Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4

被引:645
|
作者
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.
机构
[1] NCI, Surg Branch, NIH, CRC, Bethesda, MD 20892 USA
[2] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA
[3] Medarex Inc, Princeton, NJ USA
关键词
D O I
10.1200/JCO.2005.04.5716
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:2283 / 2289
页数:7
相关论文
共 50 条
  • [31] Cytotoxic T-Lymphocyte-Associated Antigen 4 Haploinsufficiency Mimics Difficult-to-Treat Inflammatory Bowel Disease
    Constant, Brad D.
    Dutmer, Cullen M.
    Arnold, Michael A.
    Hall, Caroline
    Abbott, Jordan K.
    de Zoeten, Edwin F.
    CLINICAL GASTROENTEROLOGY AND HEPATOLOGY, 2022, 20 (04) : E696 - E702
  • [32] The future of targeting cytotoxic T-lymphocyte-associated protein-4: Is there a role?
    Di Giacomo, Anna Maria
    Lahn, Michael
    Eggermont, Alexander M. M.
    Fox, Bernard
    Ibrahim, Ramy
    Sharma, Padmanee
    Allison, James P.
    Maio, Michele
    EUROPEAN JOURNAL OF CANCER, 2024, 198
  • [33] Soluble cytotoxic T-lymphocyte-associated antigen 4 (sCTLA-4) as a potential biomarker for diagnosis and evaluation of the prognosis in Glioma
    Liu, Jiajia
    Tian, Xiaoyi
    Wang, Yan
    Kang, Xixiong
    Song, Wenqi
    BMC IMMUNOLOGY, 2021, 22 (01)
  • [34] Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) in isolated vitiligo: a genotype-phenotype correlation
    Dwivedi, Mitesh
    Laddha, Naresh C.
    Imran, Mohomad
    Shah, Bela J.
    Begum, Rasheedunnisa
    PIGMENT CELL & MELANOMA RESEARCH, 2011, 24 (04) : 737 - 740
  • [35] Cytotoxic T-Lymphocyte Antigen-4 Blockade in Melanoma
    Buchbinder, Elizabeth I.
    McDermott, David F.
    CLINICAL THERAPEUTICS, 2015, 37 (04) : 755 - 763
  • [36] Cytotoxic T lymphocyte antigen-4 and immune checkpoint blockade
    Buchbinder, Elizabeth
    Hodi, F. Stephen
    JOURNAL OF CLINICAL INVESTIGATION, 2015, 125 (09): : 3377 - 3383
  • [37] Crosstalk between cytotoxic T-lymphocyte-associated antigen-4 and interleukin-12 in cytotoxic T-lymphocyte-mediated myocarditis - Adding another link to the chain
    Ahuja, Seema S.
    Estrada, Carlos A.
    Lindsey, Merry L.
    CIRCULATION RESEARCH, 2007, 101 (03) : 218 - 220
  • [38] A family with cytotoxic T-lymphocyte-associated protein 4 haploinsufficiency presenting with aplastic anaemia
    Solhaug, Terje Singsaas
    Tjonnfjord, Geir Erland
    Bjorgo, Kathrine
    Kildahl-Andersen, Odd
    BMJ CASE REPORTS, 2022, 15 (02)
  • [39] Enterocolitis in patients after antibody blockade of CTLA-4.
    Beck, KE
    Blansfield, JA
    Tran, KQ
    Hughes, MS
    Royal, RE
    Kammula, US
    Topalian, SL
    Sherry, RM
    Rosenberg, SA
    Yang, JC
    JOURNAL OF IMMUNOTHERAPY, 2005, 28 (06) : 647 - 647
  • [40] Elimination of residual metastatic prostate cancer after surgery and adjunctive cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade immunotherapy
    Kwon, ED
    Foster, BA
    Hurwitz, AA
    Madias, C
    Allison, JP
    Greenberg, NM
    Burg, MB
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (26) : 15074 - 15079