PO.CL01.06 · 临床研究
基线CD16+ NK细胞与晚期肝细胞癌nivolumab联合ipilimumab免疫治疗的临床结局相关
Baseline CD16 + NK cells are associated with clinical outcome of nivolumab plus ipilimumab immunotherapy in advanced hepatocellular carcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：nivolumab联合ipilimumab（Nivo/Ipi）的联合免疫治疗在晚期肝细胞癌（HCC）中显示出持久的缓解。然而，能够预测临床获益的可靠生物标志物仍然有限。CD16⁺（FcγRIIIa）NK细胞介导抗体依赖性细胞毒性（ADCC），可能影响作为人IgG1单克隆抗体的Ipi的疗效。我们研究了基线外周CD16⁺ NK细胞水平是否与接受Nivo/Ipi治疗的晚期HCC患者的临床结局相关。
方法：2020年3月至2023年8月期间，从韩国4家三级肿瘤中心前瞻性入组晚期HCC患者。患者接受Nivo 1 mg/kg联合Ipi 3 mg/kg每3周一次（4个周期），随后接受Nivo维持治疗（240 mg每2周一次）。在基线和第22天（第2周期第1天[C2D1]）采集外周血单个核细胞样本并通过流式细胞术分析。根据最大选择秩统计量确定的界值，将患者分为CD16⁺ NK高组和低组。对10例缓解者和20例非缓解者进行单细胞RNA测序，以鉴定治疗反应的转录组学关联。
结果：共入组并分析了55例患者。大多数患者为男性（82%），伴乙型肝炎病毒感染（81.8%），肝功能保留（Child-Pugh A 78.2%，B 21.8%）。74.5%曾接受过≥2线系统治疗，23.6%为免疫治疗初治。中位随访时间为38.7个月（范围18.3-50.1）。中位无进展生存期（PFS）为1.3个月（95% CI，1.2-1.7），中位总生存期（OS）为4.7个月（95% CI，3.8-9.1）。尽管缓解者和非缓解者之间NK细胞总数无差异（p=0.139），但缓解者的基线CD16⁺ NK细胞显著更高。CD16⁺ NK高组显示出更优的客观缓解率（60% vs 17.8%，p=0.012）、疾病控制率（70% vs 26.7%，p=0.023），以及更长的PFS（14.4个月，95% CI 1.4-未达到[NR]，p=0.017）和OS（14.7个月，95% CI 1.4-NR，p=0.079）。高基线CD16+ NK细胞比例与C2D1时调节性T细胞的下降相关，提示Ipi介导的ADCC增强。与此一致，单细胞分析也显示缓解者基线时NK细胞中CD16+表达高于非缓解者。这些发现的独立验证正在进行中。
结论：基线外周CD16⁺ NK细胞水平与接受Nivo/Ipi治疗的晚期HCC患者临床结局改善显著相关。高CD16⁺ NK细胞频率与更高的缓解率和更长的生存期相关，可能通过增强ADCC和抑制调节性T细胞实现。这些发现提示基线CD16⁺ NK细胞可能作为HCC中Nivo/Ipi的预测性生物标志物，值得进一步验证队列研究。
查看英文原文 English abstract
Background: Combination immunotherapy of nivolumab plus ipilimumab (Nivo/Ipi) has shown durable responses in advanced hepatocellular carcinoma (HCC). However, reliable biomarkers predicting clinical benefit remain limited. CD16⁺ (FcgammaRIIIa) NK cells mediate antibody-dependent cellular cytotoxicity (ADCC) and may influence the efficacy of Ipi, a human IgG1 monoclonal antibody. We investigated whether baseline peripheral CD16⁺ NK cell levels correlate with clinical outcomes in advanced HCC patients receiving Nivo/Ipi.
Method: Patients with advanced HCC were prospectively enrolled from 4 tertiary cancer centers in Korea from Mar 2020 to Aug 2023. Patients received Nivo 1 mg/kg plus Ipi 3 mg/kg every 3 weeks (4 cycles) followed by Nivo maintenance (240 mg every 2 weeks). Peripheral blood mononuclear cell samples were collected at baseline and on day 22 (Cycle 2 Day 1 [C2D1]) and analyzed by flow cytometry. Patients were classified into high and low CD16⁺ NK groups based on a cut-point determined by maximally selected rank statistics. Single-cell RNA sequencing from 10 responders and 20 non-responders was performed to identify transcriptional correlates of treatment response.
Results: 55 patients were enrolled and analyzed. Most patients were male (82%) with Hepatitis B virus infection (81.8%), and preserved liver function (Child-Pugh A 78.2%, B 21.8%). 74.5% had received ≥2 prior systemic therapies, and 23.6% were immunotherapy naïve. The median follow-up duration was 38.7 months (range, 18.3-50.1). Median progression-free survival (PFS) was 1.3 months (95% CI, 1.2-1.7), and median overall survival (OS) was 4.7 months (95% CI, 3.8-9.1). Although there were no differences in total NK cell numbers between responders and non-responders (p = 0.139), baseline CD16⁺ NK cells were significantly higher in responders. The high CD16⁺ NK group showed superior objective response rate (60% vs
17.8%, p = 0.012), disease control rate (70% vs 26.7%, p = 0.023), and longer PFS (14.4 months, 95% CI 1.4-not reached [NR], p = 0.017) and OS (14.7 months, 95% CI 1.4-NR, p = 0.079). High baseline CD16 + NK cell proportion were associated with the decline of regulatory T cells at C2D1, suggesting enhanced ADCC by Ipi. Consistently, single cell analysis also revealed higher baseline CD16 + expression in NK cells at baseline in responders than non-responders. Independent validation of these findings is ongoing.
Conclusion: Baseline peripheral CD16⁺ NK cell levels were significantly associated with improved clinical outcomes in advanced HCC patients treated with Nivo/Ipi. High CD16⁺ NK cell frequency correlated with higher response rates and prolonged survival, potentially through enhanced ADCC and suppression of regulatory T cells. These findings suggest that baseline CD16⁺ NK cells may serve as a predictive biomarker for Nivo/Ipi in HCC, warranting further validation cohorts.
利益披露 Disclosure
H. Chon, None..
N. Lee, None..
H. Yang, None..
J. Kang, None..
W. Lee, None..
S. Kong, None..
B. Kang, None..
J. Kim, None..
H. Lim, None..
J. Choi, None..
C. Kim, None.