title: Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4.
abstract: OBJECTIVE
  Cytotoxic 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.
  
  
  METHODS
  We treated 198 patients with metastatic melanoma (MM) or renal cell carcinoma (RCC) with ipilimumab.
  
  
  RESULTS
  The 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).
  
  
  CONCLUSIONS
  CTLA4 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.
authors.affiliation: Surgery Branch and Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1201, USA.
authors.forename: Kimberly E
authors.initials: KE
authors.lastname: Beck
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Blansfield
authors.forename: Khoi Q
authors.initials: KQ
authors.lastname: Tran
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Feldman
authors.forename: Marybeth S
authors.initials: MS
authors.lastname: Hughes
authors.forename: Richard E
authors.initials: RE
authors.lastname: Royal
authors.forename: Udai S
authors.initials: US
authors.lastname: Kammula
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Topalian
authors.forename: Richard M
authors.initials: RM
authors.lastname: Sherry
authors.forename: David
authors.initials: D
authors.lastname: Kleiner
authors.forename: Martha
authors.initials: M
authors.lastname: Quezado
authors.forename: Israel
authors.initials: I
authors.lastname: Lowy
authors.forename: Michael
authors.initials: M
authors.lastname: Yellin
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: James C
authors.initials: JC
authors.lastname: Yang
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000627:therapeutic use; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D004760:Enterocolitis / Q000139:chemically induced* / Q000188:drug therapy; D005260:Female; D005765:Gastrointestinal Agents / Q000627:therapeutic use; D006801:Humans; D000069285:Infliximab; D000074324:Ipilimumab; D007680:Kidney Neoplasms / Q000188:drug therapy; D008297:Male; D008545:Melanoma / Q000188:drug therapy; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D012878:Skin Neoplasms / Q000188:drug therapy
chemical_list: D000305:Adrenal Cortex Hormones; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; C556707:Ctla4 protein, mouse; D005765:Gastrointestinal Agents; D000074324:Ipilimumab; D000069285:Infliximab