Apart the fast-paced innovation in medical oncology due to the clinical development of immune checkpoint inhibitors (ICIs), most cancer patients ultimately die because of treatment resistance. Therefore, the careful selection of patients for ICI treatment is of pivotal importance to avoid giving ineffective and potentially harmful treatments and contain public health expenditures. Many efforts have been made in this direction in the last few years. However, so far, none of the explored assessments is sufficiently solid to be used as patient selection criteria. Among all cancer patients, those who benefit least from ICI treatment are patients with non-small cell lung cancer with an objective response rate of only 20%. The present project aims to identify and develop predictive biomarkers for the response of ICIs in advanced lung cancer patients, in order to obtain a more in-depth and comprehensive understanding of differences in treated patients. To do this, we plan to deeply explore both circulating tumor and host genetic markers using a high-throughput comprehensive multi-omics sequencing approach based on analysis of germline polymorphisms, blood transcriptome signatures and Whole-Exome Sequencing of circulating tumor cell-free DNA. Our innovative multi-omics approach will allow us to gain insight into resistance mechanisms to ICI and have a comprehensive view of the genetics of immune checkpoint inhibitor response, investigating both host and tumor biomarkers. Improved understanding of molecular and genetic mechanisms of clinical response and/or resistance may not only identify robust predictive and prognostic biomarkers but also guide optimal and personalized combination/sequencing of ICI therapy into the clinic.

The project is funded by European Union – Next-GenerationEU – National Recovery and Resilience PLAN (PNRR) – Mission 4, Component 2, Investiment 1.1 Fondo per il Programma Nazionale di Ricerca e Progetti di Rilevante Interesse Nazionale (PRIN). Project N. 2022ARXHR2_002