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摘要: 近年来，免疫治疗成为实体肿瘤治疗的新方法，大量免疫制剂被开发并应用于临床，其中以免疫检查点抑制剂(immune checkpoint inhibitors，ICIs)应用最为广泛，为肿瘤治疗开启了新时代。而以细胞毒性T淋巴细胞相关蛋白4(cytotoxic T-lymphocyte-associated protein 4, CTLA-4)为代表的ICIs类药物丰富了肿瘤免疫治疗方法，开启了双免疫疗法的全新治疗模式。本文就CTLA-4在晚期实体肿瘤治疗中的临床应用进行综述，以期为肿瘤免疫治疗提供参考。
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关键词:
- 实体肿瘤 /
- 免疫治疗 /
- 免疫检查点抑制剂 /
- 细胞毒性T淋巴细胞相关蛋白4
Abstract: In recent years, immunotherapy has become a new method for solid tumor treatment, and a large number of immune preparations have been developed and applied in clinical practice. Among them, immune checkpoint inhibitors (ICIs) are widely used, ushering in a new era for tumor treatment. In particular, cytotoxic T-lymphocyte-associated protein 4(CTLA-4), as a representative drug, enriches tumor immunotherapy methods and opens up a new treatment mode of dual immunotherapy. This article reviews the clinical application progress of CTLA-4 in the treatment of advanced solid tumors, with the hope of providing reference for immunotherapy of tumors.-
Keywords:
- solid tumor /
- immunotherapy /
- immune checkpoint inhibitor /
- CTLA-4
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作者贡献：李涛、郑轩和张帆负责论文撰写；张侃、杨文雨、刘鹿负责文献查阅及资料收集；胡毅负责组织选题及论文审校。利益冲突：所有作者均声明不存在利益冲突
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表 1 CheckMate-227临床试验结果
方案 “O+Y”联合治疗 Nivolumab单药 Nivolumab+化疗 含铂双药化疗 PD-L1≥50%(n=611) mOS(月) 21.2 18.1 - 14.0 DOR(月) 31.8 16.8 - 5.8 HR 0.66(95% CI: 0.52~0.84) 0.64(95% CI: 0.51~0.81) - - PD-L1≥1%(n=1189) 例数(n) 396 396 - 397 mOS(月) 17.1 15.7 - 14.9 总生存率(%) 29 - - 18 中位DOR(月) 23.2 15.5 - 6.7 HR 0.76(95% CI: 0.65~0.90) - - - PD-L1＜1%(n=550) 例数(n) 187 - 177 186 mOS(月) 17.2 - 15.2 12.2 总生存率(%) 24 - - 10 DOR(月) 18.0 - 8.3 4.8 HR 0.64(95% CI: 0.51~0.81) - - - -：未涉及；mOS: 中位总生存期；DOR: 持续缓解时间；HR: 风险比；PD-L1：程序性死亡[蛋白]配体-1 
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表 2 CTLA-4及“O+Y”联合治疗获美国FDA/我国NMPA批准的适应证
