British Society of Gastroenterology endorsed guidance for the management of immune checkpoint inhibitor-induced enterocolitis

Powell, Nick; Ibraheim, Hajir; Raine, Tim; Speight, R. Ally; Papa, Sophie; Brain, Oliver; Green, Michael; Samaan, Mark A; Spain, Lavinia; Yousaf, Nadia; Hunter, Nikki; Eldridge, Lucy; Pavlidis, Polychronis; Irving, Peter M.; Hayee, Bu’Hussain; Turajlic, Samra; Larkin, James; Lindsay, James O.; Gore, Martin

doi:10.1016/s2468-1253(20)30014-5

Cited by 38 publications

(57 citation statements)

References 140 publications

(207 reference statements)

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“…7 11 Given that CPI-induced enterocolitis is the most common cause of CPI treatment interruption, permanent discontinuation and treatment-related death, 12 13 it is important to define optimal management strategies. Gastroenterology 14 and Oncology societal guidance 10 recommend institution of Open access corticosteroids as first-line anti-inflammatory therapy. In corticosteroid refractory disease, which occurs in over a third of patients, infliximab (IFX), an anti-tumor necrosis factor (TNF) monoclonal antibody, is recommended.…”

Section: Introductionmentioning

confidence: 99%

Clinical outcomes of patients with corticosteroid refractory immune checkpoint inhibitor-induced enterocolitis treated with infliximab

Alexander

Ibraheim

Sheth

et al. 2021

J Immunother Cancer

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IntroductionImmune checkpoint inhibitors (CPIs) have changed the treatment landscape for many cancers, but also cause severe inflammatory side effects including enterocolitis. CPI-induced enterocolitis is treated empirically with corticosteroids, and infliximab (IFX) is used in corticosteroid-refractory cases. However, robust outcome data for these patients are scarce.MethodsWe conducted a multicenter (six cancer centers), cohort study of outcomes in patients treated with IFX for corticosteroid-refractory CPI-induced enterocolitis between 2007 and 2020. The primary outcome was corticosteroid-free clinical remission (CFCR) with Common Terminology Criteria for Adverse Events (CTCAE) grade 0 for diarrhea at 12 weeks after IFX initiation. We also assessed cancer outcomes at 1 year using RECIST V1.1 criteria.Results127 patients (73 male; median age 59 years) were treated with IFX for corticosteroid-refractory CPI-induced enterocolitis. Ninety-six (75.6%) patients had diarrhea CTCAE grade >2 and 115 (90.6%) required hospitalization for colitis. CFCR was 41.2% at 12 weeks and 50.9% at 26 weeks. In multivariable logistic regression, IFX-resistant enterocolitis was associated with rectal bleeding (OR 0.19; 95% CI 0.04 to 0.80; p=0.03) and absence of colonic crypt abscesses (OR 2.16; 95% CI 1.13 to 8.05; p=0.03). Cancer non-progression was significantly more common in patients with IFX-resistant enterocolitis (64.4%) as compared with patients with IFX-responsive enterocolitis (37.5%; p=0.013).ConclusionThis is the largest study to date reporting outcomes of IFX therapy in patients with corticosteroid-refractory CPI-induced enterocolitis. Using predefined robust endpoints, we have demonstrated that fewer than half of patients achieved CFCR. Our data also indicate that cancer outcomes may be better in patients developing prolonged and severe inflammatory side effects of CPI therapy.

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Section: Introductionmentioning

confidence: 99%

Clinical outcomes of patients with corticosteroid refractory immune checkpoint inhibitor-induced enterocolitis treated with infliximab

Alexander

Ibraheim

Sheth

et al. 2021

J Immunother Cancer

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“…Colonoscopy may still be useful in patients with treatment-refractory IMC as the presence of gross abnormalities in the proximal colon and persistent histologic evidence of IMC can inform the clinician's decision to initiate biologic therapy early in the treatment course. 7 Non-invasive biomarkers such as fecal calprotectin and lactoferrin have demonstrated utility in confirming the diagnosis of IMC [9][10][11] ; however, they are not routinely used to guide treatment. In addition, these biomarkers may not help identify alternative structural causes of gastrointestinal symptoms such as IMC with superimposed infection.…”

Section: Discussionmentioning

confidence: 99%

“…However, studies have shown that CTCAE criteria for colitis and diarrhea alone may not accurately predict IMC severity and prognosis. 3,4 The role of endoscopy in diagnosing and assessing IMC severity has been studied 5,6 and, according to recent guidelines, 5,7 lower endoscopy with biopsy is considered the gold standard for diagnosing IMC in addition to ruling out alternative diagnoses. Nevertheless, the optimal lower endoscopic strategy (full colonoscopy or a limited flexible sigmoidoscopy) for obtaining biopsies and assessing severity of mucosal damage remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Flexible sigmoidoscopy may be sufficient for initial evaluation of suspected immunotherapy‐mediated colitis: A cross‐sectional study

