Histopathological and immunophenotypic features of ipilimumab‐associated colitis compared to ulcerative colitis

Adler, Brittany; Pezhouh, Maryam Kherad; Kim, Amy; Luan, Lan; Zhu, Qingfeng; Gani, Faiz; Yarchoan, Mark; Chen, Jonathan; Voltaggio, Lysandra; Parian, Alyssa; Lazarev, Mark; Lauwers, Gregory Y.; Pawlik, Timothy M.; Montgomery, Elizabeth A.; Jaffee, Elizabeth M.; Le, Dung T.; Taube, Janis M.; Anders, Robert A.

doi:10.1111/joim.12744

Cited by 84 publications

(55 citation statements)

References 34 publications

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“…ICI colitis, infection and IBD show significant clinicopathological overlap, 2,4,5,24–27 and distinction is important for accurate diagnosis and optimum clinical management. The ability of some commensal segmented filamentous bacteria to induce Th17 cell accumulation in the lamina propria 28 and the ability of infectious organisms to induce PD‐L1 overexpression to promote immune evasion 21,29 could underlie the PD‐L1 epithelial overexpression observed in our cases of CMV colitis.…”

Section: Discussionmentioning

confidence: 99%

“…The skin, endocrine system and gastrointestinal (GI) tract are among the most common systems involved by IRAEs, 1 and their pathological findings frequently mimic those of idiopathic or autoimmune diseases, such as inflammatory bowel disease (IBD), 2–5 lupus nephritis, 6 myocarditis, 7,8 hypophysitis, 9 pancreatitis, and autoimmune thyroiditis 1 . Expression of checkpoint ligands in non‐tumoral tissues affected by IRAEs has been described in the pituitary gland of patients with checkpoint inhibitor‐associated hypophysitis [cytotoxic T‐lymphocyte‐associated protein 4 (CTLA4)], 9,10 myocytes of patients with ICI‐related programmed death‐ligand 1 (PD‐L1) myocarditis (PD‐L1), 7,8 and renal tubules of patients with ICI‐related acute interstitial nephritis (PD‐L1) 11 .…”

Section: Introductionmentioning

confidence: 99%

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Programmed cell death‐1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) expression in PD‐1 inhibitor‐associated colitis and its mimics

et al. 2020

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Aims Immune checkpoint inhibitors (ICIs) have revolutionised the treatment of advanced malignancies by boosting immune‐mediated destruction of neoplastic cells, but are associated with side effects stemming from generalised immune system activation against normal tissues. Checkpoint ligand expression in non‐tumoral cells of tissues affected by immune‐related adverse effects has been described in ICI‐associated hypophysitis, myocarditis, and acute interstitial nephritis. We aimed to investigate the tissue expression of the immune checkpoint receptor programmed cell death‐1 (PD‐1) and its ligand, programmed death‐ligand 1 (PD‐L1), in PD‐1 inhibitor‐associated colitis (PD1i colitis). Methods and results PD‐1 and PD‐L1 immunohistochemical expression levels were analysed in 15 cases of PD1i colitis and potential mimics—infectious colitis and inflammatory bowel disease (IBD). Increased epithelial expression of PD‐L1 was observed in PD1i colitis as compared with normal colon and infectious colitis, but the expression level was lower than that in IBD. Conversely, PD‐1 expression in inflammatory cells was higher in infectious colitis, intermediate in IBD, and minimal or absent in normal colon and in patients receiving PD‐1 inhibitors. Conclusions Although our results do not justify the use of PD‐L1 as a discriminatory marker of PD1i colitis against other entities within the differential diagnosis, they support the concept that PD1i colitis and IBD have similar pathogenetic mechanisms. They also highlight the fact that PD‐L1 epithelial overexpression is a commonly used mechanism of the gastrointestinal tract mucosa to protect itself from inflammatory‐mediated damage resulting from different aetiologies, which probably underpins the high incidence of gastrointestinal immune‐related adverse effects in patients receiving ICI therapies, in whom this mechanism is disrupted.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Programmed cell death‐1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) expression in PD‐1 inhibitor‐associated colitis and its mimics

et al. 2020

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“…Diarrhea and colitis ICI associated colitis occurs more commonly with anti-CTLA-4 and with combination therapy than with anti-PD-(L)1 antibodies alone (table 2) and untreated can lead to intestinal perforation 55. Histologically, patients have infiltration of the lamina propria with lymphocytes, plasma cells, neutrophils, and eosinophils, and crypt abscesses can sometimes be seen 65657. Colitis associated autoantibodies, such as anti- Saccharomyces cerevisiae antibodies and perinuclear anti-neutrophilic cytoplasmic antibodies are rarely present 58.…”

