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Digestive Diseases and Sciences

, Volume 55, Issue 5, pp 1396–1405 | Cite as

Refractory Colitis Following Anti-CTLA4 Antibody Therapy: Analysis of Mucosal FOXP3+ T Cells

  • James D. LordEmail author
  • Robert C. Hackman
  • Amanda Moklebust
  • John A. Thompson
  • Celestia S. Higano
  • Deborah Chielens
  • Gideon Steinbach
  • George B. McDonald
Original Article

Abstract

Ipilimumab is a humanized antibody to CTLA4 and is used to treat cancers refractory to conventional treatment. We treated 21 patients with refractory melanoma or prostate cancer with anti-CTLA4 antibody (ipilimumab), with subsequent development of significant colitis in nine cases. Two of these nine did not respond rapidly to high-dose (2 mg kg−1 day−1) glucocorticoids or infliximab. They required additional immunosuppression, and one ultimately died of opportunistic infection, representing a more refractory course than has previously been described complicating ipilimumab therapy. Both patients had received radiation to the pelvis for prostate cancer less than 1 year prior to receiving ipilimumab. We performed immunohistochemical analysis of colon biopsies from ipilimumab recipients to determine if colitis correlates with depletion of intramucosal FOXP3+ regulatory T cells (Tregs), which normally express CTLA4. However, we found no evidence of FOXP3+ T cell depletion in any of the nine patients who developed colitis.

Keywords

Ipilimumab CTLA4 FOXP3 Colitis 

Abbreviations

CTLA4

Cytotoxic T lymphocyte antigen 4

GVHD

Graft versus host disease

IBD

Inflammatory bowel disease

Tregs

Regulatory T cells

FOXP3

Forkhead box protein 3 (human nomenclature)

Notes

Acknowledgments

This work was supported by the National Institutes of Health AI48779 AI007411 (JDL) and CA18029 (RCH, GBM), as well as clinical funds from the University of Washington and the Seattle Cancer Care Alliance.

Financial Disclosures

None of the authors have personal financial relationships to disclose. However, subjects with melanoma were participants in a trial funded by the Bristol-Myers Squibb company, for which John Thompson was an investigator. Subjects with prostate cancer were participants in a trial funded by the Medarex company, for which Celestia Higano was an investigator and Deborah Chielens was a coordinator.

References

  1. 1.
    Sansom DM, Walker LS. The role of CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) in regulatory T-cell biology. Immunol Rev. 2006;212:131–148. doi: 10.1111/j.0105-2896.2006.00419.x.CrossRefPubMedGoogle Scholar
  2. 2.
    Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995;270:985–988. doi: 10.1126/science.270.5238.985.CrossRefPubMedGoogle Scholar
  3. 3.
    O’Day SJ, Hamid O, Urba WJ. Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): A novel strategy for the treatment of melanoma and other malignancies. Cancer. 2007;110:2614–2627. doi: 10.1002/cncr.23086.CrossRefPubMedGoogle Scholar
  4. 4.
    Maker AV, Phan GQ, Attia P, et al. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: A phase I/II study. Ann Surg Oncol. 2005;12:1005–1016. doi: 10.1245/ASO.2005.03.536.CrossRefPubMedGoogle Scholar
  5. 5.
    Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA. 2003;100:8372–8377. doi: 10.1073/pnas.1533209100.CrossRefPubMedGoogle Scholar
  6. 6.
    Sanderson K, Scotland R, Lee P, et al. Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and Montanide ISA 51 for patients with resected stages III and IV melanoma. J Clin Oncol. 2005;23:741–750. doi: 10.1200/JCO.2005.01.128.CrossRefPubMedGoogle Scholar
  7. 7.
    Beck KE, Blansfield JA, Tran KQ, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol. 2006;24:2283–2289. doi: 10.1200/JCO.2005.04.5716.CrossRefPubMedGoogle Scholar
  8. 8.
    Yang JC, Hughes M, Kammula U, et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother. 2007;30:825–830. doi: 10.1097/CJI.0b013e318156e47e.CrossRefPubMedGoogle Scholar
  9. 9.
    O’Mahony D, Morris JC, Quinn C, et al. A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with advanced malignancy. Clin Cancer Res. 2007;13:958–964. doi: 10.1158/1078-0432.CCR-06-1974.CrossRefPubMedGoogle Scholar
  10. 10.
    Small EJ, Tchekmedyian NS, Rini BI, Fong L, Lowy I, Allison JP. A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer. Clin Cancer Res. 2007;13:1810–1815. doi: 10.1158/1078-0432.CCR-06-2318.CrossRefPubMedGoogle Scholar
  11. 11.
    Read S, Malmstrom V, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med. 2000;192:295–302. doi: 10.1084/jem.192.2.295.CrossRefPubMedGoogle Scholar
  12. 12.
    Takahashi T, Tagami T, Yamazaki S, et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2000;192:303–310. doi: 10.1084/jem.192.2.303.CrossRefPubMedGoogle Scholar
  13. 13.
    Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH. Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J Exp Med. 2001;193:1285–1294. doi: 10.1084/jem.193.11.1285.CrossRefPubMedGoogle Scholar
  14. 14.
    Read S, Greenwald R, Izcue A, et al. Blockade of CTLA-4 on CD4+ CD25+ regulatory T cells abrogates their function in vivo. J Immunol. 2006;177:4376–4383.PubMedGoogle Scholar
  15. 15.
    Pentcheva-Hoang T, Egen JG, Wojnoonski K, Allison JP. B7-1 and B7-2 selectively recruit CTLA-4 and CD28 to the immunological synapse. Immunity. 2004;21:401–413. doi: 10.1016/j.immuni.2004.06.017.CrossRefPubMedGoogle Scholar
  16. 16.
    Epstein RJ, McDonald GB, Sale GE, Shulman HM, Thomas ED. The diagnostic accuracy of the rectal biopsy in acute graft-versus-host disease: A prospective study of thirteen patients. Gastroenterology. 1980;78:764–771.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • James D. Lord
    • 1
    • 4
    Email author
  • Robert C. Hackman
    • 2
    • 3
  • Amanda Moklebust
    • 3
  • John A. Thompson
    • 1
    • 3
  • Celestia S. Higano
    • 1
    • 3
  • Deborah Chielens
    • 3
  • Gideon Steinbach
    • 1
    • 3
  • George B. McDonald
    • 1
    • 3
  1. 1.Department of MedicineUniversity of WashingtonSeattleUSA
  2. 2.Department of PathologyUniversity of WashingtonSeattleUSA
  3. 3.Fred Hutchinson Cancer Research CenterSeattleUSA
  4. 4.Benaroya Research Institute at Virginia MasonSeattleUSA

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