This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Beck, K. E. Articles by Yang, J. C. Search for Related Content PubMed PubMed Citation Articles by Beck, K. E. Articles by Yang, J. C. Related Articles Related Editorial Related Correspondence

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.

Related Editorial

• Is Tumor Immunity the Same Thing As Autoimmunity? Implications for Cancer Immunotherapy
  Howard L. Kaufman and Jedd D. Wolchok
  JCO 2006 24: 2230-2232 [Full Text]

Related Correspondence

• Does CTLA4 Influence the Suppressive Effect of CD25+CD4+ Regulatory T Cells?
  Gianluigi Ferretti, Alessandra Felici, Maria Simona Pino, and Francesco Cognetti
  JCO 2006 24: 5469-5470 [Full Text]

This article has been cited by other articles:

				F. S. Hodi, M. Butler, D. A. Oble, M. V. Seiden, F. G. Haluska, A. Kruse, S. MacRae, M. Nelson, C. Canning, I. Lowy, et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients PNAS, February 26, 2008; 105(8): 3005 - 3010. [Abstract] [Full Text] [PDF]

				C. Tsatsanis, K. Vaporidi, V. Zacharioudaki, A. Androulidaki, Y. Sykulev, A. N. Margioris, and P. N. Tsichlis Tpl2 and ERK transduce antiproliferative T cell receptor signals and inhibit transformation of chronically stimulated T cells PNAS, February 26, 2008; 105(8): 2987 - 2992. [Abstract] [Full Text] [PDF]

				S. G. Downey, J. A. Klapper, F. O. Smith, J. C. Yang, R. M. Sherry, R. E. Royal, U. S. Kammula, M. S. Hughes, T. E. Allen, C. L. Levy, et al. Prognostic Factors Related to Clinical Response in Patients with Metastatic Melanoma Treated by CTL-Associated Antigen-4 Blockade Clin. Cancer Res., November 15, 2007; 13(22): 6681 - 6688. [Abstract] [Full Text] [PDF]

				S. H. Wrzesinski, Y. Y. Wan, and R. A. Flavell Transforming Growth Factor-{beta} and the Immune Response: Implications for Anticancer Therapy Clin. Cancer Res., September 15, 2007; 13(18): 5262 - 5270. [Abstract] [Full Text] [PDF]

				X. Zang and J. P. Allison The B7 Family and Cancer Therapy: Costimulation and Coinhibition Clin. Cancer Res., September 15, 2007; 13(18): 5271 - 5279. [Abstract] [Full Text] [PDF]

				S. S. Ahuja, C. A. Estrada, and M. L. Lindsey Crosstalk Between Cytotoxic T-Lymphocyte Associated Antigen-4 and Interleukin-12 in Cytotoxic T-Lymphocyte Mediated Myocarditis: Adding Another Link to the Chain Circ. Res., August 3, 2007; 101(3): 218 - 220. [Full Text] [PDF]

				J. Weber Review: Anti CTLA-4 Antibody Ipilimumab: Case Studies of Clinical Response and Immune-Related Adverse Events Oncologist, July 1, 2007; 12(7): 864 - 872. [Abstract] [Full Text] [PDF]

				A. Ribas, D. C. Hanson, D. A. Noe, R. Millham, D. J. Guyot, S. H. Bernstein, P. C. Canniff, A. Sharma, and J. Gomez-Navarro Tremelimumab (CP-675,206), a Cytotoxic T Lymphocyte Associated Antigen 4 Blocking Monoclonal Antibody in Clinical Development for Patients with Cancer Oncologist, July 1, 2007; 12(7): 873 - 883. [Abstract] [Full Text] [PDF]

				E. J. Small, N. S. Tchekmedyian, B. I. Rini, L. Fong, I. Lowy, and J. P. Allison A Pilot Trial of CTLA-4 Blockade with Human Anti-CTLA-4 in Patients with Hormone-Refractory Prostate Cancer Clin. Cancer Res., March 15, 2007; 13(6): 1810 - 1815. [Abstract] [Full Text] [PDF]

				D. O'Mahony, J. C. Morris, C. Quinn, W. Gao, W. H. Wilson, B. Gause, S. Pittaluga, S. Neelapu, M. Brown, T. A. Fleisher, et al. A Pilot Study of CTLA-4 Blockade after Cancer Vaccine Failure in Patients with Advanced Malignancy Clin. Cancer Res., February 1, 2007; 13(3): 958 - 964. [Abstract] [Full Text] [PDF]

				J. C. Yang and R. Childs Immunotherapy for Renal Cell Cancer J. Clin. Oncol., December 10, 2006; 24(35): 5576 - 5583. [Abstract] [Full Text] [PDF]

				J. Yang In Reply J. Clin. Oncol., December 1, 2006; 24(34): 5470 - 5471. [Full Text] [PDF]

				G. Ferretti, A. Felici, M. S. Pino, and F. Cognetti Does CTLA4 Influence the Suppressive Effect of CD25+CD4+ Regulatory T Cells? J. Clin. Oncol., December 1, 2006; 24(34): 5469 - 5470. [Full Text] [PDF]

				H. L. Kaufman and J. D. Wolchok Is Tumor Immunity the Same Thing As Autoimmunity? Implications for Cancer Immunotherapy J. Clin. Oncol., May 20, 2006; 24(15): 2230 - 2232. [Full Text] [PDF]