Immunotherapy in Advanced Biliary Tract Cancers

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 cancers, single-agent immune checkpoint blockade has a limited albeit often long-lasting clinical activity in a still ill-defined subgroup of patients. The identification of predictive biomarkers will allow a better selection of patients that may benefit from immunotherapy. Combinations of immunotherapies with each other, with chemotherapy or targeted molecular therapies are being investigated in early lines of therapy, including first-line.

Keywords: biliary tract cancers; cholangiocarcinoma; drug combination; immune checkpoint inhibitor; immunotherapy; vaccine.

Figure 1

Biological rationale for use of immune therapies in BTC. Left panel: Approximately 70% of BTC are highly infiltrated in immune cells with a strong expression of the immune checkpoints such as PD-L1 in 10–20% of cases, whereas about 30% of BTC are depleted in cytotoxic lymphocytes (T cells). Right panel: Immune BTC microenvironment and potential therapeutic implications. CTLA-4: cytotoxic T-lymphocyte antigen-4; MHC: major histocompatibility complex; PD-1: programmed cell death 1; PD-L1: programmed cell death-ligand 1; TAM: Tumor-associated macrophages.