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: 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.
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Authors | Kimberly 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 |
Journal | Journal 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 |
PMID | 16710025
(Publication Type: Journal Article, Research Support, N.I.H., Intramural)
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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
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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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