免疫检查点抑制剂在肝细胞癌肝移植中的应用

解有成; 陈顺; 李初谊; 郑英; 贾栋; 张久聪; 于晓辉

doi:10.3969/j.issn.1001-5256.2023.04.030

免疫检查点抑制剂在肝细胞癌肝移植中的应用

DOI: 10.3969/j.issn.1001-5256.2023.04.030

解有成^{1, 2},
陈顺¹,
李初谊¹,
郑英¹,
贾栋^{1, 2},
张久聪¹,
于晓辉^1, , ,

1.
中国人民解放军联勤保障部队第九四〇医院消化内科，兰州 730050
2.
甘肃中医药大学第一临床医学院，兰州 730000

基金项目:

甘肃省重点研发计划 (20YF8FA099);

甘肃省青年科技基金 (20JR10RA016);

甘肃省非感染性肝病临床医学研究中心 (21JR7RA017);

甘肃省卫健委科研计划 (GSWSKY2021-047)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：解有成负责课题设计，资料分析，撰写论文；陈顺、贾栋、郑英参与收集数据，修改论文；于晓辉、张久聪、李初谊负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
于晓辉, yuxiaohui@126.com (ORCID: 0000-0002-8633-3281)

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出版历程
- 收稿日期: 2022-07-31
- 录用日期: 2022-09-18
- 出版日期: 2023-04-20

Application of immune checkpoint inhibitors in liver transplantation for patients with hepatocellular carcinoma

Youcheng XIE^{1, 2},
Shun CHEN¹,
Chuyi LI¹,
Ying ZHENG¹,
Dong JIA^{1, 2},
Jiucong ZHANG¹,
Xiaohui YU^{1
, ,
,}

1.
Department of Gastroenterology, The 940 Hospital of Joint Service Support Force of the Chinese People's Liberation Army, Lanzhou 730050, China
2.
The First Clinical Medical School, Gansu University of Chinese Medicine, Lanzhou 730000, China

Research funding:

Gansu Provincial Key R&D Program (20YF8FA099);

Gansu Provincial Youth Science and Technology Fund (20JR10RA016);

Gansu Provincial Clinical Medical Research Centre for Non-infectious Liver Diseases (21JR7RA017);

Scientific Research Plan of Gansu Provincial Health Commission (GSWSKY2021-047)

More Information

Corresponding author: YU Xiaohui, yuxiaohui@126.com (ORCID: 0000-0002-8633-3281)

摘要

摘要: 肝移植作为肝细胞癌的根治性治疗策略之一，对米兰标准之内的患者有较好的临床效果。然而，术后高的复发率、转移率使得患者长期生存仍然面临挑战。因此，如何提高远期生存率，降低术后肿瘤转移成为亟待解决的关键难题。近年来，免疫检查点抑制剂(ICI)以其良好的安全性和客观反应性为晚期肝癌患者治疗提供了新的机遇，也成为了提高肝移植治疗效果的潜在方法。当前，早期临床研究已经报道了ICI单一及联合治疗在肝细胞癌肝移植术前降期或桥接治疗以及术后辅助治疗中的独特优势。本文旨在通过对近年来ICI在肝细胞癌肝移植中的临床试验及应用进展进行综述，并对其安全性和有效性进行探讨，以期为临床用药提供一定参考。
- 癌, 肝细胞 /
- 肝移植 /
- 免疫抑制剂
Abstract: Liver transplantation, as one of the radical treatment strategies for hepatocellular carcinoma, has a good clinical effect in patients meeting the Milan criteria; however, the high recurrence rate and metastasis rate after surgery bring great challenges to the long-term survival of such patients. Therefore, how to improve long-term survival rate and reduce postoperative tumor metastasis has become a key problem that needs to be solved urgently. In recent years, immune checkpoint inhibitors (ICIs), with their good safety and objective reactivity, have provided a new opportunity for the treatment of patients with advanced liver cancer and have become potential candidates for improving the therapeutic effect of liver transplantation. At present, early clinical studies have reported the unique advantages of ICIs used alone or in combination in downstaging or bridging therapy before liver transplantation for hepatocellular carcinoma and adjuvant therapy after liver transplantation. Therefore, this article reviews the clinical trials of ICIs in liver transplantation for hepatocellular carcinoma and the advances in the application of ICIs in recent years and discuss its safety and efficacy, in order to provide a certain reference for clinical medication.
- Carcinoma, Hepatocellular /
- Liver Transplantation /
- Immunosuppressive Agents

HTML全文

图 1 ICI在HCC患者LT术前的治疗作用

Figure 1. The role of immune checkpoint inhibitors in the preoperative treatment of liver transplant patients with hepatocellular carcinoma

下载: 全尺寸图片幻灯片

表 1 HCC一线、二线靶向药物及ICI药物

Table 1. First-and second-line targeted drugs and immune checkpoint inhibitor drugs for HCC

