A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma.
A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma.
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DOI：
10.1186/1479-5876-9-204
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发表时间：
2011-11-28
影响因子：
7.4
通讯作者：
Berman D
中科院分区：
文献类型：
--
作者：
Hamid O;Schmidt H;Nissan A;Ridolfi L;Aamdal S;Hansson J;Guida M;Hyams DM;Gómez H;Bastholt L;Chasalow SD;Berman D
伊匹木单抗是一种阻断细胞毒性T淋巴细胞抗原-4的全人单克隆抗体，在两项晚期黑色素瘤患者的III期试验中证明了总生存期的改善。本试验的主要目的是前瞻性地探索来自肿瘤微环境的候选生物标志物与伊匹单抗临床应答的相关性。在这项随机、双盲、II期生物标志物研究（ClinicalTrials.gov NCT 00261365）中，82例未经治疗或未经治疗的不可切除III/IV期黑色素瘤患者接受3或10 mg/kg伊匹单抗诱导治疗，每3周一次，共4次给药;在第24周，患者可以每12周一次接受维持剂量。根据修订的世界卫生组织缓解标准评价疗效，并持续评估安全性。在治疗前和第二次伊匹单抗给药后24至72小时收集的肿瘤活检中评价候选生物标志物。免疫相关基因的多态性也进行了评估。客观缓解率、缓解模式和安全性与伊匹单抗治疗黑色素瘤的既往试验一致。没有观察到遗传多态性和临床活动之间的关联。肿瘤活检的免疫组织化学和组织学显示，临床活动与FoxP 3（p = 0.014）和吲哚胺2，3-双加氧酶（p = 0.012）的高基线表达之间存在显著相关性，临床活动与基线和治疗开始后3周之间肿瘤浸润淋巴细胞（TIL）的增加之间存在显著相关性（p = 0.005）。对治疗前和治疗后肿瘤样本的mRNA进行的微阵列分析表明，几种免疫相关基因的表达显著增加，而与癌症和黑色素瘤有关的基因的表达减少。免疫相关肿瘤生物标志物的基线表达和治疗后TIL的增加可能与伊匹单抗的临床活性呈正相关。观察到的基因表达的药效学变化需要进一步分析，以确定治疗后出现的基因表达变化是否与临床疗效相关。需要进一步的研究来确定这些和其他与伊匹单抗临床反应相关的潜在生物标志物的预测价值。
Ipilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in two phase III trials of patients with advanced melanoma. The primary objective of the current trial was to prospectively explore candidate biomarkers from the tumor microenvironment for associations with clinical response to ipilimumab. In this randomized, double-blind, phase II biomarker study (ClinicalTrials.gov NCT00261365), 82 pretreated or treatment-naïve patients with unresectable stage III/IV melanoma were induced with 3 or 10 mg/kg ipilimumab every 3 weeks for 4 doses; at Week 24, patients could receive maintenance doses every 12 weeks. Efficacy was evaluated per modified World Health Organization response criteria and safety was assessed continuously. Candidate biomarkers were evaluated in tumor biopsies collected pretreatment and 24 to 72 hours after the second ipilimumab dose. Polymorphisms in immune-related genes were also evaluated. Objective response rate, response patterns, and safety were consistent with previous trials of ipilimumab in melanoma. No associations between genetic polymorphisms and clinical activity were observed. Immunohistochemistry and histology on tumor biopsies revealed significant associations between clinical activity and high baseline expression of FoxP3 (p = 0.014) and indoleamine 2,3-dioxygenase (p = 0.012), and between clinical activity and increase in tumor-infiltrating lymphocytes (TILs) between baseline and 3 weeks after start of treatment (p = 0.005). Microarray analysis of mRNA from tumor samples taken pretreatment and post-treatment demonstrated significant increases in expression of several immune-related genes, and decreases in expression of genes implicated in cancer and melanoma. Baseline expression of immune-related tumor biomarkers and a post-treatment increase in TILs may be positively associated with ipilimumab clinical activity. The observed pharmacodynamic changes in gene expression warrant further analysis to determine whether treatment-emergent changes in gene expression may be associated with clinical efficacy. Further studies are required to determine the predictive value of these and other potential biomarkers associated with clinical response to ipilimumab.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
82.9
作者：
Curiel, TJ;Coukos, G;Zou, WP
通讯作者：
Zou, WP
影响因子：
2.6
作者：
Cox, Maria Christina;Nofroni, Italo;Aloe-Spiriti, Maria Antonietta
通讯作者：
Aloe-Spiriti, Maria Antonietta
吲哚胺2,3-二加氧酶途径对于人浆细胞类动物树突状细胞诱导的适应性T调节细胞的产生至关重要。
DOI：
10.4049/jimmunol.181.8.5396
发表时间：
2008-10-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Chen W;Liang X;Peterson AJ;Munn DH;Blazar BR
通讯作者：
Blazar BR