Beck, Joseph A

Beck, Joseph A. 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 (= .0065 for MM and = .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 Col003 associated in malignancy patients. INTRODUCTION Cytotoxic T-lymphocyteCassociated antigen 4 (CTLA4) is usually a cell surface receptor in the beginning cloned from a cDNA library from a murine cytotoxic T-lymphocyte.1 Its ligands are CD80 and CD86 which also participate in lower affinity interactions with the costimulatory T-cell receptor CD28. Rather than costimulate, CTLA4 functions as an inducible receptor with T-cell inhibitory activity.2C5 Thus its primary role is to down-regulate T-cell activation. CTLA4 was also found constitutively expressed on inhibitory CD25+ CD4+ regulatory T cells (Treg) and CTLA4 signaling was necessary in Treg control of intestinal inflamation.6 Targeted destruction of the gene in mice causes lymphoproliferation and autoimmune disease and antimurine CTLA4 antibodies induced antitumor activity, particularly when combined with antitumor vaccination.5,7,8 This led to clinical trials of a fully human immunoglobulin G1 antibody against CTLA4, ipilimumab (formerly MDX-010; Medarex Inc, Princeton, NJ). In patients with melanoma or ovarian malignancy who also experienced antitumor vaccination, tumor necrosis and cellular infiltration was reported after ipilimumab administration,9 and other studies have also documented durable tumor regression by standard criteria. Phan et al reported 14 patients with melanoma who received anti-CTLA4 antibody (3 mg/kg every 3 weeks) in combination with antimelanoma peptide vaccines. Three patients experienced objective malignancy regression, and two patients experienced mixed responses.10 Grade 3/4 autoimmune toxicities were seen in six (43%) of 14 patients. Further trials established that tumor regression could also be seen without added vaccination. A number of grade 3/4 immune-mediated toxicities, unanticipated by preclinical screening in nonhuman primates, were encountered in patients given ipilimumab.11C13 These Col003 included dermatitis, enterocolitis, hypophysitis, uveitis, and hepatitis. Mice with their genes knocked out show lethal Emr1 lymphoproliferation as well as myocarditis and pancreatitis. 14 Administration of anti-CTLA4 antibody in mice also enhanced experimental autoimmune myasthenia gravis, 15 precipitated and exacerbated autoimmune diabetes16 and experimental autoimmune encephalomyelitis,17 and induced autoimmune gastritis.18 Population-based studies found that specific polymorphisms in the human gene were associated with increased risks of autoimmune diabetes and thyroid disease.19 Therefore, these ipilimumab-associated toxicities were thought to be possible autoimmune manifestations of CTLA4 blockade. To further investigate this hypothesis, we analyzed the most frequent ipilimumab-associated toxicity, enterocolitis, to determine its clinicopathologic characteristics, contributing factors, response to therapy, and association with tumor regression. A total of 234 patients with metastatic melanoma (MM) or renal cell carcinoma (RCC) have received ipilimumab in the Surgery Branch of the National Cancer Institute. One hundred thirty-seven of these patients experienced melanoma and received antibody with or without melanoma peptide vaccines. Sixty-one patients with metastatic clear-cell RCC were given ipilimumab without vaccination. Thirty-six additional patients receiving ipilimumab in combination with high-dose interleukin-2 (IL-2) are not included in this statement. Enterocolitis was the most frequent significant adverse occurrence, but we also observed dermatitis, hypophysitis, uveitis, hepatitis, nephritis, and one case of autoimmune meningitis. This statement presents the clinicopathologic results and outcome analysis around the 41 patients who developed enterocolitis in association with ipilimumab treatment. PATIENTS AND METHODS Patients One hundred ninety-eight patients were treated with intravenous human immunoglobulin anti-CTLA4 monoclonal antibody ipilimumab, from March 19, 2002, to July 15, 2005. All patients Col003 experienced a histologic diagnosis of stage IV cutaneous melanoma or stage IV clear-cell RCC, and experienced measurable disease. All patients experienced a life expectancy 3 months and an Eastern Cooperative Oncology Group overall performance status 2. A normal CBC, creatinine, hepatic panel, hepatitis, HIV, and autoimmunity screen was required. Patients receiving a peptide vaccine were constrained to be human leukocyte antigen (HLA) -A0201Cpositive. Patients with RCC were either IL-2 refractory or IL-2 ineligible. Patients with any other major malignancy, a history of autoimmune disease, a requirement for immunosuppressive agents, who were pregnant or nursing, or who experienced received prior ipilimumab treatment were excluded. Treatment With Ipilimumab Col003 Sufferers had been treated on three different protocols accepted by the investigational examine board from the Country wide Cancers Institute and relative to an assurance submitted with and accepted by the united states.