Predicting Response to Anti-PD-1/PD-L1 Immunotherapy by Plasma Extracellular Vesicle Analysis

Overview

The objective of this prospective multicenter study is to evaluate whether the analysis of immunological biomarkers present in circulating extracellular vesicles is associated with the response to anti-PD-1/PD-L1 treatments in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) or unresectable melanoma. Patients will receive standard-of-care treatment and will be followed according to routine clinical practice. The study involves the collection of four study-specific blood samples at different time points during follow-up, as well as the collection of standard immunohistochemistry results, thoraco-abdomino-pelvic CT scans, and tumor DNA genotyping analyses performed as part of routine care. The study aims to determine: * whether baseline biomarkers in extracellular vesicles are associated with response to anti-PD-1/PD-L1 treatment, * how these biomarkers change over the course of treatment, and * to provide exploratory data for the development of predictive immunological response signatures.

Immune checkpoint inhibitors (anti-PD-1/PD-L1) have become standard treatment for patients with advanced or metastatic non-small cell lung cancer (NSCLC) or melanoma. However, not all patients respond to these therapies, and current biomarkers are imperfect. Circulating extracellular vesicles (EVs) are nanovesicles derived from tumor and immune cells, carrying proteins, nucleic acids, and lipids. They represent an accessible and stable source of immunological biomarkers, allowing monitoring of the tumor microenvironment without additional invasive procedures. This prospective multicenter study aims to: * Collect and analyze immunological biomarkers present in EVs at baseline and during follow-up. * Assess their association with objective response to anti-PD-1/PD-L1 treatment, measured according to RECIST 1.1. * Develop an exploratory composite score combining multiple markers to predict response, stratified by cancer type (NSCLC vs melanoma). * Prospectively collect biological samples for future exploratory analyses. Study procedures for participants include: * Blood sample collection: Four study-specific blood draws performed during standard treatment or tumor assessment visits (baseline, 2nd administration, first evaluation, second evaluation). * Collection of additional information: Standard immunohistochemistry results for PD-1, PD-L1, CTLA-4, Tim-3, LAG-3, and Tigit; thoraco-abdomino-pelvic CT scans; circulating or tumor DNA genotyping analyses. * Clinical follow-up: Conducted according to routine care standards, with no changes to treatment or additional study-specific visits.