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Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4.

AbstractPURPOSE:
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.
PATIENTS AND 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).
CONCLUSION:
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.
AuthorsKimberly E Beck, Joseph A Blansfield, Khoi Q Tran, Andrew L Feldman, Marybeth S Hughes, Richard E Royal, Udai S Kammula, Suzanne L Topalian, Richard M Sherry, David Kleiner, Martha Quezado, Israel Lowy, Michael Yellin, Steven A Rosenberg, James C Yang
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 24 Issue 15 Pg. 2283-9 (May 20 2006) ISSN: 1527-7755 [Electronic] United States
PMID16710025 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
Chemical References
  • Adrenal Cortex Hormones
  • Antibodies, Monoclonal
  • Antigens, CD
  • Antigens, Differentiation
  • Antineoplastic Agents
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Cancer Vaccines
  • Ctla4 protein, mouse
  • Gastrointestinal Agents
  • Ipilimumab
  • Infliximab
Topics
  • Adrenal Cortex Hormones (therapeutic use)
  • Antibodies, Monoclonal (adverse effects, therapeutic use)
  • Antigens, CD
  • Antigens, Differentiation (immunology)
  • Antineoplastic Agents (adverse effects, therapeutic use)
  • CTLA-4 Antigen
  • Cancer Vaccines
  • Carcinoma, Renal Cell (drug therapy)
  • Enterocolitis (chemically induced, drug therapy)
  • Female
  • Gastrointestinal Agents (therapeutic use)
  • Humans
  • Infliximab
  • Ipilimumab
  • Kidney Neoplasms (drug therapy)
  • Male
  • Melanoma (drug therapy)
  • Middle Aged
  • Neoplasms (drug therapy)
  • Skin Neoplasms (drug therapy)

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