Correlation between NK function and response to trastuzumab in metastatic breast cancer patients
Correlation between NK function and response to trastuzumab in metastatic breast cancer patients
复制标题
DOI：
10.1186/1479-5876-6-25
复制
发表时间：
2008-05-16
影响因子：
7.4
通讯作者：
Matera, Lina
中科院分区：
文献类型：
--
作者：
Beano, Alessandra;Signorino, Elena;Matera, Lina
背景资料：曲妥珠单抗是一种选择性针对Her 2的单克隆抗体，并被批准用于治疗Her 2过表达的乳腺癌患者。其拟定的作用机制包括通过触发自然杀伤（NK）细胞上的Fc γ RIII介导抗体依赖性细胞毒性（ADCC）。这项研究解决了整体NK功能和trastuzumab的临床activity.Subjects和方法之间的相关性：在26例接受曲妥珠单抗单药化疗后的维持管理（8毫克/公斤负荷，然后标准剂量为6毫克/公斤，每3周）的临床和免疫反应进行了评估。在首次标准给药后收获的外周血单核细胞（PBMC）中评估了针对MHC I类阴性标准NK靶K562细胞系的细胞毒性活性和针对曲妥珠单抗包被的Her 2阳性SKBR 3细胞系的HER 2特异性ADCC。6个月后，根据RECIST标准，17例患者被评为应答者，9例为无应答者，而无进展生存期（PFS）在12个月的随访期间计算。结果：应答者具有显著较高水平的NK和ADCC活性（p < 0.05），与11例正常对照组无差异。无应答者NK活性显著低于正常对照组（P < 0.05）。在12个月时，PFS仅与NK活性显著相关。高NK活性患者的PFS显著延长，而其模式与ADCC活性高低无关。结论：曲妥珠单抗的作用机制之一是NK细胞介导的ADCC对Her 2阳性靶细胞的溶解。我们在这里表明，它的效力与短期治疗反应相关，而对肿瘤扩张的长期保护似乎是由纯NK活性介导的。
Background: Trastuzumab is a monoclonal antibody selectively directed against Her2 and approved for the treatment of Her2 overexpressing breast cancer patients. Its proposed mechanisms of action include mediation of antibody-dependent cellular cytotoxicity (ADCC) by triggering Fc gamma RIII on natural killer (NK) cells. This study addresses the correlation between overall NK function and trastuzumab's clinical activity.Subjects and methods: Clinical and immunological responses were assessed in 26 patients receiving trastuzumab monotherapy as maintenance management after chemotherapy (8 mg/kg load and then standard doses of 6 mg/kg every 3 weeks). Cytotoxic activity against the MHC class I-negative standard NK target K562 cell line and HER2-specific ADCC against a trastuzumab-coated Her2-positive SKBR3 cell line were assessed in peripheral blood mononuclear cells (PBMC) harvested after the first standard dose. After six months, seventeen patients were scored as responders and nine as non-responders according to the RECIST criteria, while Progression-Free Survival (PFS) was calculated during a 12 months follow-up.Results: The responders had significantly higher levels of both NK and ADCC activities (p < 0.05) that were not different from those of eleven normal controls. The NK activity of the non-responders was significantly (p < 0.05) lower than that of the normal controls. At twelve months, there was a marked correlation between PFS and NK activity only. PFS was significantly longer in patients with high levels of NK activity, whereas its pattern was unrelated to high or low ADCC activity.Conclusion: One of the mechanisms of action of trastuzumab is NK cell-mediated ADCC lysis of the Her2-positve target cell. We show here that its potency is correlated with the short-term response to treatment, whereas longer protection against tumor expansion seems to be mediated by pure NK activity.