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Enterocolitis in Patients With Cancer After Antibody Blockade of Cytotoxic T-Lymphocyte–Associated Antigen 4

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

From the Surgery Branch and Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD; and Medarex Inc, Princeton NJ

Address reprint requests to James C. Yang, MD, Surgery Branch, National Cancer Institute, National Institutes of Health, CRC, Room 3W, 10 Center Dr, Bethesda, MD 20892-1201; e-mail: James_Yang{at}nih.gov

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.

Supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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