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atezolizumab联合贝伐珠单抗治疗晚期肝细胞癌的临床反应和耐药性的分子关联
2022-06-26 19:35

美国基因泰克公司Yulei Wang研究团队揭示atezolizumab联合贝伐珠单抗治疗晚期肝细胞癌的临床反应和耐药性的分子关联。相关论文于2022年6月23日在线发表在《自然—医学》杂志上。

研究人员表示,atezolizumab(抗程序化死亡配体1(PD-L1))和贝伐单抗(抗血管内皮生长因子(VEGF))联合治疗已成为不可切除的肝细胞癌患者的新标准。然而,潜在的预测性生物标志物以及反应和耐药性的机制仍然不甚明了。
 
研究人员报告了对参加GO30140 1b期或IMbrave150 3期试验的358名肝细胞癌(HCC)患者的肿瘤样本进行的综合分子分析,这些患者接受了atezolizumab联合贝伐单抗、atezolizumab或索拉非尼(多激酶抑制剂)治疗。预先存在的免疫力(CD274的高表达、T效应特征和瘤内CD8+T细胞密度)与联合治疗的更好的临床结果有关。临床获益的减少与调节性T细胞(Treg)对效应性T细胞(Teff)的高比率和癌胚基因(GPC3、AFP)的表达有关。联合用药与单独使用atezolizumab相比,结果的改善与血管内皮生长因子受体2(KDR)、Treg和骨髓炎症特征的高表达有关。这些发现通过配对的治疗前和治疗后活检、原位分析和体内小鼠模型的分析得到进一步验证。
 
这项研究确定了联合治疗的关键分子相关因素,并强调抗血管内皮生长因子可能通过针对血管生成、Treg增殖和骨髓细胞炎症而与抗PD-L1协同作用。
 
附:英文原文
 
Title: Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma

Author: Zhu, Andrew X., Abbas, Alexander R., de Galarreta, Marina Ruiz, Guan, Yinghui, Lu, Shan, Koeppen, Hartmut, Zhang, Wenjun, Hsu, Chih-Hung, He, Aiwu Ruth, Ryoo, Baek-Yeol, Yau, Thomas, Kaseb, Ahmed O., Burgoyne, Adam M., Dayyani, Farshid, Spahn, Jessica, Verret, Wendy, Finn, Richard S., Toh, Han Chong, Lujambio, Amaia, Wang, Yulei

Issue&Volume: 2022-06-23

Abstract: Atezolizumab (anti-programmed death-ligand 1 (PD-L1)) and bevacizumab (anti-vascular endothelial growth factor (VEGF)) combination therapy has become the new standard of care in patients with unresectable hepatocellular carcinoma. However, potential predictive biomarkers and mechanisms of response and resistance remain less well understood. We report integrated molecular analyses of tumor samples from 358patients with hepatocellular carcinoma (HCC) enrolled in the GO30140 phase1b or IMbrave150 phase3 trial and treated with atezolizumab combined with bevacizumab, atezolizumab alone or sorafenib (multikinase inhibitor). Pre-existing immunity (high expression of CD274, T-effector signature and intratumoral CD8+Tcell density) was associated with better clinical outcomes with the combination. Reduced clinical benefit was associated with high regulatory Tcell (Treg) to effector Tcell (Teff) ratio and expression of oncofetal genes (GPC3, AFP). Improved outcomes from the combination versus atezolizumab alone were associated with high expression of VEGF Receptor 2 (KDR), Tregs and myeloid inflammation signatures. These findings were further validated by analyses of paired pre- and post-treatment biopsies, in situ analyses and in vivo mouse models. Our study identified key molecular correlates of the combination therapy and highlighted that anti-VEGF might synergize with anti-PD-L1 by targeting angiogenesis, Treg proliferation and myeloid cell inflammation.

DOI: 10.1038/s41591-022-01868-2

Source: https://www.nature.com/articles/s41591-022-01868-2

Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:87.241
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex


本期文章:《自然—医学》:Online/在线发表

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