Autoimmune complications of immunotherapy: pathophysiology and management

Abstract

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target inhibitory molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or its ligand, programmed cell death protein ligand 1 (PD-L1), and lead to immune activation in the tumor micro-environment. ICIs can induce durable treatment responses in patients with advanced cancers, but they are commonly associated with immune related adverse events (irAEs) such as rash, colitis, hepatitis, pneumonitis, and endocrine and musculoskeletal disorders. Almost all patients experience some form of irAE, but high grade irAEs occur in approximately half of those on combination therapy (eg, anti-CTLA-4 plus anti-PD-1), and up to one quarter receiving ICI monotherapy. Fatal irAEs occur in approximately 1.2% of patients on CTLA-4 blockade and 0.4% of patients receiving PD-1 or PD-L1 blockade, and case fatality rates are highest for myocarditis and myositis. IrAEs typically occur in the first three months after ICI initiation, but can occur as early as one day after the first dose to years after ICI initiation. The mainstay of treatment is with corticosteroids, but tumor necrosis factor inhibitors are commonly used for refractory irAEs. Although ICIs are generally discontinued when high grade irAEs occur, ICI discontinuation alone is rarely adequate to resolve irAEs. Consensus guidelines have been published to help guide management, but will likely be modified as our understanding of irAEs grows.

Immune-related adverse events: a retrospective look into the future of oncology in the intensive care unit

“…Particularly, colitis has been associated with anti-CTLA4, whereas pneumonitis has been related to anti-PD1 treatment [41], as shown in our study. Moreover, we confirm the risk of severe AE when ICI combinations are used [2,30,42]. If our small sample size does not allow us to compare mortality across the different types of irAEs, larger cohorts from outside of the ICU have described high mortality rates [30] in myocarditis [16][17][18][19], pneumonitis [4][5][6] and hepatitis [11][12][13] patients.…”

Pre-Existing Cardiovascular Conditions as Clinical Predictors of Myocarditis Reporting with Immune Checkpoint Inhibitors: A VigiBase Study

“…For this purpose, safety reports mentioning antineoplastic drugs other than ICIs (captured by ATC code L01) were excluded from the study group. Since patients with underlying autoimmunity may be at higher risk of ICI-related ADRs [14], we also excluded safety reports mentioning immunostimulants (ATC L03), immunosuppressors (ATC L04), and/or corticosteroids for systemic use (ATC H02). Safety reports with corticosteroids for systemic use as concomitant drugs to treat underlying autoimmune diseases or because of a transplant were excluded, while safety reports with corticosteroids for systemic use for the management of ICI-related toxicity were retained.…”

“…Of the remaining group of non-cases, 1709 safety reports were excluded for indicating ICI-related ADR(s) at the CV system or ICI-related ADR(s) representing risk factors for myocarditis (and for CV toxicity in general), and/or for indicating an ICI-related transplant, immunosuppression, infection in an immunocompromised host, or autoimmune disorder ( Figure 1 and Table S1B). The rationale behind the exclusion of these safety reports is that, on the one hand, reported ADRs at the CV system and risk factors for CV toxicity in general could be associated with the dependent variable of the present study (see Study Design below), while transplants, immunosuppression, and autoimmune disorders, on the other hand, are conditions that may affect the risk of ICI-related toxicity [14]. The remaining safety reports constituted the control group from which the controls for our study were sampled.…”

Uncoupling Therapeutic Efficacy from Immune-Related Adverse Events in Immune Checkpoint Blockade

“…In this study, 20 patients with renal cell carcinoma will be given fecal microbiota transplantation ≥7 days before initiation of ipilimumab and nivolumab combined therapy and 1–3 days before the next two treatments. The frequency of high-grade colitis will be calculated ( Chan and Bass, 2020 ).…”