Department of Oncology, National Taiwan University Hospital, and Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.
Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
Nat Rev Clin Oncol. 2024 Jun;21(6):468-482. doi: 10.1038/s41571-024-00886-y. Epub 2024 Apr 10.
Antiangiogenic agents, generally antibodies or tyrosine-kinase inhibitors that target the VEGF-VEGFR pathway, are currently among the few combination partners clinically proven to improve the efficacy of immune-checkpoint inhibitors (ICIs). This benefit has been demonstrated in pivotal phase III trials across different cancer types, some with practice-changing results; however, numerous phase III trials have also had negative results. The rationale for using antiangiogenic drugs as partners for ICIs relies primarily on blocking the multiple immunosuppressive effects of VEGF and inducing several different vascular-modulating effects that can stimulate immunity, such as vascular normalization leading to increased intratumoural blood perfusion and flow, and inhibition of pro-apoptotic effects of endothelial cells on T cells, among others. Conversely, VEGF blockade can also cause changes that suppress antitumour immunity, such as increased tumour hypoxia, and reduced intratumoural ingress of co-administered ICIs. As a result, the net clinical benefits from antiangiogenic-ICI combinations will be determined by the balance between the opposing effects of VEGF signalling and its inhibition on the antitumour immune response. In this Perspective, we summarize the results from the currently completed phase III trials evaluating antiangiogenic agent-ICI combinations. We also discuss strategies to improve the efficacy of these combinations, focusing on aspects that include the deleterious functions of VEGF-VEGFR inhibition on antitumour immunity, vessel co-option as a driver of non-angiogenic tumour growth, clinical trial design, or the rationale for drug selection, dosing and scheduling.
抗血管生成药物，一般是针对 VEGF-VEGFR 通路的抗体或酪氨酸激酶抑制剂，目前是少数几种经临床证实能提高免疫检查点抑制剂（ICI）疗效的联合用药之一。这一益处已在不同癌症类型的关键 III 期试验中得到证实，其中一些结果具有改变实践的意义；然而，许多 III 期试验也得出了阴性结果。将抗血管生成药物作为 ICI 的联合用药的依据主要基于阻断 VEGF 的多种免疫抑制作用，并诱导多种不同的血管调节作用，从而刺激免疫，如血管正常化导致肿瘤内血液灌注和流量增加，以及抑制内皮细胞对 T 细胞的促凋亡作用等。相反，VEGF 阻断也可能导致抑制抗肿瘤免疫的变化，如肿瘤缺氧增加，以及共给药的 ICI 进入肿瘤内的减少。因此，抗血管生成-ICI 联合治疗的净临床获益将取决于 VEGF 信号及其对抗肿瘤免疫反应的抑制作用之间的平衡。在本观点中，我们总结了目前已完成的评估抗血管生成药物-ICI 联合治疗的 III 期试验结果。我们还讨论了提高这些联合治疗疗效的策略，重点关注 VEGF-VEGFR 抑制对抗肿瘤免疫的有害作用、血管选择作为非血管性肿瘤生长的驱动因素、临床试验设计或药物选择、剂量和方案的原理等方面。
