Inflammatory gastrointestinal diseases associated with PD-1 blockade antibodies

Collins, Michael; Michot, Jean‐Marie; Danlos, F-X.; Mussini, Charlotte; Soularue, Émilie; Mateus, Christine; Loirat, Delphine; Buisson, Anthony; Rosa, Isabelle; Lambotte, Olivier; Laghouati, Salim; Chaput, Nathalie; Coutzac, Clélia; Voisin, Anne-Laure; Soria, Jean‐Charles; Marabelle, Aurélien; Champiat, Stéphane; Robert, Caroline; Carbonnel, Franck

doi:10.1093/annonc/mdx403

Cited by 131 publications

(129 citation statements)

References 22 publications

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“…As in anti-CTLA-4-induced colitis, most patients respond to corticosteroids, including up to 87.5% of patients with acute colitis and 57% of patients with microscopic colitis 59. Most patients (75% in our experience) with upper GI inflammation respond to corticosteroids.…”

Section: Resultsmentioning

confidence: 64%

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Enterocolitis due to immune checkpoint inhibitors: a systematic review

Soularue

Lepage

Colombel

et al. 2018

Gut

200

156

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Immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed death-1 (PD-1)/ligand are increasingly used to treat several types of cancer. These drugs enhance antitumour T-cell activity and therefore induce immune-related adverse effects (irAE), of which gastrointestinal (GI) irAE are among the most frequent and severe. This systematic literature review summarises the clinical manifestations, management and pathophysiology of GI irAE due to immune checkpoint inhibitors. GI irAE induced by anti-CTLA-4 are frequent, potentially severe and resemble IBD, whereas those induced by PD-1 blockade seem to be less frequent and clinically more diverse. Baseline symbiotic gut microbiota is associated with an enhanced antitumour response to immune checkpoint inhibitors and an increased susceptibility to developing enterocolitis, in patients treated with anti-CTLA-4. These findings open new perspectives for possible manipulation of the gut microbiota in order to better identify responders to immune checkpoint inhibitors and to increase their efficacy and safety.

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Section: Resultsmentioning

confidence: 64%

“…Two-thirds of patients investigated for GI irAE related to anti-PD-1 had an abnormal upper GI endoscopy, 10.5% (n=2) of them with necrotising gastritis59 (figure 2C). …”

Section: Resultsmentioning

confidence: 99%

Enterocolitis due to immune checkpoint inhibitors: a systematic review

Soularue

Lepage

Colombel

et al. 2018

Gut

200

156

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“…GI‐irAEs are among the most common toxicities of current ICIs, although severe GI‐irAEs are considerably more common with anti‐CTLA‐4 treatment than with treatments that target PD‐1/PD‐L1 alone . In a study of 44 patients referred to a digestive care unit for suspected anti‐PD‐1‐induced GI‐irAEs, half had alternative aetiologies identified, including intestinal metastases, reinforcing the need for histological confirmation. Diarrhoea is the most common clinical presentation for a GI‐irAE, with most patients showing histological evidence of enterocolitis .…”

Section: Introductionmentioning

confidence: 99%

“…Diarrhoea is the most common clinical presentation for a GI‐irAE, with most patients showing histological evidence of enterocolitis . The incidence of diarrhoea is reported to be up to 13% for anti‐PD‐1/PD‐L1 therapy and 35% for anti‐CTLA‐4 therapy . Severe enterocolitis, which is one of the most frequent severe irAEs, is principally caused by anti‐CTLA‐4, and, in rare cases, leads to perforation and death .…”

Section: Introductionmentioning

confidence: 99%

Immune‐related adverse events in the gastrointestinal tract: diagnostic utility of upper gastrointestinal biopsies

