The role of immunotherapy in the management of cholangiocarcinoma (CCA) is rapidly growing; however, a greater understanding of tumor microenvironment and heterogeneity is needed to overcome current challenges, according to a recently published review in Vaccines.
The incidence and mortality of CCA have significantly increased in the last 2 decades; furthermore, its typically nonspecific clinical presentation leads to delayed diagnosis in most cases and a poor prognosis, as less than 25% of cases are surgically resectable at the moment of diagnosis.
The modest success of chemotherapy for cases not eligible for surgery has led to the developing of new therapeutic alternatives for these patients, namely, immunotherapy. Immunotherapy aims to improve the natural immune response toward tumor cells and the infiltration of immune cells in the tumor microenvironment. This improvement can be achieved through 3 mechanisms: immune checkpoint inhibitors (ICIs), cancer vaccines, and adoptive cell transfer.
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Immunotherapy has already shown promising breakthroughs in kidney, lung, and colon malignancies, but its effectiveness in CCA needs to be clarified.
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Therefore the authors conducted a search of studies regarding the use of immunotherapy in CCA in PubMed.
ICI immunotherapy for CCA with monoclonal anti-PD-1 agents such as pembrolizumab, nivolumab, and durvalumab has been tested in several phase 1 and phase 2 studies, showing promising results represented by durable antitumor activity and moderate clinical effectiveness with manageable adverse effects.
Combination therapy with anti-PD-1 agents and CTLA-4 inhibitors showed a substantial response in a multicenter phase 2 study. However, in a similar trial, the combination did not significantly improve the 6-month progression-free survival rate. Several studies studying ICI and chemotherapy combinations have shown encouraging results.
Chimeric antigen receptor (CAR) T-cell therapy targeting the mucin 1 (MUC1) receptor, frequently expressed in CCA and associated with a poor prognosis, has produced high-level cytotoxicity in malignant cells in in-vitro models. In- vivo CAR-T cell trials targeting the epidermal growth factor receptor (EGFR) and the epidermal growth factor HER-2 have yielded disappointing results. Regarding the use of cancer vaccines, animal models have suggested the efficacy of DNA vaccines targeting PD-1 and CTLA-4.
The literature search highlighted the great tumor heterogeneity in CCA and the lack of predictive biomarkers as the main obstacles affecting the development of effective treatment regimens.
“Immunotherapy, consisting of ICIs, tumor vaccines, and chimeric antigen T-cell receptor conjugates, has revolutionized the management of advanced/metastatic CCA,” the authors wrote.
”The role of immunotherapy is currently under investigation, but promising results in solid malignancies have accelerated its establishment in managing advanced CCA with improved patient outcomes.”
Reference
Manthopoulou E, Ramai D, Dhar J, et al. Cholangiocarcinoma in the era of immunotherapy. Vaccines. Published online June 5, 2023. doi:10.3390/vaccines11061062
