Pfizer Global Product Development, Pfizer, La Jolla, California.
Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Res. 2018 Dec 15;78(24):6717-6725. doi: 10.1158/0008-5472.CAN-18-2652. Epub 2018 Nov 29.
PARP inhibitors drive increased DNA damage, particularly in tumors with existing defects in DNA repair. This damage not only promotes immune priming through a range of molecular mechanisms, but also leads to adaptive upregulation of programmed death ligand 1 (PD-L1) expression. In this context, PARP inhibition and programmed cell death 1(PD-1)/PD-L1-targeting antibodies represent a rationale combination. In this review, we detail the basic and translational science underpinning this promising new combination, summarize available clinical data, and discuss the key questions that remain to be addressed during future development.
聚腺苷二磷酸核糖聚合酶（PARP）抑制剂会导致 DNA 损伤增加，尤其是在存在 DNA 修复缺陷的肿瘤中。这种损伤不仅通过一系列分子机制促进免疫启动，还导致程序性死亡配体 1（PD-L1）表达的适应性上调。在这种情况下，PARP 抑制和程序性细胞死亡 1（PD-1）/PD-L1 靶向抗体代表了一种合理的联合治疗。在这篇综述中，我们详细介绍了这种有前途的新联合治疗的基础和转化科学，总结了现有临床数据，并讨论了在未来开发过程中仍需解决的关键问题。
