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Predictive Biomarkers for Checkpoint Inhibitor Immune-Related Adverse Events
Iñigo Les1,2,3, Mireia Martínez4,5, Inés Pérez-Francisco6
1Internal Medicine Department, Navarre University Hospital, 31008 Pamplona, Spain.
Abstract:
Immune-checkpoint inhibitors (ICIs) are antagonists of inhibitory receptors in the immune system, such as the cytotoxic T-lymphocyte-associated antigen-4, the programmed cell death protein-1 and its ligand PD-L1, and they are increasingly used in cancer treatment. By blocking certain suppressive pathways, ICIs promote T-cell activation and antitumor activity but may induce so-called immune-related adverse events (irAEs), which mimic traditional autoimmune disorders. With the approval of more ICIs, irAE prediction has become a key factor in improving patient survival and quality of life. Several biomarkers have been described as potential irAE predictors, some of them are already available for clinical use and others are under development; examples include circulating blood cell counts and ratios, T-cell expansion and diversification, cytokines, autoantibodies and autoantigens, serum and other biological fluid proteins, human leucocyte antigen genotypes, genetic variations and gene profiles, microRNAs, and the gastrointestinal microbiome. Nevertheless, it is difficult to generalize the application of irAE biomarkers based on the current evidence because most studies have been retrospective, time-limited and restricted to a specific type of cancer, irAE or ICI. Long-term prospective cohorts and real-life studies are needed to assess the predictive capacity of different potential irAE biomarkers, regardless of the ICI type, organ involved or cancer site.
Insights
Predicting immune-related adverse events (irAEs) from immune-checkpoint inhibitors (ICIs) is crucial for cancer patients. Current biomarkers show promise but require more extensive, real-world studies for reliable prediction across diverse scenarios.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Immune-checkpoint inhibitors (ICIs) enhance anti-tumor immunity by blocking inhibitory immune receptors like CTLA-4 and PD-1/PD-L1.
- ICIs can trigger immune-related adverse events (irAEs) that resemble autoimmune diseases, impacting patient outcomes.
- Accurate prediction of irAEs is vital for optimizing cancer patient survival and quality of life.
Purpose of the Study:
- To review and assess the current landscape of biomarkers for predicting irAEs associated with ICI therapy.
- To identify the limitations of existing irAE prediction strategies and highlight areas for future research.
Main Methods:
- Comprehensive literature review of studies investigating irAE biomarkers.
- Analysis of diverse biomarker categories including blood counts, T-cell profiles, cytokines, autoantibodies, genetic factors, and microbiome data.
- Evaluation of study designs, limitations, and generalizability of current evidence.
Main Results:
- Numerous potential irAE biomarkers have been identified, ranging from simple blood tests to complex genetic and microbiome analyses.
- Existing evidence is largely based on retrospective, limited studies, often specific to certain cancers, irAEs, or ICIs.
- The generalizability and clinical utility of most biomarkers remain uncertain due to these limitations.
Conclusions:
- While promising biomarkers for irAE prediction exist, current evidence is insufficient for broad clinical application.
- Long-term, prospective, real-world studies are essential to validate these biomarkers across various ICI treatments, cancer types, and affected organs.
