TY - JOUR
T1 - Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4
AU - Beck, Kimberly E.
AU - Blansfield, Joseph A.
AU - Tran, Khoi Q.
AU - Feldman, Andrew L.
AU - Hughes, Marybeth S.
AU - Royal, Richard E.
AU - Kammula, Udai S.
AU - Topalian, Suzanne L.
AU - Sherry, Richard M.
AU - Kleiner, David
AU - Quezado, Martha
AU - Lowy, Israel
AU - Yellin, Michael
AU - Rosenberg, Steven A.
AU - Yang, James C.
PY - 2006/5/20
Y1 - 2006/5/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33744792341&partnerID=8YFLogxK
U2 - 10.1200/JCO.2005.04.5716
DO - 10.1200/JCO.2005.04.5716
M3 - Article
C2 - 16710025
AN - SCOPUS:33744792341
SN - 0732-183X
VL - 24
SP - 2283
EP - 2289
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 15
ER -