Immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1) protein significantly improve survival in patients with advanced non-small-cell lung cancer (NSCLC), but its impact on early-stage ground-glass opacity (GGO) lesions remains unclear. This is a single-arm, phase II trial (NCT04026841) using Simon’s optimal two-stage design, of which 4 doses of sintilimab (200 mg per 3 weeks) were administrated in 36 enrolled multiple primary lung cancer (MPLC) patients with persistent high-risk (Lung-RADS category 4 or had progressed within 6 months) GGOs. The primary endpoint was objective response rate (ORR). T/B/NK-cell subpopulations, TCR-seq, cytokines, exosomal RNA, and multiplexed immunohistochemistry (mIHC) were monitored and compared between responders and non-responders. Finally, two intent-to-treat (ITT) lesions (pure-GGO or GGO-predominant) showed responses (ORR: 5.6%, 2/36), and no patients had progressive disease (PD). No grade 3–5 TRAEs occurred. The total response rate considering two ITT lesions and three non-intent-to-treat (NITT) lesions (pure-solid or solid-predominant) was 13.9% (5/36). The proportion of CD8⁺ T cells, the ratio of CD8⁺/CD4⁺, and the TCR clonality value were significantly higher in the peripheral blood of responders before treatment and decreased over time. Correspondingly, the mIHC analysis showed more CD8⁺ T cells infiltrated in responders. Besides, responders’ cytokine concentrations of EGF and CTLA-4 increased during treatment. The exosomal expression of fatty acid metabolism and oxidative phosphorylation gene signatures were down-regulated among responders. Collectively, PD-1 inhibitor showed certain activity on high-risk pulmonary GGO lesions without safety concerns. Such effects were associated with specific T-cell re-distribution, EGF/CTLA-4 cytokine compensation, and regulation of metabolism pathways.

针对程序性细胞死亡 1 (PD-1) 蛋白的免疫检查点抑制剂可显着提高晚期非小细胞肺癌 (NSCLC) 患者的生存率，但其对早期毛玻璃样病变 (GGO) 病变的影响仍然存在不清楚。这是一项单臂、II 期试验 (NCT04026841)，采用 Simon 的最佳两阶段设计，其中 36 名入组的多原发性肺癌 (MPLC) 患者接受了 4 剂信迪利单抗（每 3 周 200 毫克），且患者持续性高-风险（Lung-RADS 4 类或在 6 个月内出现进展）GGO。主要终点是客观缓解率（ORR）。对应答者和非应答者之间的 T/B/NK 细胞亚群、TCR-seq、细胞因子、外泌体 RNA 和多重免疫组织化学 (mIHC) 进行监测和比较。最后，两个意向治疗 (ITT) 病变（纯 GGO 或以 GGO 为主）显示出缓解（ORR：5.6%，2/36），并且没有患者出现疾病进展（PD）。没有发生 3-5 级 TRAE。考虑两个 ITT 病变和三个非意向治疗 (NITT) 病变（纯实性或实性为主）的总缓解率为 13.9% (5/36)。应答者外周血中CD8 ⁺ T细胞比例、CD8 ⁺ /CD4 ⁺比值和TCR克隆值在治疗前均显着升高，并随着时间的推移而下降。相应地，mIHC 分析显示应答者中有更多的 CD8 ⁺ T 细胞浸润。此外，治疗期间应答者的 EGF 和 CTLA-4 细胞因子浓度有所增加。应答者中脂肪酸代谢和氧化磷酸化基因特征的外泌体表达下调。总的来说，PD-1抑制剂对高危肺部GGO病变表现出一定的活性，且没有安全性问题。这种效应与特定的 T 细胞重新分布、EGF/CTLA-4 细胞因子补偿和代谢途径的调节有关。