Immunological adverse events of immune checkpoint inhibitors - study of their phenotypes and biomarkers

Overview

Project Summary

Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmable cell death protein 1 (PD-1) or its ligand (PD-L1) have dramatically changed the therapeutic landscape of several malignancies, showing antitumor activity and significant increasing survival in patients with metastatic disease. However, ICI are associated with frequent (about 25% of the patients) and potentially severe immune-related adverse events (IRAEs). IRAEs are caused by the inhibition of homeostatic immune regulation mechanisms and lead to "global" activation of naïve and memory T cells. No biomarkers are currently available to identify those patients at risk of developing IRAEs during or after ICI therapy.

Using an array of immunological and genetics tests, we aim to find biomarkers correlating with the development of IRAEs in melanoma patients under therapy with ICIs. This is a new area of research and our pilot study will take a wide approach: lymphocyte populations and activation, cytokine production, T-cell receptors, and patient's microbiome. Selected findings can then be tested in larger populations. We aim to find clinically relevant biomarkers and contribute for the understanding of the mechanistic processes leading to IRAEs elicited by ICIs, eventually finding predictors of IRAEs and identifying steps that may be targeted in order to modify the occurrence of IRAEs or their severity.

Main Goals

The aim of the study is to identify biomarkers that predict the risk of Immune-related adverse events from ICIs, including T cell repertoires and microbiome dysbiosis, in order to allow personalization of immunotherapy protocols and maximize therapeutic benefit. 

Project Details