Biomarkers for clinical benefit to immune checkpoint blockade treatment in NSCLC

Abstract

Pharmacological blockade of the PD-1/PD-L1 pathway has transformed the treatment landscape of advanced stage NSCLC. These immune checkpoint blocking (ICB) agents have demonstrated the capacity to induce durable responses. However, 60%-70% of patients experience disease progression within six months of treatment. This raises concerns about unnecessary exposure of patients to side effects, financial costs, and delayed access to alternative therapies. Hence, the identification of biomarkers capable of selecting patients that will not derive benefit from PD-(L)1 blockade therapy has become an urgent necessity. In this thesis, the presence of a distinct population of tumor-reactive T cells, known as PD-1T TILs, was established as a novel biomarker for long-term benefit to PD-1 blockade in NSCLC with high negative predictive value. Consequently, a tumor’s PD-1T TIL status was translated into an mRNA signature using the Nanostring nCounter platform to facilitate its implementation as biomarker in routine diagnostics. In the second part of this thesis, alternative bio-sources for biomarker assessment were explored to avoid the need for invasive and complicated biopsy procedures. A serum-based protein signature was developed to stratify patient outcomes without the need for invasive tissue biopsies. Additionally, this research demonstrated that cell-free DNA extracted from the supernatant of pleural effusion can accurately detect targetable oncogenes and resistance mechanisms. Collectively, these findings enhance the ability to tailor treatment strategies and diagnostic tools for advanced-stage NSCLC patients treated with PD-1 blockade therapy.