胆道恶性肿瘤的免疫治疗现状及研究进展

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

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 / 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.

Key words: Biliary Tract Neoplasms / Immunotherapy / Therapeutics 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 ］ 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 ］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 ］ 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 Ⅰ期临床试验
（ n =11） ^{［

38

］} CART-HER2细胞治疗HER2阳性晚期
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