药物名称	分类	靶点	剂量	策略
索拉非尼	TKI	BRAF、c-Kit、FLT-3、VEGFR-2等多靶点	400 mg，口服，2次/d	一线
仑伐替尼	TKI	EGFR1-3、FGFR1-4、PDGFR-α等多靶点	8 mg/d或12 mg/d(根据体质量)，口服，1次/d	一线
多纳非尼(国产)	TKI	VEGF、PDGF、RAF、MEK、ERK等多靶点	200 mg，口服，2次/d	一线
阿替利珠单抗+贝伐珠单抗	ICI+IgG1	PD-L1、VEGFR	阿替利珠单抗：1 200 mg，静脉滴注，每3周使用1次；贝伐珠单抗：15 mg/kg，静脉滴注，每3周使用1次	一线
信迪利单抗(国产)+贝伐珠单抗类似物	ICI+IgG1	PD-1、VEGFR	信迪利单抗：200 mg，静脉注射，每3周使用1次；贝伐珠单抗类似物：15 mg/kg，静脉注射，每3周使用1次	一线
阿帕替尼(国产)+卡瑞利珠单抗(国产)	TKI+ICI	VEGFR-2、PD-1	阿帕替尼：250 mg，口服，1次/d；卡瑞利珠单抗：200 mg(体质量≥50 kg)或3 mg/kg(体质量＜50 kg)，静脉注射，每2周使用1次	一线
仑伐替尼+帕博利珠单抗	TKI+ICI	VEGFR、PD-1	仑伐替尼：8~12mg(根据体质量)，口服，1次/d；帕博利珠单抗：200 mg，静脉滴注，每3周使用1次	一线
瑞戈非尼	TKI	EGFR、TIE2、PDGFR、FGFR等多靶点	瑞戈非尼：160 mg，口服，1次/d，21 d后停7 d，改为每4周1次	二线
阿帕替尼(国产)	TKI	VEGFR-2	单药：750 mg，口服，1次/d；联合卡瑞利珠单抗：250 mg，口服，1次/d	二线
卡瑞利珠单抗(国产)	ICI	PD-1	3 mg/kg，静脉滴注，每2周1次或每3周1次	二线
替雷利珠单抗(国产)	ICI	PD-1	200 mg，静脉注射，每3周1次	二线
帕博利珠单抗	ICI	PD-1	200 mg，静脉滴注，每3周1次	二线
纳武利尤单抗+伊匹木单抗	ICI	PD-1、CTLA-4	纳武利尤单抗：1 mg/kg，静脉滴注，每3周1次；伊匹木单抗：3mg/kg，静脉滴注，每3周1次； 4次后，纳武利尤单抗240 mg，静脉滴注，每2周1次	二线
卡博替尼	TKI	MET、VEGFR、AXL	60 mg，口服，1次/d	二线
雷莫西尤单抗	IgG1	VEGFR-2	8 mg/kg，静脉滴注，每2周1次	二线

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表 2 正在进行的或已完成的HCC患者LT应用ICI的临床试验

Table 2. Ongoing or completed clinical trials of liver transplant with ICIs for HCC

药物名称	靶点	登记号	研究阶段	入组人数(例)	给药方案	起始时间
卡瑞利珠单抗+阿帕替尼^[33]	PD-1	NCT 04035876	Ⅰ/Ⅱ期	120	卡瑞利珠单抗: 200 mg，静脉注射，每2周1次; 阿帕替尼: 250 mg，口服，1次/d	2017-12-26
帕博利珠单抗+仑伐替尼^[34]	PD-1	NCT 04425226	-	192	帕博利珠单抗: 200 mg，每3周1次，静脉注射，直到LT前＞42 d或出现严重不良反应; 仑伐替尼: 8~12 mg(根据体质量)，1次/d，每42 d口服＞38 d，直到LT前＞7 d	2020-06-11
阿替利珠单抗+贝伐珠单抗^[35]	PD-L1	NCT 05185505	Ⅳ期	24	阿替利珠单抗: 1 200 mg，每3周1次，最多8次; 贝伐珠单抗: 15 mg/kg，每3周1次，最多8次	2022-01-11
度伐利尤单抗+曲美木单抗^[36]	PD-L1 CTLA-4	NCT 05027425	Ⅱ期	30	度伐利尤单抗: 1 500 mg，静脉注射，每4周1次曲美木单抗: 300 mg，静脉注射，仅在第1个周期的第1天服用1次	2021-08-30
度伐利尤单抗+仑伐替尼^[37]	PD-L1	NCT 04443322	-	20	度伐利尤单抗: 1 500 mg，静脉注射，每4周1次，直到LT前＞42 d或发生严重不良反应; 仑伐替尼: 8~12 mg(根据体质量)，口服，1次/d，每42 d中口服＞38 d，直到LT前＞7 d	2020-06-23
卡瑞利珠单抗^[38]	PD-1	NCT 04564313	Ⅰ期	20	200 mg，静脉注射，每2周1次	2020-09-25
调强放射治疗+(帕博利珠单抗/信迪利单抗/卡瑞利珠单抗/替雷利珠单抗)+仑伐替尼^[39]	PD-1	NCT 05339581	-	78	帕博利珠单抗/信迪利单抗/卡瑞利珠单抗/替雷利珠单抗: 200 mg，每3周1次，直到LT前＞42 d或发生严重不良反应; 仑伐替尼: 8 mg，口服，1次/d，直到LT前＞7 d 调强放射治疗: 在治疗第43天开始，2 Gy/次，5次/周，50 Gy≤总剂量≤60 Gy	2022-05-21
帕博利珠单抗+信迪利单抗+度伐利尤单抗+卡瑞利珠单抗+仑伐替尼^[40]	PD-1 PD-L1	NCT 05322187	Ⅱ/Ⅲ期	15	-	2022-04-11

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