PRELIFE 

Investigation of the predictive and prognostic role of liquid biopsies in NSCLC patients treated with the anti PD 1 inhibitor Pembrolizumab

This 2-year long project aims to carry out research in the field of establishing more reliable predictive biomarkers in relation to lung cancer, which is the most common cause of cancer-related death on a global scale. To date, the prognosis of patients with non-small cell lung cancer (NSCLC) remains insufficient. These poor outcomes are directly related to the fact that more than half of patients are diagnosed with locally advanced or metastatic disease. Therefore, there is an urgent need for predictive biomarkers that might promote an earlier detection of recurrences resulting in more efficacious therapeutic interventions and higher likelihood of cure.

Recently, the use of immunotherapy/ immune checkpoint inhibitors in lung cancer has gained widespread recognition. Specifically, pembrolizumab, an antibody directed against the programmed cell death 1 (PD-1) immune checkpoint molecule has been approved for NSCLC patients whose tumors express PD-L1. Currently, the predictive biomarker used for anti-PD1/anti-PD-L1 inhibitors, is PD-L1 immunohistochemistry. However, this is hampered with several problems relating to the different antibodies and assays used.  In recent years circulating tumor cells (CTCs) have been characterized as a liquid biopsy of cancer, potentially offering similar or sometimes even superior information compared to a conventional tumor biopsy. CTCs also provide unparalleled means to interrogate metastatic biology and determine the functional relevance of novel targets for therapeutic inhibition. Circulating tumor DNA (ctDNA) is a relatively new biomarker that has been mostly investigated as a tool for “liquid biopsy,” as it harbors similar mutations to DNA extracted from a “solid” tumor biopsy.

In this project, we aim to investigate the prognostic and predictive value of differential expression of PD-L1 on CTCs in serial samples of NSCLC patients receiving the PD-1 inhibitor, Pembrolizumab. Furthermore, we intend to explore the molecular characteristics of CTCs of patients treated with immunotherapy to determine the role of proliferative, epithelial-mesenchymal-transition (EMT) and stemness in tumor progression and/ or immunotherapy resistance. Finally, we object to investigate whether quantitative ctDNA monitoring is a useful tool for assessing tumor response in patients treated with anti-PD-1 therapy and if it can be used as an early detection marker for immunotherapy-treated patients.

This research project aims to the discovery of novel biomarkers for PD-L1 expression such as CTCs, and ctDNA that are expected to predict the response to PD-1 inhibitor treatment, assess possible disease recurrence through monitoring the patients in real time and could be used as prognostic indicators of disease progression.