et al. 2019

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Aims Immune checkpoint inhibitors (ICIs) improve survival across a range of malignancies but are also associated with a spectrum of gastrointestinal (GI) immune‐related adverse events (GI‐irAEs). The aims of this study were to explore the diagnostic value of gastric and duodenal biopsies and to address considerations in the differential diagnosis. Methods and results We identified 39 patients who were treated with ICIs and had a subsequent upper GI biopsy. We recorded clinical data and endoscopic findings, and reviewed their gastric, duodenal and colonic biopsies. Twenty‐one (54%) patients were treated with an anti‐programmed cell death protein 1 (PD‐1)/anti‐programmed cell death ligand 1 antibody alone, and 17 (44%) patients were treated with a combination of anti‐cytotoxic T‐lymphocyte‐associated protein‐4 and anti‐PD‐1 antibodies. Thirty‐two (82%) patients presented with diarrhoea. Gastric alterations included periglandular inflammation and granulomas, and duodenal changes included villous blunting, intraepithelial lymphocytosis, granulomas, and neutrophilic activity. We recognised four patterns of colonic injury: (i) acute self‐limiting colitis; (ii) lymphocytic colitis; (iii) collagenous colitis; and (iv) apoptosis‐only. Twenty‐nine (74%) and 10 (26%) patients were diagnosed clinically as positive and negative for GI‐irAEs, respectively. Gastric periglandular inflammation (P = 0.004) and an increased number of colonic lamina propria mononuclear cells (P = 0.04) correlated with the clinical diagnosis of a GI‐irAE. Histological alterations associated with ICI injury were more often identified in upper GI biopsies (71%) than in colonic biopsies (65%). Conclusions The morphological spectrum of ICI‐related GI disease is broad, and mimics a range of infectious and inflammatory diseases. Gastric periglandular inflammation represents one of the more characteristic histological features of GI‐irAEs. The study underscores the importance of a comprehensive review of upper and lower GI biopsies for the diagnosis of GI‐irAEs.

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“…A 57-year-old man with poorly differentiated neuroendocrine tumor developed pseudo-obstruction after 11 doses of pembrolizumab [26]. In this case, mucosal biopsies showed chronic inflammation, but deep biopsies were not obtained.…”

Section: Discussionmentioning

confidence: 99%

Fatal enteric plexus neuropathy after one dose of ipilimumab plus nivolumab: a case report

Appelbaum¹,

Wells²,

Hiatt³

et al. 2018

j. immunotherapy cancer

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BackgroundImmune checkpoint inhibitors (ICIs) are the treatment of choice for several cancers and can be associated with remarkable clinical benefit, but can also cause serious immune-related adverse events (irAEs). Management of rare and severe irAEs is challenged by an incomplete knowledge of their natural history and pathogenetic mechanisms. We report a case of fatal acute-onset gastro-intestinal (GI) hypomotility from myenteric plexus neuropathy following a single dose of ipilimumab plus nivolumab given for treatment of Merkel cell carcinoma (MCC).Case presentationA 66-year-old man with recurrent metastatic MCC involving several organs (liver, bones and disseminated retroperitoneal lymphadenopathy) developed profound pharyngeal dysphagia and ileus that started 7 days after receiving a single administration of combination immune checkpoint blockade consisting of nivolumab (3 mg/kg) and low-dose ipilimumab (1 mg/kg). A swallowing study showed oropharyngeal dysfunction and aspiration. Imaging studies were consistent with diffuse intestinal paresis. An extensive work-up did not reveal obvious causes of these symptoms, and enteric plexopathy was suspected. Empiric immune suppressive therapy was initiated urgently. Despite an escalating immunosuppressive regimen that included high dose steroids, tacrolimus and therapeutic plasma exchange, no improvement in GI motility was seen and the patient suffered repeated episodes of aspiration. Seven weeks after the onset of GI hypomotility, the patient succumbed to sepsis from intestinal perforations. At autopsy, histologic specimens obtained from the entire GI tract (pharynx to rectum) showed near complete loss of ganglion cells within the myenteric and submucosal plexuses. An associated inflammatory infiltrate was not seen, suggesting a ‘burned out’ phase of illness. C4d complement deposition was found at the ganglionic sites, suggesting antibody-mediated pathogenesis. Remarkably, at sites of previously suspected Merkel cell metastases, no residual viable Merkel cell carcinoma was identified.ConclusionsGI-tract paresis due to myenteric neuritis is a rarely reported toxicity of ICIs. Because the window of reversibility is likely to be very brief, quick and decisive interventions are warranted. Subtle functional and anatomic perturbations of the myenteric nervous system from the use of ICIs may be more prevalent than realized and should be suspected and addressed in both clinical and investigational settings.

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Inflammatory gastrointestinal diseases associated with PD-1 blockade antibodies

Abstract: This study suggests that GI-irAE are different and less frequent with anti PD-1 than with anti CTLA-4.

Cited by 131 publications

References 22 publications

Enterocolitis due to immune checkpoint inhibitors: a systematic review

Enterocolitis due to immune checkpoint inhibitors: a systematic review

Immune‐related adverse events in the gastrointestinal tract: diagnostic utility of upper gastrointestinal biopsies

Fatal enteric plexus neuropathy after one dose of ipilimumab plus nivolumab: a case report

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