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 Topalian, Richard M. Sherry, David Kleiner, Martha Quezado, Israel Lowy, Michael Yellin, Steven A. Rosenberg, James C. Yang

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2283-2289
Number of pages7
JournalJournal of Clinical Oncology
Volume24
Issue number15
DOIs
StatePublished - May 20 2006
Externally publishedYes

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CTLA-4 Antigen
Enterocolitis
Antibodies
Neoplasms
Renal Cell Carcinoma
Melanoma
Costimulatory and Inhibitory T-Cell Receptors
Steroids
Biopsy
Clinical Pathology
Colectomy
Nephritis
Uveitis
Dermatitis
Documentation
Hepatitis
Autoimmune Diseases
Diarrhea
Adrenal Cortex Hormones
Tumor Necrosis Factor-alpha

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Beck, K. E., Blansfield, J. A., Tran, K. Q., Feldman, A. L., Hughes, M. S., Royal, R. E., ... Yang, J. C. (2006). Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. Journal of Clinical Oncology, 24(15), 2283-2289. https://doi.org/10.1200/JCO.2005.04.5716

Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. / Beck, Kimberly E.; Blansfield, Joseph A.; Tran, Khoi Q.; Feldman, Andrew L.; Hughes, Marybeth S.; Royal, Richard E.; Kammula, Udai S.; Topalian, Suzanne; Sherry, Richard M.; Kleiner, David; Quezado, Martha; Lowy, Israel; Yellin, Michael; Rosenberg, Steven A.; Yang, James C.

In: Journal of Clinical Oncology, Vol. 24, No. 15, 20.05.2006, p. 2283-2289.

Research output: Contribution to journalArticle

Beck, KE, Blansfield, JA, Tran, KQ, Feldman, AL, Hughes, MS, Royal, RE, Kammula, US, Topalian, S, Sherry, RM, Kleiner, D, Quezado, M, Lowy, I, Yellin, M, Rosenberg, SA & Yang, JC 2006, 'Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4', Journal of Clinical Oncology, vol. 24, no. 15, pp. 2283-2289. https://doi.org/10.1200/JCO.2005.04.5716
Beck, Kimberly E. ; Blansfield, Joseph A. ; Tran, Khoi Q. ; Feldman, Andrew L. ; Hughes, Marybeth S. ; Royal, Richard E. ; Kammula, Udai S. ; Topalian, Suzanne ; Sherry, Richard M. ; Kleiner, David ; Quezado, Martha ; Lowy, Israel ; Yellin, Michael ; Rosenberg, Steven A. ; Yang, James C. / Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. In: Journal of Clinical Oncology. 2006 ; Vol. 24, No. 15. pp. 2283-2289.
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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.",
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AU - Hughes, Marybeth S.

AU - Royal, Richard E.

AU - Kammula, Udai S.

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AU - Kleiner, David

AU - Quezado, Martha

AU - Lowy, Israel

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