胆道恶性肿瘤的免疫治疗现状及研究进展

李鑫; 敖建阳; 王敬晗; 姜小清

doi:10.12449/JCH251202

胆道恶性肿瘤的免疫治疗现状及研究进展

DOI: 10.12449/JCH251202

李鑫¹,
敖建阳²,
王敬晗²,
姜小清^1, , ,

1.
海军军医大学第三附属医院（东方肝胆外科医院）胆道一科，上海 200438
2.
同济大学附属东方医院肝胆胰外科，同济大学医学院肝胆胰外科研究所，上海 200120

基金项目:

上海市浦东新区卫健委重点学科建设项目 (PWZxk2022-02);

上海市浦东新区卫健委卫生计生科技青年科技项目 (PW2022B-07);

国家自然科学基金面上项目 (82472875)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：李鑫负责设计课题，收集数据，撰写论文；敖建阳、王敬晗负责分析资料，修改论文；姜小清负责拟定写作思路，指导撰写文章并最终定稿。

详细信息

通信作者:
姜小清， jxq1225@vip.sina.cn （ORCID： 0000-0003-2102-4039）

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出版历程
- 收稿日期: 2025-10-27
- 录用日期: 2025-11-17
- 出版日期: 2025-12-25

Immunotherapy for biliary tract cancer： Current status and research advances

1.
First Department of Biliary Tract Surgery，The Third Hospital of Navy Medical University （Eastern Hepatobiliary Surgery Hospital），Shanghai 200438，China
2.
Institute of Hepatobiliary and Pancreatic Surgery，Department of Hepatobiliary and Pancreatic Surgery，Shanghai East Hospital，Tongji University School of Medicine，Shanghai 200120，China

Research funding:

Key Discipline Construction Project of Shanghai Pudong New Area Health Commission (PWZxk2022-02);

The Youth Science and Technology Project of Shanghai Pudong New Area Health Commission (PW2022B-07);

General Project of National Natural Science Foundation of China (82472875)

More Information

Corresponding author: JIANG Xiaoqing， jxq1225@vip.sina.cn （ORCID： 0000-0003-2102-4039）

摘要

摘要: 胆道恶性肿瘤（BTC）是一种高度恶性、预后较差的消化道肿瘤，其有限的治疗手段和复杂的肿瘤微环境构成了临床治疗的主要挑战。本文系统梳理BTC免疫微环境的基本特征，进一步综述了免疫检查点抑制剂在BTC治疗中的作用，同时探讨癌症疫苗和过继性细胞免疫疗法等前沿策略。尽管BTC的高度异质性与免疫抑制微环境仍是制约疗效提升的主要障碍，未来基于多组学的生物标志物体系构建、新型联合策略的探索以及对免疫微环境的深度调控有望改善BTC患者的预后。
- 胆道肿瘤 /
- 免疫疗法 /
- 治疗学
Abstract: Biliary tract cancer （BTC） is a highly malignant gastrointestinal tumor with a poor prognosis， and its limited treatment options and complex tumor microenvironment have posed significant challenges in clinical treatment. This article systematically describes the fundamental features of the immunosupressive microenvironment in BTC and reviews the role of immune checkpoint inhibitors in the treatment of BTC， as well as the emerging strategies such as cancer vaccines and adoptive cell transfer therapy. Although the improvement in treatment outcome is limited by high tumor heterogeneity and the immunosuppressive microenvironment， it is expected to improve the prognosis of BTC patients by constructing a biomarker system based on multi-omics， exploring novel combined treatment strategies， and deeply regulating the tumor microenvironment.
- Biliary Tract Neoplasms /
- Immunotherapy /
- Therapeutics

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表 1 BTC免疫治疗响应相关生物标志物及相关研究

Table 1. Biomarkers and related research related to the response of immunotherapy for BTC

生物标志物	关键研究	研究方案	研究结果	参考文献
dMMR和MSI	多中心回顾性队列研究（n=48）	37例MSI/dMMR BTC患者接受 ICI治疗	中位OS为40.9个月，3年总生存率为53.8%，总体ORR为36%，完全缓解率为17%，中位PFS为 11.24个月	［16］
	KEYNOTE-158研究（Phase Ⅱ，n=22）	22例MSI/dMMR BTC患者接受帕博利珠单抗治疗	中位OS为24.3个月，ORR为40.9%	［17］
	5项单臂研究汇总分析	多项研究中MSI/dMMR BTC患者接受帕博利珠单抗治疗	ORR为27%，反应持续时间为11.6～19.6个月	［18］
TMB	Lin等对中国BTC患者的基因组研究（n=803）	803例中46例BTC患者接受TMB 匹配的靶向治疗	整体队列的中位TMB为1.23个Mut/Mb，4.1%患者的TMB≥9.36 Mut/Mb，被定义为高TMB；46例靶向治疗队列的ORR为26.1%，PFS为5个月， 56.8%患者PFS获益	［19］
TMB	整合临床和分子分析（n=26）	26例晚期微卫星稳定型的BTC 患者中17例进行高通量测序	TMB水平高低与PFS无关，高TMB与高ORR 相关	［20］
PD-L1表达	TOPAZ-1临床试验（Phase Ⅲ，n=685）	341例患者接受度伐利尤单抗联合GC方案，344例患者接受安慰剂联合GC方案	PD-L1的TAP高低与患者的生存获益无关（TAP ≥1%：HR=0.79 vs TAP<1%：HR=0.86）	［5］
	KEYNOTE-966临床试验（Phase Ⅲ， n=1 069）	533例患者接受帕博利珠单抗联合GC方案，536例患者接受安慰剂联合GC方案	无论患者肿瘤的PD-L1的CPS高低，添加帕博利珠单抗都能带来生存获益（CPS<1：HR=0.79 vs CPS>1：HR=0.85）	［6］
	KEYNOTE-028研究（Phase Ⅰb，n=475）	475例晚期PD-L1阳性的实体瘤患者	BTC患者中PD-L1表达越高，ORR和PFS表现越好	［21］
注：dMMR，错配修复缺陷；MSI，微卫星不稳定；BTC，胆道恶性肿瘤；ICI，免疫检查点抑制剂；OS，总生存期；ORR，客观缓解率；PFS，无进展生存期；TMB，肿瘤突变负荷；GC方案，吉西他滨和顺铂方案；PD-L1，程序性死亡配体1；TAP，肿瘤区域阳性比例；CPS，综合阳性评分。

