Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance

Martins, Filipe; Latifyan, Sofiya; Sykiotis, Gerasimos P.; Lamine, Faïza; Maillard, Michel H.; Fraga, Montserrat; Shabafrouz, Keyvan; Ribi, Camillo; Cairoli, Anne; Guex-Crosier, Yan; Küntzer, Thierry; Michielin, Olivier; Peters, Solange; Coukos, George; Spertini, François; Thompson, John A.; Obéid, Michel

doi:10.1038/s41571-019-0218-0

Cited by 1,361 publications

(1,269 citation statements)

References 171 publications

Supporting

Mentioning

1,183

Contrasting

Unclassified

Order By: Relevance

“…Antitumor immunotherapies using ICIs target T‐cell‐negative feedback loops, augmenting the immune response to attack cancer cells . However, unwanted consequences of their mechanisms of action lead to a unique spectrum of adverse events, most of which are immune‐related adverse events (irAEs) . irAEs can be observed in most organs, with varying frequencies and severities .…”

Section: Introductionmentioning

confidence: 99%

Immune checkpoint inhibitor‐associated pituitary‐adrenal dysfunction: A systematic review and meta‐analysis

Lü

Lan

et al. 2019

Cancer Medicine

View full text Add to dashboard Cite

With the growing use of immune checkpoint inhibitors (ICIs), case reports of rare yet life‐threatening pituitary‐adrenal dysfunctions, particularly for hypopituitarism, are increasingly being published. In this analysis, we focus on these events by including the most recent publications and reports from early phase I/II and phase III clinical trials and comparing the incidence and risks across different ICI regimens. PubMed, Embase, and the Cochrane Library were systematically searched from inception to April 2019 for clinical trials that reported on pituitary‐adrenal dysfunction. The rates of events, odds ratios (ORs), and 95% confidence intervals (CIs) were obtained using random effects meta‐analysis. The analyses included data from 160 trials involving 40 432 participants. The rate was 2.43% (95% CI, 1.73%‐3.22%) for all‐grade adrenal insufficiency and 3.25% (95% CI, 2.15%‐4.51%) for hypophysitis. Compared with the placebo or other therapeutic regimens, ICI agents were associated with a higher incidence of serious‐grade adrenal insufficiency (OR 3.19, 95% CI, 1.84 to 5.54) and hypophysitis (OR 4.77, 95% CI, 2.60 to 8.78). Among 71 serious‐grade hypopituitarism instances in 12 336 patients, there was a significant association between ICIs and hypopituitarism (OR 3.62, 95% CI, 1.86 to 7.03). Substantial heterogeneity was noted across the studies for the rates of these events, which in part was attributable to the different types of ICIs and varied phases of the clinical trials. Although the rates of these events were low, the risk was increased following ICI‐based treatment, particularly for CTLA‐4 inhibitors, which were associated with a higher incidence of pituitary‐adrenal dysfunction than PD‐1/PD‐L1 inhibitors.

show abstract

Section: Introductionmentioning

confidence: 99%

Immune checkpoint inhibitor‐associated pituitary‐adrenal dysfunction: A systematic review and meta‐analysis

Lü

Lan

et al. 2019

Cancer Medicine

View full text Add to dashboard Cite

show abstract

“…These agents have led to the occurrence of a new spectrum of immune-related adverse events (irAEs) ranging from moderate to severe and life-threatening ones. These side effects include a wide variety of adverse events such as endocrine abnormalities (thyroid dysfunction, adrenal insufficiency and hypophysitis), gastrointestinal events (colitis, hepatitis), and dermatological or respiratory events (interstitial pneumonitis), which merit a high index of suspicion with clear therapeutic strategies in order to prevent irreversible outcomes [22].…”

Section: Role Of Icis In Cancermentioning

confidence: 99%

“…On the other hand, data on the hematological irAEs secondary to ICIs seems to be more comforting. Their occurrence is uncommon with different forms of adverse events including autoimmune thrombocytopenia and neutropenia, antibody-mediated hemolytic anemia and thrombotic thrombocytopenic purpura [22]. These adverse events highlight the crosstalk between the humoral and cellular immunity and the Treg-mediated self-tolerance [22].…”

Section: Immunosuppression and Icismentioning

confidence: 99%

“…Their occurrence is uncommon with different forms of adverse events including autoimmune thrombocytopenia and neutropenia, antibody-mediated hemolytic anemia and thrombotic thrombocytopenic purpura [22]. These adverse events highlight the crosstalk between the humoral and cellular immunity and the Treg-mediated self-tolerance [22]. In fact, ICIs might play a role in boosting pathogen-specific immune response in contrast to other immune checkpoints agonists such as Abatacept [26].…”

Section: Immunosuppression and Icismentioning

confidence: 99%

See 1 more Smart Citation

Do checkpoint inhibitors compromise the cancer patients’ Immunity and Increase the Vulnerability to COVID-19 Infection?

