Abstract:Biliary tract cancers are rare tumors with a poor prognosis. Two-thirds of these primary liver malignancies are diagnosed at advanced stages where therapeutic options are limited. Whereas several molecular targeted therapies emerge in biliary tract cancers, immunotherapy is still investigational, the only approved immunotherapy to date being the immune checkpoint inhibitor pembrolizumab for the small fraction of patients with microsatellite-instable tumors. In microsatellite-stable, pre-treated biliary tract c… Show more
“…While its role in BTCs is not yet clearly established [ 6 ], it has been explored in some phase 2 and 3 trials [ 7 ]. There are several ongoing trails employing immunotherapy with PD-1 and PD-L1 inhibitors or CTLA4 agents, alone or with cytotoxic therapy, or other targeted molecular therapies [ 8 ]. Response rates around 40% have been found in patients with MSI tumors [ 9 ].…”
Biliary tract cancers (BTCs) have limited response to systemic therapy and poor prognosis. Immunotherapy in BTCs has been investigated in recent years. Here, we report a case of locally advanced, unresectable gallbladder adenocarcinoma that progressed on chemotherapy. The patient was then treated with ipilimumab and nivolumab, which resulted in tumor shrinkage and autoimmune hepatitis, but established technical resectability. He underwent complete resection through extended right hepatectomy with en bloc cholecystectomy bile duct resection, hepatic and portal lymphadenectomy and Roux-Y hepaticojejunostomy reconstruction. The final pathology revealed a pathologic complete response. The scope of operative intervention after immunotherapy is still evolving for BTCs. Establishing resectability in tumors not susceptible to cytotoxic agents but responding to immunotherapy not only facilitates curative intent resection but also enhances the importance of infection prevention through operative stent-free long-term biliary decompression. Immunotherapy may also carry a unique risk profile for post-operative morbidity potential as in this case with autoimmune hepatitis.
“…While its role in BTCs is not yet clearly established [ 6 ], it has been explored in some phase 2 and 3 trials [ 7 ]. There are several ongoing trails employing immunotherapy with PD-1 and PD-L1 inhibitors or CTLA4 agents, alone or with cytotoxic therapy, or other targeted molecular therapies [ 8 ]. Response rates around 40% have been found in patients with MSI tumors [ 9 ].…”
Biliary tract cancers (BTCs) have limited response to systemic therapy and poor prognosis. Immunotherapy in BTCs has been investigated in recent years. Here, we report a case of locally advanced, unresectable gallbladder adenocarcinoma that progressed on chemotherapy. The patient was then treated with ipilimumab and nivolumab, which resulted in tumor shrinkage and autoimmune hepatitis, but established technical resectability. He underwent complete resection through extended right hepatectomy with en bloc cholecystectomy bile duct resection, hepatic and portal lymphadenectomy and Roux-Y hepaticojejunostomy reconstruction. The final pathology revealed a pathologic complete response. The scope of operative intervention after immunotherapy is still evolving for BTCs. Establishing resectability in tumors not susceptible to cytotoxic agents but responding to immunotherapy not only facilitates curative intent resection but also enhances the importance of infection prevention through operative stent-free long-term biliary decompression. Immunotherapy may also carry a unique risk profile for post-operative morbidity potential as in this case with autoimmune hepatitis.
“…Due to the limited efficacy of chemotherapy treatments in patients with BTC, major efforts have been necessary to better understand the complex molecular landscape of cholangiocarcinoma (CCA) to identify novel therapeutic targets [ 15 ]. Of note, alongside gastrointestinal stromal tumor, melanoma and non-small cell lung cancer, CCA is considered one of the cancers with the highest prevalence of oncogenic driver [ 2 , 16 ]. Robust evidence, derived from large genomic profile analysis suggest that around half of CCA displays a clinically actionable oncogenic alteration [ 15 , 17 , 18 ] ( Figure 1 ).…”
Section: The Heterogenous Molecular Landscape Of Biliary Tract Cancermentioning
confidence: 99%
“…Biliary tract cancers (BTC) represent a heterogeneous and aggressive group of tumors that originate from the epithelium of intrahepatic (IHCC), extrahepatic (EHCC), distal biliary tree, or from the gallbladder (GBC) [ 1 ]. The incidence of BTC differs from the various geographic area, being considered rare in Europe and USA, with an incidence of 1–3 cases per 100,000 people, and a major health problem in other countries, including China, Japan, Korea and Thailand with 5.7 to 85 cases per 100,000 people [ 1 , 2 , 3 , 4 ].…”
Section: Introductionmentioning
confidence: 99%
“…At the same time, immunotherapy has dramatically changed the therapeutic armamentarium of several malignancies, transforming, in some cases, a disease with a metastatic and poor prognosis into a curable one [ 12 , 13 ]. However, while different gastrointestinal malignancies, including hepatocellular carcinoma (HCC), benefit from immune checkpoint inhibitors (ICIs), the efficacy of immunotherapy in BTC remains limited [ 1 , 2 , 14 ].…”
Biliary tract cancers (BTC) represent a heterogeneous and aggressive group of tumors with dismal prognosis. For a long time, BTC has been considered an orphan disease with very limited therapeutic options. In recent years a better understanding of the complex molecular landscape of biology is rapidly changing the therapeutic armamentarium. However, while 40–50% of patients there are molecular drivers susceptible to target therapy, for the remaining population new therapeutic options represent an unsatisfied clinical need. The role of immunotherapy in the continuum of treatment of patients with BTC is still debated. Despite initial signs of antitumor-activity, single-agent immune checkpoint inhibitors (ICIs) demonstrated limited efficacy in an unselected population. Therefore, identifying the best partner to combine ICIs and predictive biomarkers represents a key challenge to optimize the efficacy of immunotherapy. This review provides a critical analysis of completed trials, with an eye on future perspectives and possible biomarkers of response.
“…The prognosis of CAA is grim because it is usually detected at a locally advanced, inoperable stage and barely responds to standard chemotherapy, radiotherapy, and immunotherapy. 1 , 2 In strict contrast to PSC, another type of cholangitis referred to as primary biliary cholangitis (PBC), which has a strong autoimmune component, does not predispose to CAA ( Figure 1A ). Figure 1.…”
It has been an open conundrum why primary sclerosing cholangitis (PSC) is a major risk factor for developing cholangiocarcinoma (CAA), while primary biliary cholangitis (PBC) is not. In mouse models of PSC and PBC, it turned out that the latter condition, an autoimmune disease affecting the bile ducts, reduces transgene-induced cholangiocarcinogenesis, as well as the progression of subcutaneously implanted CCA. This CCA-delaying effect is lost upon depletion of T lymphocytes and involves tumor infiltration by T cell clonotypes that are also found in PBC lesions. Hence, organ-specific autoimmunity may improve immunosurveillance.
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