 1.1.ResultsIn cohort 1, baseline levels of these antibodies were higher in the responder group, although statistical significance was only reached for NY-ESO-1 (p = 0.007). In cohort 2, significantly higher antibody baseline levels for MelanA/MART1 (p = 0.003) and gp100 (p = 0.029) were found. After pooling the results from both cohorts, higher levels of MelanA/MART1 (p = 0.013), TRP1/TYRP1 (p = 0.048), TRP2/TYRP2 (p = 0.047) and NY-ESO-1 (p = 0.005) specific antibodies at baseline were independently associated with response.ConclusionsMelanoma-associated antibodies may be candidate biomarkers for response and survival in metastatic melanoma patients being treated with CIs. These markers may be used to complement patient assessment, in combination with PD-L1 status, tumor-infiltrating lymphocytes and tumor mutational burden, with the aim to predict outcome of CI treatment in patients with metastatic melanoma.Trial registrationEthikkommission Ostschweiz, EKOS 16/079 https://ongoingprojects.swissethics.ch/runningProjects_list.php?q=%28BASECID~contains~2016-00998%29&orderby=dBASECID.
Highlights
Long-term survival of stage IV melanoma patients has improved significantly with the development of immune checkpoint inhibitors (CIs)
In this study, we addressed the role of pre-existing Melanocyte differentiation antigen (MDA) and C/T antigen specific antibodies as potential biomarkers for CI response and survival in patients suffering from metastatic melanoma
We demonstrate for the first time in two independent melanoma patient cohorts that responders to CI therapy have higher pre-treatment levels of antibodies specific for MDA (TRP1/Tyrosinase-related proteins 1 (TYRP1), TRP2/TYRP2, gp100, MelanA/ MART1) and the C/T antigen NY-ESO-1
Summary
Long-term survival of stage IV melanoma patients has improved significantly with the development of immune checkpoint inhibitors (CIs). Survival of patients suffering from metastatic melanoma has significantly improved since the introduction of immune checkpoint inhibitors (CIs). The cytotoxic-T-lymphocyte-associated-protein-4 (CTLA4) targeting antibody ipilimumab was the first clinically approved CI, with a significantly increased response rate compared to previous treatments and a survival rate of about 20% after 10 years in patients with advanced melanoma [1,2,3]. The anti-programmed-cell-death-protein-1 (PD1) antibodies nivolumab and pembrolizumab show response rates of around 40% as single agents, and improved progression free survival (PFS) and overall survival (OS) compared to chemotherapy or ipilimumab [4,5,6,7]. While irAEs are manageable in most patients, fatal cases have been reported [1]
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