Activation of Peripheral-Blood Granulocytes Is Strongly Correlated With Patient Outcome After Immunotherapy With Anti-GD2 Monoclonal Antibody and Granulocyte-Macrophage Colony-Stimulating Factor
Activation of Peripheral-Blood Granulocytes Is Strongly Correlated With Patient Outcome After Immunotherapy With Anti-GD2 Monoclonal Antibody and Granulocyte-Macrophage Colony-Stimulating Factor
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DOI：
10.1200/jco.2011.37.6236
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发表时间：
2012-02-01
影响因子：
45.3
通讯作者：
Cheung, Nai-Kong V.
中科院分区：
文献类型：
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作者：
Cheung, Irene Y.;Hsu, Katharine;Cheung, Nai-Kong V.
目的使用抗gd2单克隆抗体和粒细胞-巨噬细胞集落刺激因子（GM-CSF）辅助治疗高危神经母细胞瘤（NB）已取得成功。虽然有充分的证据表明抗体如何靶向NB，但GM-CSF在体内的作用尚不清楚。本报告探讨了粒细胞活化及其与治疗结果的关系。纳入NCT00072358的患者接受多个治疗周期，每个治疗周期由抗gd2抗体3F8加皮下（SC） GM-CSF组成。在第1周期第0天和第4天采集151例患者外周血（PB）样本。在第4周期，35例PB患者接受静脉注射（IV）而不是SC GM-CSF。流式细胞术检测CD11a、CD63、CD87和CD11b及其活化表位CBRM1/5。结果将第1周期第4天的PB样品与第0天的PB样品进行比较，5个活化标志物阳性的粒细胞中有5个显著增加。cbrm1 /5阳性粒细胞的频率和平均荧光强度的变化与无进展生存相关（PFS; P = 0.024和P = 0.008）。一项多变量分析发现，cbrm1 /5阳性粒细胞增加和杀手免疫球蛋白样受体配体缺失是PFS的阳性独立预后因素，而在方案开始前的二线环磷酰胺治疗对预后有负面影响。35例在第1周期接受SC GM-CSF和第4周期接受IV GM-CSF的患者在IV GM-CSF后CBRM1/5的激活明显降低。相比之下，在两个周期中接受SC GM-CSF的63例患者具有相当的CBRM1/5激活。结论ongm - csf诱导的体内粒细胞活化与改善患者预后相关。当GM-CSF通过SC途径而不是IV途径给予时，这种激活更为明显。[J]中华临床杂志，30(3):426-432。(C) 2011年美国临床肿瘤学会
PurposeAdjuvant therapy using anti-GD2 monoclonal antibody and granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown treatment success for patients with high-risk neuroblastoma (NB). Although there is ample evidence on how the antibody targets NB, in vivo contribution by GM-CSF remains unclear. This report investigates granulocyte activation and its correlation with treatment outcome.Patients and MethodsPatients enrolled onto NCT00072358 received multiple treatment cycles, each consisting of anti-GD2 antibody 3F8 plus subcutaneous (SC) GM-CSF. Peripheral-blood (PB) samples from 151 patients were collected on day 0 and day 4 of cycle 1. PB from a subgroup of 35 patients had intravenous (IV) instead of SC GM-CSF during cycle 4. Samples were analyzed by flow cytometry for CD11a, CD63, CD87, and CD11b and its activation epitope CBRM1/5.ResultsComparing cycle 1 day 4 PB samples with day 0 PB samples, five of five activation marker-positive granulocytes were significantly higher. The change in frequency and mean fluorescence intensity of CBRM1/5-positive granulocytes correlated with progression-free survival (PFS; P = .024 and P = .008, respectively). A multivariable analysis identified increasing CBRM1/5-positive granulocytes and missing killer immunoglobulin-like receptor ligand as positive independent prognostic factors for PFS, whereas second-line cyclophosphamide-based therapy before protocol entry negatively influenced outcome. Thirty-five patients who received SC GM-CSF at cycle 1 and IV GM-CSF at cycle 4 had significantly less CBRM1/5 activation after IV GM-CSF. In contrast, 63 patients who received SC GM-CSF at both cycles had comparable CBRM1/5 activation.ConclusionGM-CSF-induced granulocyte activation in vivo is associated with improved patient outcome. This activation was more apparent when GM-CSF was given by the SC route instead of IV route. J Clin Oncol 30: 426-432. (C) 2011 by American Society of Clinical Oncology