Berman David, Parker Susan M, Siegel Jonathan, Chasalow Scott D, Weber Jeffrey, Galbraith Susan, Targan Stephan R, Wang Hanlin L
Bristol-Myers Squibb Company, Princeton, New Jersey, USA.
Cancer Immun. 2010 Nov 24;10:11.
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.
伊匹单抗阻断细胞毒性T淋巴细胞抗原4（CTLA-4）可导致免疫介导的肿瘤消退以及免疫相关不良事件（irAEs），包括腹泻和结肠炎。进行当前分析是为了促进对潜在作用机制的理解，并识别有助于预测和管理伊匹单抗诱导的胃肠道irAEs的潜在生物标志物。未经治疗或先前接受过治疗的不可切除III/IV期黑色素瘤患者（n = 115）接受开放标签的伊匹单抗治疗（每3周10 mg/kg，共4剂），并随机接受盲法预防性口服布地奈德（9 mg/d，至第16周逐渐减量）或安慰剂。观察指标包括肠道活检的组织学评估、炎症性肠病（IBD）血清学标志物评估、粪便钙卫蛋白水平以及免疫相关基因的多态性。伊匹单抗导致胃肠道黏膜免疫失调，表现为针对肠道菌群的抗体水平改变、炎症细胞浸润到胃肠道黏膜以及与腹泻和结肠炎临床证据相关的粪便钙卫蛋白增加。伊匹单抗诱导的针对微生物菌群的抗体滴度模式以及炎症的组织学特征和部位与经典IBD不同。预防性布地奈德不能预防伊匹单抗诱导的肠道炎症。尽管观察到结肠炎症与2级或更高程度腹泻之间存在关联，但没有基线生物标志物能够可靠地预测胃肠道毒性的发生。虽然经典IBD和伊匹单抗相关的胃肠道毒性均由免疫介导，但观察到的生物标志物模式表明，伊匹单抗相关的胃肠道毒性可能是一种独特的临床病理实体。
