Facts and Hopes in Prediction, Diagnosis, and Treatment of Immune-Related Adverse Events

Abstract

Over the past decade, the use of immune checkpoint inhibitors (ICI) has expanded across a wide spectrum of oncology indications. Immune-related adverse events (irAE) from ICIs represent a significant source of morbidity, and in rare instances, can lead to treatment-related mortality. There are significant opportunities to better identify patients at increased risk for immune-related toxicity, diagnose irAEs more accurately and earlier in their course, and develop more individualized therapeutic strategies once complications arise. Clinical characteristics, germline and somatic genetic features, microbiome composition, and circulating biomarkers have all been associated with higher risk of developing irAEs in retrospective series. Many of these data suggest that both antitumor and anti-host ICI-associated immune reactions may be driven by common features of either the tumor or the patient's preexisting immune milieu. While irAE diagnosis is currently based on clinical history, exclusion of alternative etiologies, and sometimes pathologic confirmation, novel blood-based and radiographic assays are in development to identify these complications more precisely. Anecdotal reports and small case series have highlighted the potential role of targeted immunomodulatory agents to treat irAEs, though further prospective investigation is needed to evaluate more rigorously their use in these settings. In this review, we highlight the current state of knowledge about predicting, diagnosing, and treating irAEs with a translational focus and discuss emerging strategies which aim to improve each of these domains.

Figure 1

Mechanisms of selected immunosuppressive agents reported in the treatment of gastrointestinal (A) and cutaneous (B) immune-related adverse events (irAEs). Monoclonal antibodies developed for other inflammatory indications have been used in the steroid-refractory setting. Examples include infliximab (anti-TNF), dupilimumab (anti-IL-4), guselkinumab (anti-IL-23), and ustekinumab (anti IL-12/23). Small molecules such as tofacitinib (anti-JAK1/3) have also been used.

Figure 1

Mechanisms of selected immunosuppressive agents reported in the treatment of gastrointestinal (A) and cutaneous (B) immune-related adverse events (irAEs). Monoclonal antibodies developed for other inflammatory indications have been used in the steroid-refractory setting. Examples include infliximab (anti-TNF), dupilimumab (anti-IL-4), guselkinumab (anti-IL-23), and ustekinumab (anti IL-12/23). Small molecules such as tofacitinib (anti-JAK1/3) have also been used.