Evolving insights into the mechanisms of toxicity associated with immune checkpoint inhibitor therapy

Mangan, Brendan L.; McAlister, Renee; Balko, Justin M.; Johnson, Douglas B.; Moslehi, Javid; Gibson, Andrew; Phillips, Elizabeth

doi:10.1111/bcp.14433

Cited by 41 publications

(28 citation statements)

References 110 publications

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“… 13 14 The pathophysiology of ICI-induced myocarditis remains poorly understood. 23 Since the histological lesions observed are similar to those observed during acute cardiac transplant cell rejection, experts logically recommended drugs indicated in this situation. These include high doses of methylprednisolone (1 g per day for 3 days) as well as ATG, MMF or tacrolimus.…”

Section: Discussionmentioning

confidence: 94%

Intensified immunosuppressive therapy in patients with immune checkpoint inhibitor-induced myocarditis

Cautela

Zeriouh

Gaubert

et al. 2020

J Immunother Cancer

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BackgroundMyocarditis is a rare but life-threatening adverse event of cancer treatments with immune checkpoint inhibitors (ICIs). Recent guidelines recommend the use of high doses of corticosteroids as a first-line treatment, followed by intensified immunosuppressive therapy (IIST) in the case of unfavorable evolution. However, this strategy is empirical, and no studies have specifically addressed this issue. Therefore, we aimed to investigate and compare the clinical course, management and outcome of ICI-induced myocarditis patients requiring or not requiring IIST.MethodsThis case–control study included all patients consecutively admitted to The Mediterranean University Center of Cardio-Oncology (Aix-Marseille University, France) for the diagnosis of ICI-induced myocarditis according to Bonaca’s criteria and treated with or without IIST. In addition, we searched PubMed and included patients from previously published case reports treated with IIST in the analysis. The clinical, biological, imaging, treatment, all-cause death and cardiovascular death data of patients who required IIST were compared with those of patients who did not.ResultsA total of 60 patients (69±12 years) were included (36 were treated with IIST and 24 were not). Patients requiring IIST were more likely to have received a combination of ICIs (39% vs 8%, p=0.01), and developed the first symptoms/signs of myocarditis earlier after the onset of ICI therapy (median, 18 days vs 60 days, p=0.002). They had a significantly higher prevalence of sustained ventricular arrhythmia, complete atrioventricular block, cardiogenic shock and troponin elevation. Moreover, they were more likely to have other immune-related adverse events simultaneously (p<0.0001), especially myositis (p=0.0002) and myasthenia gravis (p=0.009). Patients who required IIST were more likely to die from any cause (50% vs 21%, p=0.02). Among them, patients who received infliximab were more likely to die from cardiovascular causes (OR, 12.0; 95% CI 2.1 to 67.1; p=0.005).ConclusionThe need for IIST was more common in patients who developed myocarditis very early after the start of ICI therapy, as well as when hemodynamic/electrical instability or neuromuscular adverse events occurred. Treatment with infliximab might be associated with an increased risk of cardiovascular death.

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Section: Discussionmentioning

confidence: 94%

Intensified immunosuppressive therapy in patients with immune checkpoint inhibitor-induced myocarditis

Cautela

Zeriouh

Gaubert

et al. 2020

J Immunother Cancer

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“…Host factors, intestinal microbiota, genetic risk factors, and specific antigen exposures may all be involved in irAEs ( 25 ). Viruses or co-administered drugs can also provoke irAEs ( 26 ). CTLA-4 and PD1/PD-L1 inhibitors usually display different irAEs.…”

Section: Introductionmentioning

confidence: 99%

Immune Check Point Inhibitors and Immune-Related Adverse Events in Small Cell Lung Cancer

Hou

Zhou

et al. 2021

Front. Oncol.

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Small cell lung cancer (SCLC) is a malignant solid tumor. In recent years, although immune check point inhibitors (ICIs) have achieved important advances in the treatment of SCLC, immune-related adverse events (irAEs) have occurred at the same time during the therapeutic period. Some irAEs lead to dose reduction or treatment rejection. The immune microenvironment of SCLC is complicated, therefore, understanding irAEs associated with ICIs is of great importance and necessity for the clinical management of SCLC. However, the lack of comprehensive understanding of irAEs in patients with SCLC remains remarkable. This review aims to provide an up-to-date overview of ICIs and their associated irAEs in patients with SCLC based on present clinical data.

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“…Checkpoint inhibition is now widely adopted in cancer immunotherapy to re-invigorate anti-tumor T-cell responses, but dysregulation is not antigen-specific and immune-mediated ADR are common (Naidoo et al, 2015;Saw et al, 2017;Lomax et al, 2019). While reactions are varied and typically reported as enhanced immunogenicity to self (Mangan et al, 2020), emerging small cohort studies describe a high incidence of DHR in immune checkpoint inhibitortreated patients (Imafuku et al, 2017;Ford et al, 2018). These studies remain only clinical observations and distinct checkpoint alleles have not been identified in genome-wide association studies; however, given the influence of multiple, counteracting co-signaling pathways, it may be that single variants have a low individual effect for which the previous studies have been underpowered.…”

Section: Dynamic Dysregulation Imposed By Immune Checkpoints Spans Gementioning

confidence: 99%

Genomic Risk Factors Driving Immune-Mediated Delayed Drug Hypersensitivity Reactions

Deshpande

Hertzman

et al. 2021

Front. Genet.

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Adverse drug reactions (ADRs) remain associated with significant mortality. Delayed hypersensitivity reactions (DHRs) that occur greater than 6 h following drug administration are T-cell mediated with many severe DHRs now associated with human leukocyte antigen (HLA) risk alleles, opening pathways for clinical prediction and prevention. However, incomplete negative predictive value (NPV), low positive predictive value (PPV), and a large number needed to test (NNT) to prevent one case have practically prevented large-scale and cost-effective screening implementation. Additional factors outside of HLA contributing to risk of severe T-cell-mediated DHRs include variation in drug metabolism, T-cell receptor (TCR) specificity, and, most recently, HLA-presented immunopeptidome-processing efficiencies via endoplasmic reticulum aminopeptidase (ERAP). Active research continues toward identification of other highly polymorphic factors likely to impose risk. These include those previously associated with T-cell-mediated HLA-associated infectious or auto-immune disease such as Killer cell immunoglobulin-like receptors (KIR), epistatically linked with HLA class I to regulate NK- and T-cell-mediated cytotoxic degranulation, and co-inhibitory signaling pathways for which therapeutic blockade in cancer immunotherapy is now associated with an increased incidence of DHRs. As such, the field now recognizes that susceptibility is not simply a static product of genetics but that individuals may experience dynamic risk, skewed toward immune activation through therapeutic interventions and epigenetic modifications driven by ecological exposures. This review provides an updated overview of current and proposed genetic factors thought to predispose risk for severe T-cell-mediated DHRs.

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Evolving insights into the mechanisms of toxicity associated with immune checkpoint inhibitor therapy

Cited by 41 publications

References 110 publications

Intensified immunosuppressive therapy in patients with immune checkpoint inhibitor-induced myocarditis

Intensified immunosuppressive therapy in patients with immune checkpoint inhibitor-induced myocarditis

Immune Check Point Inhibitors and Immune-Related Adverse Events in Small Cell Lung Cancer

Genomic Risk Factors Driving Immune-Mediated Delayed Drug Hypersensitivity Reactions

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