Einstein David J, McDermott David F
Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Beth Israel Deaconess Medical Center, and Dana-Farber/Harvard Cancer Center Kidney Cancer Program, Boston, Massachusetts.
Clin Adv Hematol Oncol. 2017 Jun;15(6):478-488.
Targeted and immune-based therapies have improved outcomes in advanced kidney cancer, yet novel strategies are needed to extend the duration of these benefits and expand them to more patients. Combined inhibition of vascular endothelial growth factor (VEGF) and the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathways with therapeutic agents already in clinical use may offer such a strategy. Here, we describe the development and clinical evaluation of VEGF inhibitors and, separately, PD-1/PD-L1 inhibitors. We present preclinical evidence of interaction between these pathways and the rationale for combined blockade. Beyond well-known effects on pathologic angiogenesis, VEGF blockade also may decrease immune tolerance and enhance PD-1/PD-L1 blockade. We conclude with the results of several early trials of combined VEGF and PD-1/PD-L1 blockade, which demonstrate encouraging antitumor activity, and we pose questions for future study.
靶向治疗和免疫治疗已改善了晚期肾癌的治疗效果，但仍需要新的策略来延长这些益处的持续时间并将其惠及更多患者。联合使用临床中已有的治疗药物抑制血管内皮生长因子（VEGF）以及程序性死亡蛋白1（PD-1）/程序性死亡配体1（PD-L1）信号通路或许能提供这样一种策略。在此，我们描述了VEGF抑制剂以及PD-1/PD-L1抑制剂的研发与临床评估。我们展示了这些信号通路之间相互作用的临床前证据以及联合阻断的理论依据。除了对病理性血管生成的已知作用外，VEGF阻断还可能降低免疫耐受并增强PD-1/PD-L1阻断。我们以VEGF与PD-1/PD-L1联合阻断的几项早期试验结果作为总结，这些结果显示出令人鼓舞的抗肿瘤活性，同时我们也提出了未来研究的问题。
