School of Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan.
Semin Liver Dis. 2018 Nov;38(4):379-388. doi: 10.1055/s-0038-1673621. Epub 2018 Oct 24.
Multikinase inhibitors with antiangiogenic properties used to be standard therapy for patients with advanced hepatocellular carcinoma (HCC). Recently, several antiangiogenic agents (lenvatinib, cabozantinib, and ramucirumab) have demonstrated antitumor activity for advanced HCC in randomized controlled trials. However, the landscape of drug development for HCC may change dramatically with the advent of immune checkpoint inhibitor therapy, particularly the anti-programmed cell death-1 (anti-PD1) agents. In addition, early-phase clinical trials of combination of anti-PD-1 and antiangiogenic agents have shown very promising anti-tumor activity in patients with advanced HCC. Therefore, the critical research questions at present are whether this combination strategy will be the next generation of standard therapy and which antiangiogenic agents will be the optimal partner for the combination. All of the 4 multikinase inhibitors for HCC (sorafenib, regorafenib, lenvatinib, and cabozantinib) have been reported to have immune modulatory effects. The authors systematically reviewed the pre-clinical evidence of their immune modulatory effects to explore whether these effects were mediated by angiogenesis inhibition or by other "off-target" effects on the tumor microenvironment. Studies of sorafenib comprised the majority (58 of the 71) of the research articles reviewed. Potentially beneficial effects on anti-tumor immunity may result from increased M1 polarization of macrophages and stimulation of CD8 T cell function. On the other hand, high dosage of the kinase inhibitors in pre-clinical models and hypoxia associated with angiogenesis may contribute to immune suppression in the tumor microenvironment. Sorafenib and other multikinase inhibitors may promote anti-tumor immunity through modulation of multiple immune cell types as well as the tumor microenvironment. The optimal immune modulatory dosage should be defined to facilitate design of future combination regimens.
多激酶抑制剂具有抗血管生成特性，曾被用作晚期肝细胞癌（HCC）患者的标准治疗方法。最近，几项抗血管生成药物（仑伐替尼、卡博替尼和雷莫芦单抗）在随机对照试验中显示出对晚期 HCC 的抗肿瘤活性。然而，随着免疫检查点抑制剂治疗的出现，HCC 的药物开发格局可能会发生巨大变化，特别是抗程序性细胞死亡-1（抗 PD-1）药物。此外，抗 PD-1 和抗血管生成药物联合的早期临床试验显示，晚期 HCC 患者的抗肿瘤活性非常有前景。因此，目前的关键研究问题是这种联合策略是否将成为下一代标准治疗方法，以及哪种抗血管生成药物将是联合治疗的最佳选择。所有 4 种用于 HCC 的多激酶抑制剂（索拉非尼、瑞戈非尼、仑伐替尼和卡博替尼）都被报道具有免疫调节作用。作者系统地回顾了它们的免疫调节作用的临床前证据，以探讨这些作用是否是通过抑制血管生成还是通过对肿瘤微环境的其他“脱靶”作用来介导的。在综述的研究论文中，索拉非尼的研究占多数（71 篇中的 58 篇）。巨噬细胞 M1 极化和 CD8 T 细胞功能的刺激可能会导致抗肿瘤免疫的潜在有益影响。另一方面，在临床前模型中，激酶抑制剂的高剂量和与血管生成相关的缺氧可能会导致肿瘤微环境中的免疫抑制。索拉非尼和其他多激酶抑制剂可能通过调节多种免疫细胞类型以及肿瘤微环境来促进抗肿瘤免疫。应该定义最佳的免疫调节剂量，以促进未来联合方案的设计。
