Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4
Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4
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DOI：
10.1200/jco.2005.04.5716
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发表时间：
2006-05-20
影响因子：
45.3
通讯作者：
Yang, James C.
中科院分区：
文献类型：
--
作者：
Beck, Kimberly E.;Blansfield, Joseph A.;Yang, James C.
目的细胞毒性T淋巴细胞相关抗原4 （CTLA4）是一种抑制T细胞的受体。敲除小鼠体内的CTLA4会导致致死性淋巴细胞增殖，而人类CTLA4的多态性与自身免疫性疾病有关。抗ctla4抗体ipilimumab （MDX-010）的试验已经导致持久的癌症消退和免疫介导的毒性。一份报告的诊断，病理，治疗，临床结果，和免疫介导小肠结肠炎看到伊匹单抗的意义。患者和方法我们用伊匹单抗治疗了198例转移性黑色素瘤（MM）或肾细胞癌（RCC）患者。结果总客观肿瘤有效率为14%。我们观察到几种免疫介导的毒性，包括皮炎、小肠结肠炎、垂体炎、葡萄膜炎、肝炎和肾炎。小肠结肠炎，由3/4级临床表现和/或活检记录定义，是最常见的主要毒性（21%的患者）。患者表现为腹泻，活检显示嗜中性粒细胞和淋巴细胞炎症。大多数发生小肠结肠炎的患者对大剂量全身皮质类固醇有反应。没有证据表明类固醇治疗影响肿瘤反应。5例患者出现穿孔或需要结肠切除术。另外4例类固醇难治性小肠结肠炎患者似乎对英夫利昔单抗阻断肿瘤坏死因子α反应迅速。目的：小肠结肠炎患者的肿瘤缓解率为MM的36%和RCC的35%，而非小肠结肠炎患者的肿瘤缓解率分别为11%和2% （MM和RCC的P = 0.0065和P = 0.0016）。结论ctla4可能是肿瘤耐受和免疫介导的小肠结肠炎的重要组成部分，这些现象在癌症患者中有显著相关性。
PurposeCytotoxic T-lymphocyte-associated antigen 4 (CTLA4) is an inhibitory receptor on T cells. Knocking out CTLA4 in mice causes lethal lymphoproliferation, and polymorphisms in human CTLA4 are associated with autoimmune disease. Trials of the anti-CTLA4 antibody ipilimumab (MDX-010) have resulted in durable cancer regression and immune-mediated toxicities. A report on the diagnosis, pathology, treatment, clinical outcome, and significance of the immune-mediated enterocolitis seen with ipilimumab is presented.Patients and MethodsWe treated 198 patients with metastatic melanoma (MM) or renal cell carcinoma (RCC) with ipilimumab.ResultsThe overall objective tumor response rate was 14%. We observed several immune mediated toxicities including dermatitis, enterocolitis, hypophysitis, uveitis, hepatitis, and nephritis. Enterocolitis, defined by grade 3/4 clinical presentation and/or biopsy documentation, was the most common major toxicity (21% of patients). It presented with diarrhea, and biopsies showed both neutrophilic and lymphocytic inflammation. Most patients who developed enterocolitis responded to high-dose systemic corticosteroids. There was no evidence that steroid administration affected tumor responses. Five patients developed perforation or required colectomy. Four other patients with steroid-refractory enterocolitis appeared to respond promptly to tumor necrosis factor alpha blockade with infliximab. Objective tumor response rates in patients with enterocolitis were 36% for MM and 35% for RCC, compared with 11% and 2% in patients without enterocolitis, respectively (P =.0065 for MM and P =.0016 for RCC).ConclusionCTLA4 seems to be a significant component of tolerance to tumor and in protection against immune mediated enterocolitis and these phenomena are significantly associated in cancer patients.