Silva

Trieu

Rajan

et al. 2021

J of Gastro and Hepatol

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Background and Aim: Immune checkpoint inhibitors (ICIs) have shown promise in treating a variety of cancers. Their increased use coincides with increased incidence of immunotherapy-mediated colitis (IMC), a common adverse effect. Optimal strategy for endoscopic evaluation of IMC (full colonoscopy or flexible sigmoidoscopy) is not welldefined. Methods: Retrospective review of all patients at City of Hope referred to gastroenterology for evaluation of IMC due to gastrointestinal symptoms was performed. Patients with an existing histologic diagnosis of IMC established at an outside hospital or a diagnosis of infectious or chronic colitis were excluded. Results: We identified 51 symptomatic patients on ICIs prompting evaluation for IMC with colonoscopy (47/51) or flexible sigmoidoscopy (4/51). All distal rectosigmoid biopsies during flexible sigmoidoscopy demonstrated histologic evidence of IMC. In full colonoscopy, IMC was either present in all segments of colon simultaneously (35/47) or absent from all segments (12/47). No isolated proximal colonic biopsies demonstrated IMC. Endoscopically normal mucosa demonstrated histologic evidence of IMC up to 68.6% of the time. Endoscopically abnormal right, transverse, and left colon had low sensitivity (35.3%, 34.3%, and 41.7%, respectively) and high specificity (100.0%, 100.0%, and 91.7%, respectively) for histological presence of IMC. Conclusions: Distal colon biopsies in patients on ICI therapy with diarrhea and suspected IMC were sufficient for diagnosing IMC in our cohort. Further, we found histologic evidence of IMC in biopsies taken from normal-appearing mucosa in a number of patients, suggesting that a normal endoscopic appearance does not preclude the presence of IMC and biopsies should be taken from both normal and abnormal-appearing mucosa.

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“…Neutrophil accumulation in the colon is a key feature of CPI-colitis 27 , therefore, we also evaluated the colonic myeloid compartment. There was also signi cant accumulation of CD11b + Gr-1 high neutrophils and Ly6C high MHC class II − in ammatory monocytes in the colon of mice treated with FMT and CPI (Figs.…”

Section: The Composition Of the Intestinal Microbiota Regulates Susceptibility To Immune Checkpoint Inhibitor-induced Colitismentioning

confidence: 99%

Immune checkpoint inhibitor-induced colitis is mediated by CXCR6+ polyfunctional lymphocytes and is dependent on the IL23/IFNγ axis

Cozzetto

Liu

et al. 2022

Preprint

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Immune checkpoint inhibitors (CPIs) have revolutionised cancer treatment, with previously untreatable disease now amenable to potential cure. Combination regimens of anti-CTLA-4 and anti-PD-1 show enhanced efficacy but are prone to off-target immune-mediated tissue injury, particularly at the barrier surfaces. CPI-induced colitis is a common and serious complication. To probe the impact of immune checkpoints on intestinal homeostasis, mice were challenged with combination anti-CTLA-4/anti-PD-1 immunotherapy and manipulation of the intestinal microbiota. Colonic immune responses were profiled using bulk and single-cell RNA-sequencing and flow cytometry. CPI-colitis was dependent on the composition of the intestinal microbiota and was characterized by remodelling of mucosal lymphocytes with induction of polyfunctional lymphocyte responses characterized by increased expression of interferon-γ (IFNγ), other pro-inflammatory cytokines/chemokines (Il22, Il17a Ccl3, Ccl4 and Ccl9), cytotoxicity molecules (Gzmb, Gzma, Prf1, Nkg7) and the chemokine receptor Cxcr6. In comparison with mucosal lymphocytes in the steady state, polyfunctional lymphocytes from both CD4+ and CD8+ lineages upregulated costimulatory molecules and checkpoint molecules in CPI-colitis, indicating that these cells are tightly regulated. CPI-colitis was attenuated following depletion of effector lymphocytes or following blockade of the IL23/IFNγ axis. This study provides new mechanistic insights into CPI-colitis, identifying polyfunctional, cytotoxic lymphocytes as key mediators of disease. Therapeutic targeting of their effector response or regulatory networks, including the IL23/IFNγ axis likely holds the key to preventing and reversing CPI-colitis.

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British Society of Gastroenterology endorsed guidance for the management of immune checkpoint inhibitor-induced enterocolitis

Cited by 38 publications

References 140 publications

Clinical outcomes of patients with corticosteroid refractory immune checkpoint inhibitor-induced enterocolitis treated with infliximab

Clinical outcomes of patients with corticosteroid refractory immune checkpoint inhibitor-induced enterocolitis treated with infliximab

Flexible sigmoidoscopy may be sufficient for initial evaluation of suspected immunotherapy‐mediated colitis: A cross‐sectional study

Immune checkpoint inhibitor-induced colitis is mediated by CXCR6+ polyfunctional lymphocytes and is dependent on the IL23/IFNγ axis

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