Section: Clinical Presentation Of Checkpoint Inhibitor Associated Autmentioning

confidence: 99%

“…These irAEs commonly affect the skin, colon, liver, lungs, endocrine organs, and joints, but can affect almost any organ. IrAEs can mimic autoimmune diseases seen in other settings, but often differ at the level of tissue pathology 56. Unlike the treatment of autoimmune diseases in other settings, irAE treatment paradigms must take into account the potential impact of immunosuppression on cancer outcomes.…”

Section: Introductionmentioning

confidence: 99%

Autoimmune complications of immunotherapy: pathophysiology and management

Chan

Bass

2020

BMJ

100

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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.

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“…In addition to TMB and antigen presentation-related parameters, the model identified a set of prior to therapy observables such as CD8 T cell clonality in blood or abundance of Teff and Treg and their ratio in the tumor, as well as parameters such as the density of naïve T cell in the blood, number of TdLNs, and T cell killing rate as important markers for higher chance of tumor shrinkage. Although we have not been able to readily validate the prediction of the model due to scarcity of available data in the literature, the future research aims to quantify the numbers of different cell types in the resected tumor samples from the patients using a validated multiplex immunofluorescence approach (25,37). One of the limitations of the current model is the assumption that naïve T cells of all TCR (T cell receptor) variations are always available in excess.…”

Section: Discussionmentioning

confidence: 99%

A Computational Model of Neoadjuvant PD-1 Inhibition in Non-Small Cell Lung Cancer

Jafarnejad

Gong

Gabrielson

et al. 2019

AAPS J

100

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Immunotherapy and immune checkpoint blocking antibodies such as anti-PD-1 are approved and significantly improve the survival of advanced non-small cell lung cancer (NSCLC) patients, but there has been little success in identifying biomarkers capable of separating the responders from non-responders before the onset of the therapy. In this study, we developed a quantitative system pharmacology (QSP) model to represent the anti-tumor immune response in human NSCLC that integrated our knowledge of tumor growth, antigen processing and presentation, T cell activation and distribution, antibody pharmacokinetics, and immune checkpoint dynamics. The model was calibrated with the available data and was used to identify potential biomarkers as well as patient-specific response based on the patient parameters. The model predicted that in addition to tumor mutational burden (TMB), a known biomarker for anti-PD-1 therapy in NSCLC, the number of effector T cells and regulatory T cells in the tumor and blood is a predictor of the responders. Furthermore, the model simulated a set of 12 patients with known TMB and MHC/antigen-binding affinity from a recent clinical trial ( ClinicalTrials.gov number, NCT02259621) on neoadjuvant nivolumab therapy in resectable lung cancer and predicted an augmented durable response in patients with adjuvant nivolumab treatment in addition to the clinical trial protocol of neoadjuvant nivolumab treatment followed by resection. Overall, the model provides a valuable framework to model tumor immunity and response to immune checkpoint blockers to enhance biomarker discovery and performing virtual clinical trials to aid in design and interpretation of the current trials with fewer patients. Electronic supplementary material The online version of this article (10.1208/s12248-019-0350-x) contains supplementary material, which is available to authorized users.

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Histopathological and immunophenotypic features of ipilimumab‐associated colitis compared to ulcerative colitis

Abstract: Ipi-AC is a distinct pathologic entity with notable clinical and histopathological differences compared to UC. These findings provide insights into the pathophysiology of immune-related adverse events (iAEs) from ipilimumab therapy.

Cited by 84 publications

References 34 publications

Programmed cell death‐1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) expression in PD‐1 inhibitor‐associated colitis and its mimics

Programmed cell death‐1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) expression in PD‐1 inhibitor‐associated colitis and its mimics

Autoimmune complications of immunotherapy: pathophysiology and management

A Computational Model of Neoadjuvant PD-1 Inhibition in Non-Small Cell Lung Cancer

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