Abstract
Ipilimumab has revolutionized malignant melanoma therapy, but a better understanding of the mechanisms behind treatment response and adverse effects is needed. In this work, the immune system of ipilimumab treated patients was monitored to investigate potential mechanisms of action that may correlate with treatment outcome. Blood samples from 43 advanced melanoma patients were taken before, during and at the end of treatment. Hematological parameters were measured and flow cytometry analysis was performed in fresh samples within two hours of sample collection. Strong differences in markers CD45RA, CCR7, HLA-DR and CD15 between fresh and cryopreserved samples were observed. Ipilimumab treatment increased absolute lymphocyte counts, eosinophils, effector T cells and their activation status, whilst diminishing the suppressive side of the immune response, acting on regulatory T cells and myeloid derived suppressor cells (MDSCs). These effects were visible after one ipilimumab infusion and, regarding eosinophil counts, correlated with onset of adverse events. Monocytic MDSCs were decreased in response to treatment only in patients with clinical benefit; additionally, patients with a lower frequency of these cells after the first ipilimumab infusion experienced increased overall survival. CD8 effector memory T cell frequencies at the end of treatment were higher in patients with clinical benefit and positively correlated with survival. These data show that a clinical response to ipilimumab not only requires reshaping T cell populations, but additionally involves a reduction in suppressive cells such as monocytic MDSCs. Our work could provide insight on predicting treatment outcome, assisting clinicians in offering the best personalized therapeutic approach.
Highlights
The role of the immune system in the surveillance and elimination of several types of human cancers has been known for a long time, but not until recently has this knowledge been transformed into clinically useful cancer therapies
Extensive immune monitoring was carried out in patients with advanced melanoma with the intent of shedding some light on the circulating cellular populations that are targeted by ipilimumab treatment, their evolution during treatment, and their possible correlations with treatment outcome and survival
Combining patients with stable disease and patients with partial response in a “clinical benefit” group is supported by the fact that both groups showed no differences in median overall survival (MOS) and presented similar lactate dehydrogenase (LDH) levels
Summary
The role of the immune system in the surveillance and elimination of several types of human cancers has been known for a long time, but not until recently has this knowledge been transformed into clinically useful cancer therapies. Blocking the checkpoint receptor CTLA-4 with the monoclonal antibody ipilimumab is the first treatment that has been proven to improve overall survival in patients with advanced melanoma. Ipilimumab has been shown to increase long term survival in over 20% of patients with advanced melanoma [3], adverse events, while manageable, are frequent [4]. Given the emerging combination therapy strategies combining ipilimumab with other agents such as PD-1/PD1-L checkpoint blockade [5], such biomarkers would be of great usefulness when ipilimumab is used as a single or combined therapeutic agent in the treatment of advanced melanoma
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