Lo Justin H, Agarwal Rajiv, Goff Laura W, Heumann Thatcher R
Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Cancers (Basel). 2023 Jun 23;15(13):3312. doi: 10.3390/cancers15133312.
Biliary tract cancers (BTCs), comprising intrahepatic, perihilar, and distal cholangiocarcinoma as well as gallbladder adenocarcinoma, continue to be challenging to manage. Conventional chemotherapy regimens for advanced disease are limited in both options and benefits, and more effective perioperative regimens are also needed. Over the last decade, immunotherapy has had a profound impact on the management of many solid tumor types, particularly in using immune checkpoint inhibition to enable a tumor-directed T cell response. Immunotherapy administered on its own has had limited utility in BTCs, in part due to a hostile immune microenvironment and the relative infrequency of biomarker-based tumor-agnostic indications for immunotherapy. However, immunotherapy in conjunction with chemotherapy, molecularly targeted therapies, and/or anti-angiogenic therapies has gained traction, supported by evidence that these agents can impart favorable immunomodulatory effects on the tumor microenvironment. The TOPAZ-1 trial led to the first BTC-specific immunotherapy approval, establishing the combination of durvalumab with gemcitabine and cisplatin as the preferred first-line treatment for advanced or metastatic disease. Recently, the KEYNOTE-966 trial showed positive results for the combination of pembrolizumab with gemcitabine and cisplatin in the same setting, adding further evidence for the addition of immune checkpoint inhibition to the standard chemotherapy backbone. Meanwhile, advances in the molecular profiling of BTCs has contributed to the recent proliferation of molecularly targeted therapeutics for the subset of BTCs harboring alterations in , , MAP kinase signaling, , and beyond, and there has been great interest in investigating combinations of these agents with immunotherapy. Emerging immunotherapy strategies beyond immune checkpoint inhibition are also being studied in BTCs, and these include immunostimulatory receptor agonists, Wnt signaling modulators, adoptive cell therapy, and cancer vaccines. A large number of trials are underway to explore promising new combinations and immune-targeted strategies, offering opportunities to expand the role of immunotherapy in BTC management in the near future.
胆道癌（BTCs）包括肝内胆管癌、肝门周围胆管癌、远端胆管癌以及胆囊腺癌，其治疗仍然具有挑战性。针对晚期疾病的传统化疗方案在选择和疗效方面都很有限，因此也需要更有效的围手术期治疗方案。在过去十年中，免疫疗法对许多实体瘤类型的治疗产生了深远影响，尤其是通过免疫检查点抑制来激发肿瘤定向T细胞反应。单独使用免疫疗法在BTCs中的效用有限，部分原因是免疫微环境不利以及基于生物标志物的肿瘤非特异性免疫疗法适应症相对较少。然而，免疫疗法与化疗、分子靶向疗法和/或抗血管生成疗法联合使用已获得关注，有证据表明这些药物可对肿瘤微环境产生有利的免疫调节作用。TOPAZ-1试验促成了首个BTC特异性免疫疗法的获批，确立了度伐利尤单抗与吉西他滨和顺铂联合用药作为晚期或转移性疾病的首选一线治疗方案。最近，KEYNOTE-966试验表明帕博利珠单抗与吉西他滨和顺铂联合用药在相同情况下取得了阳性结果，为在标准化疗基础上加用免疫检查点抑制提供了更多证据。与此同时，BTCs分子谱分析的进展推动了针对具有 、 、MAP激酶信号传导等改变及其他改变的BTCs亚群的分子靶向治疗药物的近期激增，人们对研究这些药物与免疫疗法的联合用药也兴趣浓厚。BTCs中也在研究免疫检查点抑制之外的新兴免疫疗法策略，这些策略包括免疫刺激受体激动剂、Wnt信号调节剂、过继性细胞疗法和癌症疫苗。大量试验正在进行，以探索有前景的新联合用药和免疫靶向策略，为在不久的将来扩大免疫疗法在BTC治疗中的作用提供了机会。
