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

doi:10.1200/jco.2005.04.5716

Cited by 833Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesImmunotoxicology and immune responses

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

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Beck, Kimberly E., Blansfield, Joseph A., Tran, Khoi Q., Feldman, Andrew L., Hughes, Marybeth S., Royal, Richard E., Kammula, Udai S., Topalian, Suzanne L. +7 more·2006·Journal of Clinical Oncology

DOI 10.1200/jco.2005.04.5716PMC PMC2140223

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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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Autoimmune colitis, vitiligo, and autoantibody production are now included in CTCAE grading of immune-related adverse events due to immunotherapy.
“Autoimmune colitis, vitiligo, and autoantibody production are now included in CTCAE grading of irAEs due to immunotherapy [1, 4, 6, 20, 22, 34].”
From Immune reconstitution and clinical recovery following anti-CD28 antibody (TGN1412)-induced cytokine storm (2021) · cites this paper as [34]
The Abstract and Other Immune Mediated Toxicities section report grade 3/4 enterocolitis after ipilimumab treatment, supporting the colitis portion of the claim. Our copy does not establish that colitis, vitiligo, or autoantibody production are included in CTCAE grading; searches for CTCAE, vitiligo, and autoantibodies did not find that point. Page numbers were not available in the indexed passages. (LLM, conf=0.79)
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ICI-associated colitis is routinely managed with immunosuppressive therapy, including corticosteroids and/or anti-TNF-alpha agents, which have significant side effects.
“ICI-associated colitis is routinely treated with immunosuppressive therapy, including corticosteroids and/or agents targeting tumor necrosis factor alpha (TNF-alpha), all of which have significant side effects.”
From Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis (2018) · cites this paper as [7]

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Authors: Beck, K. E., Blansfield, J. A., Tran, K. Q., Feldman, A. L., Hughes, M. S., Royal, R. E., Kammula, U. S., Topalian, S. L., Sherry, R. M., Kleiner, D., Quezado, M., Lowy, I., Yellin, M., Rosenberg, S. A., & Yang, J. C.
Affiliations: National Institutes of Health (US)
ORCID: Blansfield, Joseph A.
Feldman, Andrew L.
Kammula, Udai S.
Topalian, Suzanne L.
Sherry, Richard M.
Kleiner, David
Quezado, Martha
Lowy, Israel
Yellin, Michael
Rosenberg, Steven A.
Yang, James C.
Venue: Journal of Clinical Oncology
Publisher: American Society of Clinical Oncology (ASCO)
Published: 2006-05-20
Volume: 24
Issue: 15
Pages: 2283-2289
ISSN: 0732-183X (ISSN-L)
1527-7755
DOI: 10.1200/jco.2005.04.5716
PMC: PMC2140223
OpenAlex: W2107150019
Cited by: 833
References: 31
Citations by year: 2026: 6 · 2025: 12 · 2024: 28 · 2023: 28 · 2022: 34 · 2021: 40 · 2020: 90 · 2019: 56 · 2018: 63 · 2017: 51 · 2016: 58 · 2015: 47 · 2014: 37 · 2013: 46 · 2012: 37
FWCI: 21.33
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Oncology (publishedVersion)
PubMed (publishedVersion)
Research Explorer (The University of Manchester) (publishedVersion, other-oa)
PubMed Central (acceptedVersion)
Funders: American Society of Clinical Oncology
National Institutes of Health
National Cancer Institute (Z01SC003811)
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
Keywords: immune-related adverse events, CTLA-4 blockade, ipilimumab, metastatic melanoma, renal cell carcinoma, immune checkpoint inhibitors, corticosteroid therapy, infliximab, tumor response, colectomy, perforation
MeSH terms: Infliximab, Ipilimumab, Adrenal Cortex Hormones, Antibodies, Monoclonal, Antigens, Differentiation, Antineoplastic Agents, Carcinoma, Renal Cell, Enterocolitis, Female, Gastrointestinal Agents, Humans, Kidney Neoplasms, Male, Melanoma, Middle Aged, Neoplasms, Skin Neoplasms, Antigens, CD, Cancer Vaccines, CTLA-4 Antigen

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