多次给予抗 PD-L1 人源 IgG1 单克隆抗体avelumab 后的外周免疫组分析。
Analyses of the peripheral immunome following multiple administrations of avelumab, a human IgG1 anti-PD-L1 monoclonal antibody.
机构信息
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, Bethesda, MD USA.
Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD USA.
出版信息
J Immunother Cancer. 2017 Feb 21;5:20. doi: 10.1186/s40425-017-0220-y. eCollection 2017.
BACKGROUND
Multiple anti-PD-L1/PD-1 checkpoint monoclonal antibodies (MAb) have shown clear evidence of clinical benefit. All except one have been designed or engineered to omit the possibility to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) as a second potential mode of anti-tumor activity; the reason for this is the concern of lysis of PD-L1 positive immune cells. Avelumab is a fully human IgG1 MAb which has been shown in prior in vitro studies to mediate ADCC versus a range of human tumor cells, and clinical studies have demonstrated anti-tumor activity versus a range of human cancers. This study was designed to investigate the effect on immune cell subsets in the peripheral blood of cancer patients prior to and following multiple administrations of avelumab.
METHODS
One hundred twenty-three distinct immune cell subsets in the peripheral blood of cancer patients ( = 28) in a phase I trial were analyzed by flow cytometry prior to and following one, three, and nine cycles of avelumab. Changes in soluble (s) CD27 and sCD40L in plasma were also evaluated. In vitro studies were also performed to determine if avelumab would mediate ADCC of PBMC.
RESULTS
No statistically significant changes in any of the 123 immune cell subsets analyzed were observed at any dose level, or number of doses, of avelumab. Increases in the ratio of sCD27:sCD40L were observed, suggesting potential immune activation. Controlled in vitro studies also showed lysis of tumor cells by avelumab versus no lysis of PBMC from five donors.
CONCLUSIONS
These studies demonstrate the lack of any significant effect on multiple immune cell subsets, even those expressing PD-L1, following multiple cycles of avelumab. These results complement prior studies showing anti-tumor effects of avelumab and comparable levels of adverse events with avelumab versus other anti-PD-1/PD-L1 MAbs. These studies provide the rationale to further exploit the potential ADCC mechanism of action of avelumab as well as other human IgG1 checkpoint inhibitors.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT01772004 (first received: 1/14/13; start date: January 2013) and NCT00001846 (first received date: 11/3/99; start date: August 1999).
背景
多种抗 PD-L1/PD-1 检查点单克隆抗体（MAb）已显示出明确的临床获益证据。除一种外，所有 MAb 均被设计或工程化为避免介导抗体依赖性细胞介导的细胞毒性（ADCC）作为第二种潜在的抗肿瘤活性模式；其原因是担心裂解 PD-L1 阳性免疫细胞。阿维鲁单抗（avelumab）是一种完全人源 IgG1 MAb，先前的体外研究表明，它可以介导针对一系列人类肿瘤细胞的 ADCC，并且临床研究表明它对一系列人类癌症具有抗肿瘤活性。本研究旨在研究在接受阿维鲁单抗多次给药之前和之后，癌症患者外周血中的免疫细胞亚群的变化。
方法
在一项 I 期试验中，分析了 28 例癌症患者外周血中的 123 种不同的免疫细胞亚群，通过流式细胞术进行分析，在接受一个、三个和九个周期的阿维鲁单抗治疗之前和之后。还评估了血浆中可溶性（s）CD27 和 sCD40L 的变化。此外，还进行了体外研究以确定阿维鲁单抗是否会介导 PBMC 的 ADCC。
结果
在任何剂量水平或阿维鲁单抗剂量次数下，均未观察到分析的 123 种免疫细胞亚群中的任何一种发生统计学显著变化。观察到 sCD27:sCD40L 比值增加，表明潜在的免疫激活。对照体外研究还表明，阿维鲁单抗可以裂解肿瘤细胞，而来自五个供体的 PBMC 则不会裂解。
结论
这些研究表明，在接受多个周期的阿维鲁单抗治疗后，即使是表达 PD-L1 的免疫细胞亚群，也没有任何显著影响。这些结果补充了先前表明阿维鲁单抗具有抗肿瘤作用以及与其他抗 PD-1/PD-L1 MAb 相比具有相似水平不良事件的研究。这些研究为进一步利用阿维鲁单抗以及其他人类 IgG1 检查点抑制剂的潜在 ADCC 作用机制提供了依据。
试验注册
ClinicalTrials.gov 标识符：NCT01772004（首次接收：1/14/13；开始日期：2013 年 1 月）和 NCT00001846（首次接收日期：11/3/99；开始日期：1999 年 8 月）。
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