Department of Oncology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai 200438, China.
Department of Oncology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai 200438, China.
Hepatobiliary Pancreat Dis Int. 2022 Oct;21(5):440-449. doi: 10.1016/j.hbpd.2022.08.015. Epub 2022 Sep 7.
Biliary tract cancers (BTCs) comprise a heterogeneous group of aggressive malignancies with unfavorable prognoses. The benefit of chemotherapy seems to have reached a bottleneck and, therefore, new effective therapeutic strategies for advanced BTCs are needed. Molecularly targeted therapies in selected patients are rapidly changing the situation. However, the low frequency of specific driver alterations in BTCs limits their wide application. Recently, immunotherapeutic approaches are also under active investigation in BTCs, but the role of immunotherapy in BTCs remains controversial.
PubMed, Web of Science, and meeting resources were searched for relevant articles published from January 2017 to May 2022. The search aimed to identify current and emerging immunotherapeutic approaches for BTCs. Information on clinical trials was obtained from https://clinicaltrials.gov/ and http://www.chictr.org.cn/.
Immunotherapy in BTC patients is currently under investigation, and most of the investigations focused on the application of immune checkpoint inhibitors (ICIs). However, only a subgroup of BTCs with microsatellite-instability high (MSI-H)/DNA mismatch repair-deficient (dMMR) or tumor mutational burden-high (TMB-H) benefit from monotherapy of ICIs, and limited activity was observed in the second or subsequent settings. Nevertheless, promising results come from studies of ICIs in combination with other therapeutic approaches, including chemotherapy, in advanced BTCs, with a moderate toxicity profile. Recent studies demonstrated that compared to GEMCIS alone, durvalumab plus GEMCIS significantly improved patient survival (TOPAZ-1 trial) and that ICIs-combined chemoimmunotherapy is poised to become a new frontline therapy option, regardless of TMB and MMR/MSI status. Adoptive cell therapy and peptide- or dendritic-based cancer vaccines are other immunotherapeutic options that are being studied in BTCs. Numerous biomarkers have been investigated to define their predictive role in response to ICIs, but no predictive biomarker has been validated, except MSI-H/dMMR.
The role of immunotherapy in BTCs is currently under investigation and the results of ongoing studies are eagerly anticipated. Several studies have demonstrated the safety and efficacy of ICIs in combination with chemotherapy in treatment-naive patients, such as the phase III TOPAZ-1 trial, which will change the standard care of first-line chemotherapy for advanced BTCs. However, further research is needed to understand the best combination with immunotherapy and to discover more predictive biomarkers to guide clinical practice.
胆道癌（BTC）是一组具有不良预后的侵袭性恶性肿瘤。化疗的益处似乎已经达到了瓶颈，因此需要为晚期 BTC 提供新的有效治疗策略。在选定的患者中进行的分子靶向治疗正在迅速改变这种情况。然而，BTC 中特定驱动因素改变的低频限制了其广泛应用。最近，BTC 中的免疫治疗方法也在积极研究中，但免疫治疗在 BTC 中的作用仍存在争议。
从 2017 年 1 月至 2022 年 5 月，检索了 PubMed、Web of Science 和会议资源中发表的相关文章。该检索旨在确定当前和新兴的 BTC 免疫治疗方法。从 https://clinicaltrials.gov/ 和 http://www.chictr.org.cn/ 获取临床试验信息。
BTC 患者的免疫治疗正在进行研究，大多数研究都集中在免疫检查点抑制剂（ICIs）的应用上。然而，只有微卫星不稳定高（MSI-H）/DNA 错配修复缺陷（dMMR）或肿瘤突变负担高（TMB-H）的 BTC 亚组从单药 ICI 治疗中获益，并且在二线或后续治疗中观察到有限的活性。尽管如此，来自晚期 BTC 中 ICI 与其他治疗方法（包括化疗）联合治疗的研究结果令人鼓舞，且具有适度的毒性特征。最近的研究表明，与 GEMCIS 单药治疗相比，度伐利尤单抗联合 GEMCIS 显著改善了患者的生存（TOPAZ-1 试验），ICI 联合化疗免疫治疗有望成为一种新的一线治疗选择，无论 TMB 和 MMR/MSI 状态如何。过继细胞疗法和基于肽或树突状细胞的癌症疫苗是正在 BTC 中研究的其他免疫治疗选择。已经研究了许多生物标志物来定义它们对 ICI 反应的预测作用，但除了 MSI-H/dMMR 外，没有验证过预测性生物标志物。
免疫治疗在 BTC 中的作用正在研究中，目前正在急切期待正在进行的研究结果。几项研究已经证明了 ICI 联合化疗在初治患者中的安全性和有效性，例如 III 期 TOPAZ-1 试验，这将改变晚期 BTC 一线化疗的标准治疗方法。然而，需要进一步研究以了解与免疫治疗的最佳联合，并发现更多预测性生物标志物以指导临床实践。
