Refractory colitis following anti-CTLA4 antibody therapy: analysis of mucosal FOXP3+ T cells.
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.
Lord
James D
JD
Department of Medicine, University of Washington, Seattle, WA, USA. jdlord@u.washington.edu
Hackman
Robert C
RC
Moklebust
Amanda
A
Thompson
John A
JA
Higano
Celestia S
CS
Chielens
Deborah
D
Steinbach
Gideon
G
McDonald
George B
GB
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000627:therapeutic use; D001706:Biopsy; D002423:Cause of Death; D003092:Colitis / Q000139:chemically induced* / Q000175:diagnosis / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D000074324:Ipilimumab