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Cholangiocarcinoma: the role of genetic and epigenetic factors; current and prospective treatment with checkpoint inhibitors and immunotherapy.

ABSTRACT: Cholangiocarcinoma (CCA) represents 3% of all gastrointestinal cancers worldwide and is the second most common primary liver tumor after hepatocellular carcinoma. CCA is an aggressive tumor that involves the intrahepatic, perihilar and distal biliary tree, with a poor prognosis and an increasing incidence worldwide. Various genetic and epigenetic factors have been implicated in CCA development. Gene mutations involving apoptosis control and cell cycle evolution, histone modifications, methylation dysregulation and abnormal expression of non-coding RNA are the most important of these factors. Regarding treatment, surgical resection, cisplatin and gemcitabine have long been the most common treatment options, but 5-year survival (7-20%) is disappointing. For that reason, inhibitors and small molecules related to specific mutations and molecular pathways have been introduced. Among them, immunotherapy seems to be a promising treatment in CCA, with multiple regimens being under clinical trial studies. The combinatorial therapy of traditional CCA treatment with tyrosine kinase inhibitors and/or immunotherapy seem to be the future, depending on the molecular profile of each patient's tumor.

SUBMITTER: Sarantis P

PROVIDER: S-EPMC8748131 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Cholangiocarcinoma: the role of genetic and epigenetic factors; current and prospective treatment with checkpoint inhibitors and immunotherapy.

Sarantis Panagiotis P Tzanetatou Eleftheria Dikoglou ED Ioakeimidou Evangelia E Vallilas Christos C Androutsakos Theodoros T Damaskos Christos C Garmpis Nikolaos N Garmpi Anna A Papavassiliou Athanasios G AG Karamouzis Michalis V MV

American journal of translational research 20211215 12

Cholangiocarcinoma (CCA) represents 3% of all gastrointestinal cancers worldwide and is the second most common primary liver tumor after hepatocellular carcinoma. CCA is an aggressive tumor that involves the intrahepatic, perihilar and distal biliary tree, with a poor prognosis and an increasing incidence worldwide. Various genetic and epigenetic factors have been implicated in CCA development. Gene mutations involving apoptosis control and cell cycle evolution, histone modifications, methylatio ...[more]

PMID: 35035673

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Project description:Malignant cells have the capacity to rapidly grow exponentially and spread in part by suppressing, evading, and exploiting the host immune system. Immunotherapy is a form of oncologic treatment directed towards enhancing the host immune system against cancer. In recent years, manipulation of immune checkpoints or pathways has emerged as an important and effective form of immunotherapy. Agents that target cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1) are the most widely studied and recognized. Immunotherapy, however, extends beyond immune checkpoint therapy by using new molecules such as chimeric monoclonal antibodies and antibody drug conjugates that target malignant cells and promote their destruction. Genetically modified T cells expressing chimeric antigen receptors are able to recognize specific antigens on cancer cells and subsequently activate the immune system. Native or genetically modified viruses with oncolytic activity are of great interest as, besides destroying malignant cells, they can increase anti-tumor activity in response to the release of new antigens and danger signals as a result of infection and tumor cell lysis. Vaccines are also being explored, either in the form of autologous or allogenic tumor peptide antigens, genetically modified dendritic cells that express tumor peptides, or even in the use of RNA, DNA, bacteria, or virus as vectors of specific tumor markers. Most of these agents are yet under development, but they promise to be important options to boost the host immune system to control and eliminate malignancy. In this review, we have provided detailed discussion of different forms of immunotherapy agents other than checkpoint-modifying drugs. The specific focus of this manuscript is to include first-in-human phase I and phase I/II clinical trials intended to allow the identification of those drugs that most likely will continue to develop and possibly join the immunotherapeutic arsenal in a near future.

Project description:BackgroundCholangiocarcinoma (CCA) encompasses a heterogeneous group of malignant tumors with dismal prognosis and increasing incidence worldwide. Both late diagnosis due to the lack of early symptoms and the refractory nature of these tumors seriously compromise patients' welfare and outcomes.SummaryDuring the last decade, immunotherapy and, more specifically, modulation of immune checkpoints-mediated signaling pathways have been under the spotlight in the field of oncology, emerging as a potential therapeutic approach for the treatment of several cancers, including CCA. Generally, high expression levels of immune checkpoints in patients with CCA have been associated with worse clinical outcomes, particularly with shorter overall survival and relapse-free survival. Thus, immune checkpoint inhibitors (ICIs), which mainly constitute different monoclonal antibodies, have been developed in order to hamper the immune checkpoint-mediated pathways. Interestingly, chemotherapy may increase the expression of immune checkpoints, while other therapeutic approaches such as ablative and targeted therapies may enhance their antitumor activity. In this sense, several clinical trials evaluated the safety and efficacy of ICIs for CCA, both as a monotherapy and in combination with other ICIs or loco-regional and systemic therapies. Additionally, many other clinical trials are currently ongoing and results are eagerly awaited. Here, we summarize the key aspects of immune checkpoint molecules as prognostic factors and therapeutic targets in CCA, highlighting the most recent advances in the field and future research directions.Key messages(1) Effective therapeutic approaches for CCA are urgently needed. (2) Expression levels of immune checkpoints in patients with CCA have been proposed to be related with clinical outcomes. (3) Combination of different ICIs may outperform the efficacy of ICI monotherapy for CCA treatment. (4) Recent studies point toward the combination of ICIs and other common therapies, especially chemotherapy, as a promising strategy for treatment of CCA patients.

Dataset Information

Cholangiocarcinoma: the role of genetic and epigenetic factors; current and prospective treatment with checkpoint inhibitors and immunotherapy.

Publications

Cholangiocarcinoma: the role of genetic and epigenetic factors; current and prospective treatment with checkpoint inhibitors and immunotherapy.

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