Abramson Cancer Center, University of Pennsylvania, 12 Floor South Pavilion, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA.
Cancer Cell. 2018 Apr 9;33(4):563-569. doi: 10.1016/j.ccell.2018.03.008.
Most tumors are unresponsive to immune checkpoint blockade, especially if deep immunosuppression in the tumor develops prior to and prevents T cell immunosurveillance. Failed or frustrated T cell priming often needs repair before successful sensitization to PD-1/PD-L1 blockade. CD40 activation plays a critical role in generating T cell immunity, by activating dendritic cells, and converting cold tumors to hot. In preclinical studies, agonistic CD40 antibodies demonstrate T cell-dependent anti-tumor activity, especially in combination with chemotherapy, checkpoint inhibitory antibodies, and other immune modulators. With the advent of multiple CD40 agonists with acceptable single-agent toxicity, clinical evaluation of CD40 combinations has accelerated.
大多数肿瘤对免疫检查点阻断无反应，尤其是在肿瘤中预先发生并阻止 T 细胞免疫监视的深度免疫抑制的情况下。在对 PD-1/PD-L1 阻断成功致敏之前，失败或受挫的 T 细胞启动通常需要修复。CD40 激活通过激活树突状细胞并将冷肿瘤转化为热肿瘤，在产生 T 细胞免疫方面发挥着关键作用。在临床前研究中，激动性 CD40 抗体通过与化疗、检查点抑制抗体和其他免疫调节剂联合使用，显示出 T 细胞依赖性抗肿瘤活性。随着具有可接受的单一药物毒性的多种 CD40 激动剂的出现，CD40 联合治疗的临床评估已经加速。
