Torrens Laura, Montironi Carla, Puigvehí Marc, Mesropian Agavni, Leslie Jack, Haber Philipp K, Maeda Miho, Balaseviciute Ugne, Willoughby Catherine E, Abril-Fornaguera Jordi, Piqué-Gili Marta, Torres-Martín Miguel, Peix Judit, Geh Daniel, Ramon-Gil Erik, Saberi Behnam, Friedman Scott L, Mann Derek A, Sia Daniela, Llovet Josep M
Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
Translational Research in Hepatic Oncology, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Universitat De Barcelona, Barcelona, Spain.
Hepatology. 2021 Nov;74(5):2652-2669. doi: 10.1002/hep.32023. Epub 2021 Sep 27.
Lenvatinib is an effective drug in advanced HCC. Its combination with the anti-PD1 (programmed cell death protein 1) immune checkpoint inhibitor, pembrolizumab, has generated encouraging results in phase Ib and is currently being tested in phase III trials. Here, we aimed to explore the molecular and immunomodulatory effects of lenvatinib alone or in combination with anti-PD1.
We generated three syngeneic models of HCC in C57BL/6J mice (subcutaneous and orthotopic) and randomized animals to receive placebo, lenvatinib, anti-PD1, or combination treatment. Flow cytometry, transcriptomic, and immunohistochemistry analyses were performed in tumor and blood samples. A gene signature, capturing molecular features associated with the combination therapy, was used to identify a subset of candidates in a cohort of 228 HCC patients who might respond beyond what is expected for monotherapies. In mice, the combination treatment resulted in tumor regression and shorter time to response compared to monotherapies (P < 0.001). Single-agent anti-PD1 induced dendritic and T-cell infiltrates, and lenvatinib reduced the regulatory T cell (Treg) proportion. However, only the combination treatment significantly inhibited immune suppressive signaling, which was associated with the TGFß pathway and induced an immune-active microenvironment (P < 0.05 vs. other therapies). Based on immune-related genomic profiles in human HCC, 22% of patients were identified as potential responders beyond single-agent therapies, with tumors characterized by Treg cell infiltrates, low inflammatory signaling, and VEGFR pathway activation.
Lenvatinib plus anti-PD1 exerted unique immunomodulatory effects through activation of immune pathways, reduction of Treg cell infiltrate, and inhibition of TGFß signaling. A gene signature enabled the identification of ~20% of human HCCs that, although nonresponding to single agents, could benefit from the proposed combination.
乐伐替尼是治疗晚期肝细胞癌（HCC）的一种有效药物。它与抗程序性死亡蛋白1（PD1）免疫检查点抑制剂帕博利珠单抗联合使用，在Ib期试验中取得了令人鼓舞的结果，目前正在进行III期试验。在此，我们旨在探讨乐伐替尼单独使用或与抗PD1联合使用的分子和免疫调节作用。
我们在C57BL/6J小鼠中建立了三种同基因HCC模型（皮下和原位），并将动物随机分组，分别接受安慰剂、乐伐替尼、抗PD1或联合治疗。对肿瘤和血液样本进行了流式细胞术、转录组学和免疫组织化学分析。利用一个捕捉与联合治疗相关分子特征的基因特征，在228例HCC患者队列中识别出一部分可能比单药治疗预期效果更好的候选患者。在小鼠中，与单药治疗相比，联合治疗导致肿瘤消退且反应时间更短（P < 0.001）。单药抗PD1诱导树突状细胞和T细胞浸润，而乐伐替尼降低调节性T细胞（Treg）比例。然而，只有联合治疗显著抑制了与转化生长因子β（TGFβ）途径相关的免疫抑制信号，并诱导了免疫活性微环境（与其他治疗相比，P < 0.05）。基于人类HCC中与免疫相关的基因组图谱，22%的患者被确定为单药治疗以外的潜在反应者，其肿瘤的特征是Treg细胞浸润、低炎症信号和血管内皮生长因子受体（VEGFR）途径激活。
乐伐替尼联合抗PD1通过激活免疫途径、减少Treg细胞浸润和抑制TGFβ信号发挥独特的免疫调节作用。一个基因特征能够识别约20%的人类HCC，这些HCC虽然对单药无反应，但可能从所提出的联合治疗中获益。
