Risk Factors and Biomarkers for Immune-Related Adverse Events: A Practical Guide to Identifying High-Risk Patients and Rechallenging Immune Checkpoint Inhibitors

Abstract

Immune-related adverse events (irAEs) are a range of complications associated with the use of immune-checkpoint inhibitors (ICIs). Two major classes of ICIs widely used are Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) and Programmed Cell death-1 (PD-1)/Programmed death-ligand 1 (PD-L1) inhibitors. High-grade irAEs are life-threatening and often cause a severe decline in performance status in such that patients do not qualify for any further anticancer treatments. It is difficult to generalize the evidence in the current literature on risk factors or biomarkers for the entire class of ICIs as the studies so far are either disease-specific (e.g., lung cancer or melanoma) or ICI agent-specific (e.g., pembrolizumab, ipilimumab) or irAE-specific (e.g., pneumonitis or gastritis). In this review, risk factors and biomarkers to consider before initiating or monitoring ICI are listed with a practical purpose in day-to-day practice. Risk factors are grouped into demographics and social history, medical history, and medication history, tumor-specific and agent-specific risk factors. A higher risk of irAE is associated with age <60 years, high body mass index, women on CTLA4 and men on PD-1/PD-L1 agents, and chronic smokers. Patients with significant kidney (Stage IV-V), cardiac (heart failure, coronary artery disease, myocardial infarction, hypertension), and lung (asthma, pulmonary fibrosis, and chronic obstructive pulmonary disease) are at a higher risk of respective organ-specific irAEs. Pre-existing autoimmune disease and chronic use of certain drugs (proton pump inhibitors, diuretics, anti-inflammatory drugs) also increase the irAE-risk. Biomarkers are categorized into circulating blood counts, cytokines, autoantibodies, HLA genotypes, microRNA, gene expression profiling, and serum proteins. The blood counts and certain protein markers (albumin and thyroid-stimulating hormone) are readily accessible in current practice. High neutrophil-lymphocyte ratio, eosinophil/monocyte/lymphocyte counts; TSH and troponins at diagnosis and drop in the white count and lymphocyte count can predict irAE. Other biomarkers with limited evidence are cytokines, autoantibodies, HLA genotypes, microRNA, and gene expression profiling. With fast-expanding approvals for ICIs in various cancer types, knowledge on risk factors and biomarkers can help providers assess the irAE-risk of their patients. Prospective disease and agent-specific studies are needed to provide further insight on this essential aspect of ICI therapy.

PD-1 inhibitor-based adverse events in solid tumors: A retrospective real-world study

“…Although early research shown that multiple factors were involved in the occurrence of irAEs, containing patient characteristics, medical history, medication history, ICIs type, therapeutic regimen and tumor type ( Chennamadhavuni et al, 2022 ), there is still some debate about risk factors for irAEs. Some studies have reported that predictors for irAEs include concomitant chemotherapy, ICIs type, a higher body mass index, being female, C-reactive protein, neutrophil lymphocyte ratio, and smoking history ( Suazo-Zepeda et al, 2021 ; Chennamadhavuni et al, 2022 ), whereas another study demonstrated no statistically significant irAE risk differences between the sexes (odds ratio [OR] = 1.19, 95% CI = 0.91–1.54, two-sided p = 0.21) ( Jing et al, 2021 ). A real-world study also showed that serum albumin level ≥3.6 g/dl and history of Type I hypersensitivity reactions were risk factors for irAEs, but BIM, age and sex were not significant factors ( Shimozaki et al, 2021 ).…”

“…With the increase in attention for irAEs, some studies showed that some baseline co-medications, such as antibiotics, PPI, diuretics and ACEI/ARD, could be associated with irAE. The underlying mechanisms was that altered anti-cancer activity to ICI were related to decreased incidence of irAEs, and gut microbial diversity was decreased by antibiotics ( Kostine et al, 2021 ; Chennamadhavuni et al, 2022 ; Jing et al, 2022 ; Zhao et al, 2022 ). However, their clear relevance and the mechanism needs to be further studied in the future.…”

Current Therapeutic Strategies for Metastatic Triple-Negative Breast Cancer: From Pharmacists’ Perspective

“…Clinically, circulating blood cell counts are a biomarker that is accessible in current clinical practice. Other biomarkers such as cytokines, autoantibodies, serum proteins, intestinal microbiota, microRNA and gene profiling need more research before they can be adopted in practice [ 112 ]. (7) Due to the non-specific characteristics of irAEs symptoms, for many patients and medical staff, they are difficult to detect and recognize.…”

Severe Immune-Related Adverse Events: A Case Series of Patients Needing Hospital Admission in a Spanish Oncology Referral Center and Review of the Literature

“…The reason why only certain patients develop irAEs while others do not ever experience them after months of treatment is still not well known. Multiple studies have reported different potential personal risk factors, such as a history of autoimmune disease, high body mass index, and significant kidney disease, among others [ 17 ].…”