This study aimed to investigate whether cyclophosphamide (C) and adriamycin (A) induction therapy (IT) prior to nivolumab could enhance the efficacy of nivolumab in previously treated patients with non-squamous (NSQ) non-small-cell lung cancer (NSCLC) with less than 10% programmed death-ligand 1 (PD-L1) expression. Twenty-two enrolled patients received four cycles of CA-IT every 3 weeks. Nivolumab was given 360 mg every 3 weeks from the second cycle and 480 mg every 4 weeks after four cycles of CA-IT. The median progression-free survival (PFS) and overall survival (OS) were 2.4 months and 11.6 months, respectively. Fluorescence-activated cell sorting revealed the lowest ratio of myeloid-derived suppressor cells (MDSCs) to CD8+T-cells in the responders. Proteomic analysis identified a consistent upregulation of extracellular matrix-receptor interactions and phagosome pathways in the responders. Among the differentially expressed proteins, the transferrin receptor protein (TFRC) was higher in the responders before treatment (fold change > 1.2). TFRC validation with an independent cohort showed the prognostic significance of either OS or PFS in patients with low PD-L1 expression. In summary, CA-IT did not improve nivolumab efficacy in NSQ-NSCLCs with low PD-L1 expression; however, it induced decreasing MDSC, resulting in a durable response. Higher baseline TFRC levels predicted a favorable response to nivolumab in NSCLC with low PD-L1 expression.
本研究旨在探讨在程序性死亡配体1（PD-L1）表达低于10%的既往治疗过的非鳞状非小细胞肺癌（NSQ-NSCLC）患者中，于纳武利尤单抗治疗前采用环磷酰胺（C）联合阿霉素（A）诱导治疗（IT）是否能增强纳武利尤单抗的疗效。22例入组患者每3周接受一次CA-IT，共四个周期。从第二周期开始，每3周给予360 mg纳武利尤单抗，完成四个周期CA-IT后改为每4周480 mg。中位无进展生存期（PFS）和总生存期（OS）分别为2.4个月和11.6个月。荧光激活细胞分选显示，应答者中髓源性抑制细胞（MDSCs）与CD8+T细胞的比值最低。蛋白质组学分析发现，应答者细胞外基质-受体相互作用和吞噬体通路持续上调。在差异表达蛋白中，应答者治疗前转铁蛋白受体蛋白（TFRC）水平较高（倍数变化>1.2）。通过独立队列对TFRC进行验证，结果显示在PD-L1低表达患者中，TFRC对OS或PFS具有预后意义。总之，CA-IT未能改善PD-L1低表达NSQ-NSCLC患者对纳武利尤单抗的疗效，但可诱导MDSC减少，从而产生持久应答。较高的基线TFRC水平可预测PD-L1低表达NSCLC患者对纳武利尤单抗的良好应答。
肿瘤(癌症)患者之家