Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2006 May 20;24(15):2283-9.
doi: 10.1200/JCO.2005.04.5716.

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

Kimberly E Beck  1 , 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
Affiliations

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

Kimberly E Beck et al. J Clin Oncol. .

Abstract

Purpose: 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.

PubMed Disclaimer

Figures

Fig 1
Fig 1
The interval from last dose of ipilimumab (MDX-010) to the onset of symptoms of enterocolitis. An interval of 0 days indicates a patient who received ipilimumab while having some symptoms, and those with intervals of more than 21 days had stopped ipilimumab dosing but went on to develop enterocolitis later.
Fig 2
Fig 2
The number of doses of ipilimumab given before the onset of symptoms of enterocolitis.
Fig 3
Fig 3
Representative photomicrographs of histopathologic features of enterocolitis. (A) Neutrophilic infiltration with colonic crypt destruction (hematoxylin and eosin, ×400). (B) Small bowel mucosa showing markedly increased surface intraepithelial lymphocytes and expansion of lamina propria with mononuclear cells (hematoxylin and eosin, ×200). (C) Two adjacent colonic glands showing cryptitis in the upper gland and intraepithelial lymphocytosis and crypt cell apoptosis in the lower gland (hematoxylin and eosin, ×400).
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Brunet JF, Dosseto M, Denizot F, et al. The inducible cytotoxic T-lymphocyte-associated gene transcript CTLA-1 sequence and gene localization to mouse chromosome 14. Nature. 1986;322:268–271. - PubMed
    1. Walunas TL, Lenschow DJ, Bakker CY, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity. 1994;1:405–413. - PubMed
    1. Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 1995;182:459–465. - PMC - PubMed
    1. Krummel MF, Allison JP. CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J Exp Med. 1996;183:2533–2540. - PMC - PubMed
    1. Chambers CA, Krummel MF, Boitel B, et al. The role of CTLA-4 in the regulation and initiation of T-cell responses. Immunol Rev. 1996;153:27–46. - PubMed

Publication types

MeSH terms