Background and Aims: Treatment with atezolizumab and bevacizumab has been approved as one of the standards of care for patients with advanced hepatocellular carcinoma (HCC). The median overall survival (OS) upon available treatments still remains below 2 years, urgently suggesting better stratification tools to identify ideal candidates for this treatment and potentially allowing personalized approaches. In this study, we evaluated the potential role of extracellular vesicles (EVs) as a novel biomarker in patients receiving atezolizumab and bevacizumab for HCC. Methods: We characterized EVs in 212 longitudinal serum samples from an observational cohort of 53 individuals with advanced HCC, who started therapy with atezolizumab plus bevacizumab at our center between January 2020 and March 2022. Results: In our cohort, the overall efficacy of atezolizumab and bevacizumab was comparable to previously published phase III data. We detected significantly smaller EVs in treatment responders, while enlarged EVs were associated with significantly decreased efficacy of atezolizumab and bevacizumab in terms of OS. A decrease in vesicle size during immunotherapy was related to a longer progression-free survival (PFS). A univariate Cox regression analysis including various clinicopathological parameters (e.g., tumor stage, markers of inflammation, organ dysfunction, or tumor markers) revealed vesicle size as an independent prognostic marker in HCC patients receiving atezolizumab and bevacizumab. Moreover, higher vesicle concentrations and lower zeta potentials were identified as a positive prognostic factor throughout treatment. Conclusions: Distinct EV characteristics such as vesicle size, concentration, and zeta potential represent promising novel biomarkers in patients with advanced HCC receiving atezolizumab and bevacizumab, potentially helping to identify optimal candidates for checkpoint inhibitor-based treatments.
背景与目的：阿特珠单抗联合贝伐珠单抗治疗已被批准作为晚期肝细胞癌（HCC）患者的标准治疗方案之一。现有治疗手段下的中位总生存期（OS）仍不足两年，这迫切要求开发更优的分层工具以识别该治疗的理想候选者，并可能实现个体化治疗策略。本研究评估了细胞外囊泡（EVs）作为接受阿特珠单抗与贝伐珠单抗治疗的HCC患者新型生物标志物的潜在价值。方法：我们对53例晚期HCC患者（2020年1月至2022年3月期间在本中心开始接受阿特珠单抗联合贝伐珠单抗治疗）观察队列中的212份纵向血清样本进行EVs表征分析。结果：本队列中阿特珠单抗与贝伐珠单抗的总体疗效与既往发表的III期数据相当。治疗应答者体内检测到显著更小的EVs，而增大的EVs与阿特珠单抗和贝伐珠单抗在OS方面的疗效显著降低相关。免疫治疗期间囊泡尺寸的减小与更长的无进展生存期（PFS）相关。包含多种临床病理参数（如肿瘤分期、炎症标志物、器官功能障碍或肿瘤标志物）的单变量Cox回归分析显示，囊泡尺寸是接受阿特珠单抗与贝伐珠单抗治疗的HCC患者的独立预后标志物。此外，较高的囊泡浓度和较低的Zeta电位被确认为整个治疗过程中的积极预后因素。结论：囊泡尺寸、浓度和Zeta电位等特异性EV特征可作为接受阿特珠单抗与贝伐珠单抗治疗的晚期HCC患者的新型生物标志物，有望帮助识别基于检查点抑制剂治疗的最佳候选者。
肿瘤(癌症)患者之家