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表 2 BTC免疫治疗策略

Table 2. Immunotherapy strategies for BTC

治疗方案	关键研究	研究方案	研究结果
ICI
ICI单药治疗	KEYNOTE-158试验（Phase Ⅱ，n=104）^［25］	PD-1抑制剂帕博利珠单抗治疗晚期 BTC患者	61例PD-L1阳性患者的中位OS为7.2个月，中位PFS为1.9个月；43例PD-L1阴性患者的中位OS为9.3个月，中位PFS为2.1个月
	KEYNOTE-028试验（Phase Ⅰb，n=24）^［25］		中位OS为5.7个月，中位PFS为1.8个月
	Ⅱ期临床试验（n=54）^［26］	PD-L1抑制剂度伐利尤单抗治疗晚期 BTC患者	中位OS为14.24个月，中位PFS为3.68个月，疾病控制率为59%
ICI联合化疗（GC方案）	TOPAZ-1临床试验（Phase Ⅲ，n=685）^［5］	341例患者接受度伐利尤单抗联合GC 方案，344例患者接受安慰剂联合GC 方案	联合方案相比单纯化疗，显著延长中位OS （12.8个月vs 11.5个月）和中位PFS（7.2个月 vs 5.7个月）
	KEYNOTE-966 临床试验（Phase Ⅲ，n=1 069）^［6］	533例患者接受帕博利珠单抗联合GC 方案，536例患者接受安慰剂联合GC 方案	联合方案相比单纯化疗，显著延长中位OS （12.7个月vs 10.9个月）和中位PFS（6.5个月 vs 5.6个月）
	Ⅱ期临床试验（n=32）^［27］	PD-1抑制剂纳武利尤单抗治疗晚期 BTC患者	15例患者达到客观缓解，包括5例完全缓解，疾病控制率为92.6%，中位OS为8.5个月，中位PFS为6.1个月
	Ⅱ期临床试验（n=30）^［28］	PD-1抑制剂信迪利单抗治疗晚期BTC 患者	中位OS为15.9个月，中位PFS为5.1个月， ORR为36.7%
ICI联合靶向治疗	Ⅱ期临床试验（n=32）^［29］	PD-1抑制剂帕博利珠单抗联合激酶抑制剂仑伐替尼治疗BTC患者	中位OS为11个月，中位PFS为4.9个月，ORR 为25%，疾病控制率为78.1%
	REGOMUNE试验（n=34）^［30］	PD-L1抑制剂阿维鲁单抗联合多激酶抑制剂瑞戈非尼治疗晚期BTC患者	4例患者部分缓解，11例患者疾病稳定，疾病控制率为51.7%，中位OS为11.9个月
	多中心Ⅱ期临床试验^［31］	PD-L1抑制剂阿替利珠单抗联合MEK 靶向抑制剂考比替尼治疗晚期BTC 患者	延长PFS（3.65个月vs 1.87个月），肿瘤进展或死亡的风险降低42%
ICI联合其他治疗
双免疫检查点抑制疗法	临床试验（n=39）^［32］	PD-1抑制剂纳武利尤单抗联合CTLA-4 抑制剂伊匹木单抗治疗晚期BTC患者	ORR为23%，疾病控制率为44%
ICI联合放疗	临床试验（n=20）^［33］	CTLA-4抑制剂替西木单抗联合微波消融治疗BTC患者	2例患者在未消融病灶观察到持久应答
多免疫联合化疗	ZSAB-TOP研究（n=45）^［34］	PD-1抑制剂替雷利珠单抗和TIGIT抑制剂欧司珀利单抗联合GC方案治疗晚期 BTC患者	ORR为51.2%，疾病控制率为82.9%
癌症疫苗	Ⅰ期临床试验^［35］	多肽疫苗（CDCA1、CDH3、KIF20A）治疗晚期BTC患者	PFS为3.4个月，中位OS为9.7个月
癌症疫苗	一项术后联合免疫疗法^［36］	树突状细胞疫苗联合激活T细胞回输（ATVAC）治疗术后BTC患者	联合方案的中位PFS为18.3个月（vs 7.7个月），中位OS为31.9个月（vs 17.4个月）
过继性免疫细胞疗法	Ⅰ期临床试验（n=19）^［37］	CART-EGFR细胞治疗EGFR阳性晚期 BTC患者	10例患者病情稳定，1例患者完全缓解，中位 PFS为4个月
过继性免疫细胞疗法	Ⅰ期临床试验（n=11）^［38］	CART-HER2细胞治疗HER2阳性晚期 BTC患者	4例患者得到有效控制，中位PFS为4.8个月
注：ICI，免疫检查点抑制剂；PD-1，程序性死亡受体1；PD-L1，程序性死亡配体1；BTC，胆道恶性肿瘤；OS，总生存期；PFS，无进展生存期；GC方案，吉西他滨和顺铂方案；ORR，客观缓解率；MEK，丝裂原活化蛋白激酶激酶。

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