序号 临床试验 获批时间 适应证 治疗方案 1 MDX010-20 2011年5月 成人或儿童(≥12岁)不可切除或转移性黑色素瘤 Ipilimumab 3 mg/kg，每3周×44次+ gp100 2 EORTC 18071/CA184-029 2015年10月 病理显示累及局部淋巴结超过1 mm且包括淋巴结在内完全切除的皮肤黑色素瘤术后辅助治疗 Ipilimumab 10 mg/kg，每3周×44次→每12周×3年 3 CheckMate-067 2016年1月 此前未经治疗的不可切除或转移性黑色素瘤 Nivolumab 1 mg/kg+Ipilimumab 3 mg/kg，每3周×44次→Nivolumab 240/480 mg，每2或4周 4 CheckMate-214 2018年4月 此前未经治疗的中高危不可切除晚期肾细胞癌 Nivolumab 3 mg/kg+Ipilimumab 1 mg/kg，每3周×44次→Nivolumab 240/480 mg，每2或4周 5 CheckMate-142 2018年7月 经氟尿嘧啶类、奥沙利铂和伊立替康治疗后进展的MSI-H/dMMR转移性mCRC Nivolumab 3 mg/kg+Ipilimumab 1 mg/kg，每3周×44次→Nivolumab 240/480 mg，每2或4周 6 CheckMate-040 2020年3月 既往接受过索拉非尼治疗的不可切除HCC Nivolumab 1 mg/kg+Ipilimumab 3 mg/kg，每3周×44次→Nivolumab 240/480 mg，每2或4周 7 CheckMate-227 2020年5月 一线治疗PD-L1≥1%，无EGFR/ALK突变转移性NSCLC Nivolumab 3 mg/kg，每2周+Ipilimumab 1 mg/kg，每6周 8 CheckMate-9LA 2020年5月 一线无EGFR/ALK突变的转移性NSCLC Nivolumab 360 mg，每3周+Ipilimumab 1 mg/kg，每6周+含铂双药化疗，每3周×42次→Nivolumab 360 mg，每3周+Ipilimumab 1 mg/kg，每6周 9 CheckMate-743 2020年10月 未经治疗且不可切除MPM Nivolumab 3 mg/kg+Ipilimumab 1 mg/kg，每3周 10 - 2022年6月 既往含铂化疗治疗失败的复发或转移性宫颈癌 Candonilimab 6 mg/kg，每2周(NMPA附条件批准) 11 HIMALAYA 2022年10月 不可切除HCC Tremelimumab 300 mg，1次+Durvalizumab 1500 mg，每4周(STRIDE法) -：未提及；MSI-H：微卫星高度不稳定；dMMR：错配修复缺陷；mCRC：转移性结直肠癌；HCC：肝细胞癌；NSCLC：非小细胞肺癌；MPM：恶性胸膜间皮瘤; FDA: 食品药品监督管理局；NMPA: 国家药品监督管理局；CTLA-4:细胞毒性T淋巴细胞相关蛋白4；PD-L1：同表 1
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表 3 CheckMate系列研究中联合治疗剂量
临床试验 起始剂量 维持剂量 Nivolumab Ipilimumab Nivolumab Ipilimumab CheckMate-067/649/040 1 mg/kg, 每3周 3 mg/kg, 每3周 240 mg, 每2周/480 mg, 每4周 - CheckMate-142/214/040 3 mg/kg, 每3周 1 mg/kg, 每3周 240 mg, 每2周/480mg, 每4周 - CheckMate-227/9LA/142/040/743 3 mg/kg, 每2周 1 mg/kg, 每6周 3 mg/kg, 每2周 1 mg/kg, 每6周 -：未使用
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表 4 CTLA-4单药或联合治疗AE发生率[%(n/N)]
药物(剂量) 皮疹 肺炎 肾炎 总体 2级 3~5级 激素治疗 Ipilimumab(3 mg/kg) 15(76/511) 12(61/511) 2.5(13/511) 43(33/76) - - Ipilimumab(10 mg/kg) 25(118/471) 21(99/471) 4(19/471) 70(83/118) - - Nivolumab+Ipilimumab(1 mg/kg) 16(108/666) 4.2(28/666) 3.5(23/666) - 3.9(26/666) Nivolumab+ Ipilimumab(3 mg/kg) 35(17/49) - - 12(6/49) 10(5/49) - 药物(剂量) 内分泌系统 总体 垂体炎 肾上腺皮质功能不全 甲状腺功能亢进 甲状腺功能减退 甲状腺炎 糖尿病 Ipilimumab(3 mg/kg) 4
(21/511)- - - - - - Ipilimumab(10 mg/kg) 28
(132/471)- - - - - - Nivolumab+Ipilimumab(1 mg/kg) 4.4
(29/666)7
(48/666)12
(80/666)18
(122/666)3.3
(22/666)2.3
(15/666)- Nivolumab+ Ipilimumab(3 mg/kg) - - 18
(9/49)10
(5/49)22
(11/49)- - -：未涉及；CTLA-4：同表 2；AE: 不良事件
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