Kattan

Assi

2020

Immunotherapy

View full text Add to dashboard Cite

Since we are not able to consider ICIs treatment as highly immunosuppressive, avoiding it in cancer patients to reduce coronavirus infections could deprive these patients from a highly active class of drugs. "The severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) has been declared a pandemic by the WHO that claimed the lives of thousands of people within a few months. Cancer patients represent a vulnerable population due to the acquired immunodeficiency associated with anti-cancer therapy. Immune checkpoint inhibitors have largely impacted the prognosis of a multitude of malignancies with significant improvement in survival outcomes and a different, tolerable toxicity profile. In this paper, we assess the safety of ICI administration in cancer patients during the coronavirus pandemic in order to guide the usage of these highly efficacious agents.

show abstract

“…This function is disrupted by environmental factors and/or host genetic factors that cause activation of immune responses that leads to IEC damage and perpetuation of the aberrant inflammation 1 2 3 4 . The non-infectious inflammatory diseases that occur in the intestinal tract such as autoimmune inflammatory bowel diseases (IBD), immune checkpoint blocker (ICB) mediated colitis, and alloimmune T cell mediated gastrointestinal graft-versus-host disease (GI-GVHD) often have similar symptoms and cause significant morbidity and mortality 1 5 6 . Although the pathophysiology of each of these diseases is a complex interplay of the environmental and genetic factors, T cell mediated damage of IECs plays a vital role in the cause and severity of all of these conditions.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Complex II In Intestinal Epithelial Cells Regulates T-cell Mediated Immunopathology

Fujiwara

Mathew

Kovalenko

et al. 2020

Preprint

View full text Add to dashboard Cite

Keywords: mitochondria, succinate dehydrogenase, bone marrow transplantation, graft-versus-host 22 disease, intestinal epithelium 23 24 25Summary 26Intestinal epithelial cell (IEC) damage by T cells contributes to alloimmune, autoimmune and iatrogenic 27 diseases such as graft-versus-host disease (GVHD), inflammatory bowel disease (IBD) and immune 28 checkpoint blockade (ICB) mediated colitis, respectively. Despite significant advances in understanding 29 the aberrant biology of T cells in these diseases, little is known about how the fundamental biological 30 processes of the target IECs influence the disease severity. Here, through analyses of metabolic 31 pathways of IECs, we identified disruption of oxidative phosphorylation without a concomitant change 32 in glycolysis and an increase in succinate levels in several distinct in vivo models of T cell mediated 33 mediated gastrointestinal graft-versus-host disease (GI-GVHD) often have similar symptoms and cause 50 significant morbidity and mortality 1 5 6 . Although the pathophysiology of each of these diseases is a 51 complex interplay of the environmental and genetic factors, T cell mediated damage of IECs plays a 52 vital role in the cause and severity of all of these conditions. Immunosuppression with corticosteroids, 53 and anti-cytokine therapies have shown good results with adverse effects, but are still incomplete 5 7 8 . 54The biology and treatments of these diseases are often understood and targeted from the immune cell 55 3 and inflammation perspective, but the pathogenesis and severity from host IEC target cell perspective 56 remain undefined. 57 58 Emerging data in recent years have brought into focus the central role of immune cell metabolism in the 59 regulation of intestinal inflammatory diseases. APCs, including macrophages and dendritic cells, and T 60 cells show changes in metabolic programming, including morphological alterations in mitochondria, 61transitioning from glycolysis dependence (pro-inflammatory macrophages and effector T cells) to 62 oxidative phosphorylation (OXPHOS) dependence (anti-inflammatory macrophages and memory T 63 cells) 9 10 11 and regulate intestinal T cell mediated diseases such as GI GVHD and IBD. However, 64whether the metabolism of the targets of these pathogenic T cells in these diseases, the IECs, are 65 perturbed or reprogrammed, and if so, whether this has an impact on the disease severity remains 66 unknown. The mammalian GI tract is a relatively hypoxic region and thus, IECs are uniquely adapted to 67 this hypoxic environment 12 13 . In this study, we aimed to determine the metabolic changes in IECs when 68 they are targeted by pathogenic T effector cells. We found that in the context of pathogenic T cell 69 mediated damage, the IECs demonstrated a reduction in OXPHOS and accumulated succinate as a result 70 of decrease in SDHA, a component of mitochondrial complex II. The reduction of SDHA in IECs 71 aggravated disease severity in multiple T cell mediated models such as the alloimmune mediated GI 72 GVHD, ...

show abstract

Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance

Cited by 1,361 publications

References 171 publications

Immune checkpoint inhibitor‐associated pituitary‐adrenal dysfunction: A systematic review and meta‐analysis

Immune checkpoint inhibitor‐associated pituitary‐adrenal dysfunction: A systematic review and meta‐analysis

Do checkpoint inhibitors compromise the cancer patients’ Immunity and Increase the Vulnerability to COVID-19 Infection?

Mitochondrial Complex II In Intestinal Epithelial Cells Regulates T-cell Mediated Immunopathology

Contact Info

Product

Resources

About