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document
Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma . Blockade of cytotoxic T-lymphocyte antigen-4 ( CTLA-4 ) by ipilimumab leads to immune-mediated tumor regression and immune-related adverse events ( irAEs ) , including diarrhea and colitis . The current analyses were undertaken to promote an understanding of the underlying mechanism of action and to identify potential biomarkers that could help in the prediction and management of ipilimumab-induced gastrointestinal irAEs . Treatment-naïve or previously treated patients with unresectable stage III/IV melanoma ( n = 115 ) received open-label ipilimumab ( 10 mg/kg every 3 weeks for four doses ) and were randomized to receive concomitant blinded prophylactic oral budesonide ( 9 mg/d with gradual taper through week 16 ) or placebo . Outcome measures included histologic assessment of bowel biopsies and assessment of serologic markers of inflammatory bowel disease ( IBD ) , fecal calprotectin levels , and polymorphisms in immune-related genes . Ipilimumab resulted in dysregulation of gastrointestinal mucosal immunity as evidenced by altered antibody levels to enteric flora , inflammatory cell infiltration into gastrointestinal mucosa , and increased fecal calprotectin associated with diarrhea and clinical evidence of colitis . The pattern of ipilimumab-induced antibody titers to microbial flora and the histologic features and location of the inflammation were distinct from classic IBD . Prophylactic budesonide did not prevent ipilimumab-induced bowel inflammation . Despite an observed association between colonic inflammation and grade 2 or higher diarrhea , no baseline biomarkers could reliably predict development of gastrointestinal toxicity . Although classic IBD and ipilimumab-related gastrointestinal toxicity are both immune mediated , the observed pattern of biomarkers suggests ipilimumab-related gastrointestinal toxicity may be a distinct clinicopathologic entity .
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Intervention_Pharmacological
ipilimumab
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Outcome_Physical
histologic assessment of bowel biopsies
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Outcome_Physical
assessment of serologic markers of inflammatory bowel disease ( IBD )
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Outcome_Physical
fecal calprotectin levels
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Outcome_Physical
polymorphisms in immune-related genes
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Outcome_Physical
levels to enteric flora
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Outcome_Physical
inflammatory cell infiltration
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Outcome_Physical
fecal calprotectin
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Outcome_Physical
diarrhea
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Outcome_Physical
colitis
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Outcome_Physical
diarrhea
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Participant_Condition
melanoma