Abstract
Biliary tract cancer, and intrahepatic cholangiocarcinoma (iCC) in particular, represents a rather uncommon, highly aggressive malignancy with unfavorable prognosis. Therapeutic options remain scarce, with platinum-based chemotherapy is being considered as the gold standard for the management of advanced disease. Comprehensive molecular profiling of tumor tissue biopsies, utilizing multi-omics approaches, enabled the identification of iCC’s intratumor heterogeneity and paved the way for the introduction of novel targeted therapies under the scope of precision medicine. Yet, the unmet need for optimal care of patients with chemo-refractory disease or without targetable mutations still exists. Immunotherapy has provided a paradigm shift in cancer care over the past decade. Currently, immunotherapeutic strategies for the management of iCC are under intense research. Intrinsic factors of the tumor, including programmed death-ligand 1 (PD-L1) expression and mismatch repair (MMR) status, are simply the tip of the proverbial iceberg with regard to resistance to immunotherapy. Acknowledging the significance of the tumor microenvironment (TME) in both cancer growth and drug response, we broadly discuss about its diverse immune components. We further review the emerging role of immunotherapy in this rare disease, summarizing the results of completed and ongoing phase I–III clinical trials, expounding current challenges and future directions.
Highlights
Primary hepatic malignancies, which represent the fourth cause of cancer-related death worldwide, can be mainly classified as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma [1,2]
The incidence of intrahepatic cholangiocarcinoma (iCC) has been consistently rising in high-income countries, from 0.1 to 0.6 cases per 100,000 over the last three decades [2,5,6], whereas the mortality rates follow the incidence pattern [7,8]. iCC is defined as a desmoplastic stromarich adenocarcinoma of cholangiocyte origin, arising proximal to the secondary biliary ducts [9,10]
Manipulations of the immune checkpoints programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) are among the immune escape mechanisms of cancer cells and the PD-1/programmed death-ligand 1 (PD-L1) pathway seems to play a pivotal role in the development of a tumor-tolerant tumor microenvironment (TME) in biliary tract cancer (BTC) [137,138]
Summary
Primary hepatic malignancies, which represent the fourth cause of cancer-related death worldwide, can be mainly classified as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCC) [1,2]. Since 2010, the combination of gemcitabine and cisplatin represents the standard of care for patients with locally advanced or metastatic disease, based on the results of the landmark phase III ABC-02 study and the phase II BT22 trial [22,23]. The compelling results of the phase III ClarIDHy trial, regarding the use of ivosidenib in IDH-mutated cholangiocarcinoma, have been recently presented at the 2021 Gastrointestinal Cancers Symposium [36]. Despite these emerging advances towards an individualized treatment plan for iCC, there still exists a paucity of efficacious therapeutic options for this highly challenging and biological heterogeneous malignancy. We summarize and critically discuss current evidence, challenges, and future perspectives with regards to the emerging role of immunotherapy in iCC
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