Discovery Oncology, Merck & Co. Inc, South San Francisco, California, USA
Discovery Oncology, Merck & Co. Inc, South San Francisco, California, USA.
J Immunother Cancer. 2020 Oct;8(2). doi: 10.1136/jitc-2020-001584.
Programmed cell death protein 1 (PD-1) and CTLA4 combination blockade enhances clinical efficacy in melanoma compared with targeting either checkpoint alone; however, clinical response improvement is coupled with increased risk of developing immune-related adverse events (irAE). Delineating the mechanisms of checkpoint blockade-mediated irAE has been hampered by the lack of animal models that replicate these clinical events.
We have developed a mouse model of checkpoint blockade-mediated enterocolitis via prolonged administration of an Fc-competent anti-CTLA4 antibody.
Sustained treatment with Fc-effector, but not Fc-mutant or Fc-null, anti-CTLA4 antagonist for 7 weeks resulted in enterocolitis. Moreover, combining Fc-null or Fc-mutant CTLA4 antagonists with PD-1 blockade results in potent antitumor combination efficacy indicating that Fc-effector function is not required for combination benefit.
These data suggest that using CTLA4 antagonists with no Fc-effector function can mitigate gut inflammation associated with anti-CTLA4 antibody therapy yet retain potent antitumor activity in combination with PD-1 blockade.
与单独靶向检查点相比，程序性死亡蛋白 1（PD-1）和 CTLA4 联合阻断增强了黑色素瘤的临床疗效；然而，临床反应的改善伴随着免疫相关不良事件（irAE）风险的增加。由于缺乏能够复制这些临床事件的动物模型，因此，检查点阻断介导的 irAE 的机制仍不清楚。
我们通过延长 Fc 功能完整的抗 CTLA4 抗体的给药时间，建立了一种检查点阻断介导的结肠炎小鼠模型。
持续 7 周给予 Fc 效应，但不是 Fc 突变体或 Fc 缺失型抗 CTLA4 拮抗剂治疗可导致结肠炎。此外，将 Fc 缺失型或 Fc 突变型 CTLA4 拮抗剂与 PD-1 阻断联合使用可产生强大的抗肿瘤联合疗效，表明 Fc 效应功能对于联合治疗获益不是必需的。
这些数据表明，使用无 Fc 效应功能的 CTLA4 拮抗剂可以减轻与抗 CTLA4 抗体治疗相关的肠道炎症，同时保留与 PD-1 阻断联合使用的强大抗肿瘤活性。
