Loxo Oncology at Lilly, Eli Lilly and Company, New York City, New York, United States of America.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America.
PLoS One. 2022 Jul 18;17(7):e0268244. doi: 10.1371/journal.pone.0268244. eCollection 2022.
Prolonged activation of vascular endothelial growth factor receptor-2 (VEGFR-2) due to mis-regulation of the VEGF pathway induces aberrant blood vessel expansion, which supports growth and survival of solid tumors. Therapeutic interventions that inhibit the VEGFR-2 pathway have therefore become a mainstay of cancer treatment. Non-clinical studies have recently revealed that blockade of angiogenesis can modulate the tumor microenvironment and enhance the efficacy of concurrent immune therapies. Ramucirumab is an FDA-approved anti-angiogenic antibody that inhibits VEGFR-2 and is currently being evaluated in clinical studies in combination with anti-programmed cell death (PD-1) axis checkpoint inhibitors (pembrolizumab, durvalumab, or sintilimab) across several cancer types. The purpose of this study is to establish a mechanistic basis for the enhanced activity observed in the combined blockade of VEGFR-2 and PD-1-axis pathways. Pre-clinical studies were conducted in murine tumor models known to be responsive to anti-PD-1 axis therapy, using monoclonal antibodies that block mouse VEGFR-2 and programmed death-ligand 1 (PD-L1). Combination therapy resulted in enhanced anti-tumor activity compared to anti-PD-L1 monotherapy. VEGFR-2 blockade at early timepoints post-anti-PD-L1 therapy resulted in a dose-dependent and transient enhanced infiltration of T cells, and establishment of immunological memory. VEGFR-2 blockade at later timepoints resulted in enhancement of anti-PD-L1-driven immune cell infiltration. VEGFR-2 and PD-L1 monotherapies induced both unique and overlapping patterns of immune gene expression, and combination therapy resulted in an enhanced immune activation signature. Collectively, these results provide new and actionable insights into the mechanisms by which concurrent VEGFR-2 and PD-L1 antibody therapy leads to enhanced anti-tumor efficacy.
血管内皮生长因子受体-2（VEGFR-2）的长期激活由于 VEGF 途径的失调导致异常的血管扩张，这支持了实体瘤的生长和存活。因此，抑制 VEGFR-2 途径的治疗干预已成为癌症治疗的主要方法。最近的非临床研究表明，血管生成的阻断可以调节肿瘤微环境并增强同时进行的免疫治疗的疗效。雷莫芦单抗是一种获得 FDA 批准的抗血管生成抗体，可抑制 VEGFR-2，目前正在几种癌症类型的临床试验中与抗程序性细胞死亡（PD-1）轴检查点抑制剂（pembrolizumab、durvalumab 或 sintilimab）联合进行评估。本研究的目的是为观察到的 VEGFR-2 和 PD-1 轴途径联合阻断增强的活性建立机制基础。在对抗 PD-1 轴治疗有反应的已知小鼠肿瘤模型中进行了临床前研究，使用了阻断小鼠 VEGFR-2 和程序性死亡配体 1（PD-L1）的单克隆抗体。与抗 PD-L1 单药治疗相比，联合治疗导致抗肿瘤活性增强。在抗 PD-L1 治疗后早期进行 VEGFR-2 阻断导致 T 细胞的剂量依赖性和短暂增强浸润，并建立免疫记忆。在稍后的时间点进行 VEGFR-2 阻断会增强抗 PD-L1 驱动的免疫细胞浸润。VEGFR-2 和 PD-L1 的单药治疗诱导了独特和重叠的免疫基因表达模式，联合治疗导致了增强的免疫激活特征。总之，这些结果为同时进行的 VEGFR-2 和 PD-L1 抗体治疗导致增强的抗肿瘤疗效的机制提供了新的和可行的见解。
