Bristol Myers Squibb Global Clinical Research, Shanghai, China.
Adv Exp Med Biol. 2020;1248:61-82. doi: 10.1007/978-981-15-3266-5_4.
The first generation of immune checkpoint inhibitors (ICIs) including anti-CTLA-4 and anti-PD-1/anti-PD-L1 has achieved profound and great success. Till 2019 Q1, there are nine ICIs landing the oncology market: Ipilimumab (anti-CTLA-4, Bristol-Myers Squibb), Nivolumab (anti-PD-1, Bristol-Myers Squibb), Pembrolizumab (anti-PD-1, Merck), Atezolizumab (anti-PD-L1, Roche/Genentech), Durvalumab (anti-PD-L1, Astra Zeneca), Tremelimumab (anti-CTLA-4, Astra Zeneca), Cemiplimab (anti-PD-1, Sanofi/Regeneron), Toripalimab (anti-PD-1, Junshi), and Sintilimab (anti-PD-1, Innovent), which have covered the majority of hematologic and solid malignancies' indication. Beyond the considerable benefits for the patients, frustrated boundary still exists: limited response rate in monotherapy in late-stage population, poor effectiveness in neoplasms with immune desert and immune excluded types, and immune-related toxicities, some are life-threatened and with higher incidence in I-O combination regiment. Moreover, clinicians observed some cases switching to progression after achieving partial or complete response, indicating treatment failure or drug resistance. So people begin looking for the next generation of immune checkpoint members.
第一代免疫检查点抑制剂（ICIs）包括抗 CTLA-4 和抗 PD-1/抗 PD-L1，已经取得了深刻而巨大的成功。截至 2019 年第一季度，已有九种 ICI 进入肿瘤市场：Ipilimumab（抗 CTLA-4，百时美施贵宝）、Nivolumab（抗 PD-1，百时美施贵宝）、Pembrolizumab（抗 PD-1，默克）、Atezolizumab（抗 PD-L1，罗氏/基因泰克）、Durvalumab（抗 PD-L1，阿斯利康）、Tremelimumab（抗 CTLA-4，阿斯利康）、Cemiplimab（抗 PD-1，赛诺菲/再生元）、Toripalimab（抗 PD-1，君实生物）和 Sintilimab（抗 PD-1，信达生物），这些药物已经涵盖了大多数血液系统恶性肿瘤和实体瘤的适应证。除了给患者带来巨大的益处外，仍存在令人沮丧的局限性：晚期人群中单药治疗的反应率有限，在免疫荒漠型和免疫排除型肿瘤中的疗效不佳，以及免疫相关毒性，有些是威胁生命的，在免疫检查点抑制剂联合治疗中发生率更高。此外，临床医生观察到一些患者在获得部分或完全缓解后出现进展，表明治疗失败或耐药。因此，人们开始寻找下一代免疫检查点成员。
