Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial.
Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial.
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DOI：
10.1158/1078-0432.ccr-10-0569
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发表时间：
2010-05-15
期刊：
影响因子：
--
通讯作者：
Sharma P
中科院分区：
文献类型：
--
作者：
Carthon BC;Wolchok JD;Yuan J;Kamat A;Ng Tang DS;Sun J;Ku G;Troncoso P;Logothetis CJ;Allison JP;Sharma P
CTLA-4 blockade is being explored in numerous clinical trials as an immune based therapy for different malignancies. Our group conducted the first pre-operative clinical trial with the anti-CTLA-4 antibody ipilimumab in 12 patients with localized urothelial carcinoma of the bladder. Six patients were treated with 3mg/kg/dose of anti-CTLA-4 and six patients were treated with 10mg/kg/dose of antibody. Primary endpoints of the study were safety and immune monitoring. Most drug-related adverse events consisted of grade 1/2 toxicities. All patients had measurable immunologic pharmacodynamic effects, consisting of an increased frequency of CD4+ICOShi T cells in tumor tissues and the systemic circulation. To determine if CD4+ICOShi T cells could be a correlative marker for clinical outcome after treatment with anti-CTLA-4, a cohort of metastatic melanoma patients was studied retrospectively for frequency of CD4+ICOShi T cells and survival. Data from this small cohort of patients indicated that an increased frequency of CD4+ICOShi T cells, sustained over a period of 12 weeks of therapy, correlates with increased likelihood of clinical benefit consisting of overall survival. Our trial demonstrates that anti-CTLA-4 therapy has a tolerable safety profile in the pre-surgical setting and that a pre-operative model can be used to obtain biological data on human immune responses, which can efficiently guide the monitoring of patients treated in the metastatic disease setting.
