Current Progress and Future Perspectives of Immune Checkpoint Inhibitors in Biliary Tract Cancer

Seesaha, Poshita-Kumari; Wang, Kangxin; Wang, Guo-Qun; Cui, Ting-Yun; Zhao, Fengjiao; Pan, Long; Li, Xiangcheng; Shu, Yongqian; Chen, Xiaofeng

doi:10.2147/ott.s269671

Cited by 6 publications

(6 citation statements)

References 57 publications

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“…Earlier studies have shown that ICIs are less effective in previously treated patients with BTC. 4 More recently, ICIs in combination with chemotherapy appear to have better efficacy and are well tolerated as a first-line therapy. 4 Specifically, in a phase Ⅱ single-arm study (NCT03486678), we evaluated the combination of camrelizumab, an anti-PD-1 antibody, with gemcitabine and oxaliplatin (GEMOX) as first-line treatment in advanced BTC.…”

Section: Introductionmentioning

confidence: 99%

“…4 More recently, ICIs in combination with chemotherapy appear to have better efficacy and are well tolerated as a first-line therapy. 4 Specifically, in a phase Ⅱ single-arm study (NCT03486678), we evaluated the combination of camrelizumab, an anti-PD-1 antibody, with gemcitabine and oxaliplatin (GEMOX) as first-line treatment in advanced BTC. 5 In 37 participants, we reported that the ORR and disease control rate were 54% and 89%, while the median progression-free survival and OS were 6.2 months and 12.1 months, respectively.…”

Section: Introductionmentioning

confidence: 99%

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Genomic alterations in biliary tract cancer predict prognosis and immunotherapy outcomes

Chen

Wang

Liu

et al. 2021

J Immunother Cancer

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BackgroundRecently, immunotherapy with immune checkpoint inhibitors (ICIs) has shown promising efficacy in biliary tract cancer (BTC), which includes gallbladder cancer (GBC) and cholangiocarcinoma (CHOL). Understanding the association between immunotherapy outcomes and the genomic profile of advanced BTC may further improve the clinical benefits from immunotherapy.MethodsGenomic tumor DNA was isolated from 98 Chinese patients with advanced BTC and used for targeted next-generation sequencing of 416 cancer-related genes to identify the genomic alterations common to advanced BTC. Thirty-four patients had received ICI camrelizumab plus gemcitabine and oxaliplatin (from the NCT03486678 trial) as a first-line treatment. Tumor-infiltrating immune cells were evaluated using immunofluorescence staining.ResultsKRAS and TP53 mutations were much more frequent in the advanced-stage BTC cohort than in other cohorts with mostly early stage disease. Specifically, KRAS-TP53 co-mutations were favored in advanced CHOL, with a favorable response to immunotherapy, while single KRAS mutations predicted poor prognosis and immunotherapy outcomes for CHOL. Compared with GBC, CHOL had more mutations in genes involved in KRAS signaling; a high mutation load in these genes correlated with poor immunotherapy outcomes and may subsequently cause inferior immunotherapy outcomes for CHOL relative to GBC. Furthermore, a genomic signature including 11 genes was developed; their mutated subtype was associated with poor prognosis and immunotherapy outcomes in both CHOL and GBC. Transcriptome analyses suggested immune dysfunction in the signature mutated subtype, which was validated by tumor microenvironment (TME) evaluation based on detection of immune cell infiltration. Importantly, the signature wild-type subtype with favorable TME may be an advantageous population of immunotherapy.ConclusionsGenomic alterations in advanced BTC were associated with specific prognosis and immunotherapy outcomes. Combining genomic classification with TME evaluation further improved the stratification of immunotherapy outcomes.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genomic alterations in biliary tract cancer predict prognosis and immunotherapy outcomes

Chen

Wang

Liu

et al. 2021

J Immunother Cancer

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“…Due to the heterogeneity and complexity of BTCs, the prevalence of the well-known biomarkers such as programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), and MSI/dMMR is still unclear. Moreover, except for MSI/dMMR, their predictive role is yet to be established [ 81 ].…”

Section: Systemic Treatment For Btcsmentioning

confidence: 99%

Current options and future directions of systemic therapy for advanced biliary tract cancer

Prete

Cammarota

D’Alessio

et al. 2021

Exploration of Targeted Anti-Tumor Therapy

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Biliary tract cancers (BTCs) are aggressive tumors arising from different portions of the biliary tree and classified according to the anatomical location in intrahepatic (i) cholangiocarcinoma (CCA, iCCA), perihilar CCA (pCCA), and distal CCA (dCCA), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC). Due to their silent behavior, BTCs are frequently diagnosed at advanced stages when the prognosis is poor. The available chemotherapeutic options are palliative and unfortunately, most patients will die from their disease between 6 and 18 months from diagnosis. However, over the last decade, amounting interest has been posed on the genomic landscape of BTCs and deep-sequencing studies have identified different potentially actionable driver mutations. Hence, the promising results of the early phase clinical studies with targeted agents against isocitrate dehydrogenase (IDH) 1 mutation or fibroblast growth factor (FGF) receptor(FGFR) 2 aberrations inintrahepatic tumors, and other agents against humanepidermal growth factor receptor (HER) 2 overexpression/mutations, neurotrophic tyrosine receptor kinase (NTRK) fusions or B-type Raf kinase (BRAF) mutations across different subtypes of BTCs, have paved the way for a “precision medicine” strategy for BTCs. Moreover, despite the modest results when used as monotherapy, beyond microsatellite instability-high (MSI-H) tumors, immune checkpoint inhibitors are being evaluated in combination with platinum-based chemotherapy, possibly further expanding the therapeutic landscape of advanced BTCs. This review aims to provide an overview of the approved systemic therapies, the promising results, and the ongoing studies to explore the current and future directions of advanced BTC systemic treatment.

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“…Cancer immunotherapy, especially immune checkpoint inhibitors (ICIs), has emerged as the most promising treatment for many malignant diseases. Prior studies with convincing evidence have shown that ICI alone could not benefit BTC patients (8). Several trials with a small sample size had a promising ORR of 13% to 22% in response to ICIs (9,10), which dropped to 5.8% as the number of patients increased to 104 (10).…”

Section: Introductionmentioning

confidence: 99%

Immune-related RNA signature predicts outcome of PD-1 inhibitor-combined GEMCIS therapy in advanced intrahepatic cholangiocarcinoma

Zeng¹,

Yuan²,

Chen³

et al. 2022

Front. Immunol.

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BackgroundImmune checkpoint inhibitor (ICI)-combined chemotherapy in advanced intrahepatic cholangiocarcinoma has been proved to have more efficacy in a series of clinical trials. However, whether the tumor microenvironment (TME) plays a vital role in immune-combined therapy has not been rigorously evaluated.MethodsFirstly, we assayed the immunogenic properties of GEM-based chemotherapy. Then, 12 ICC patients treated with PD-1 inhibitor (sintilimab) combined with gemcitabine and cisplatin (GemCis) from a phase 2 clinical trial (ChiCTR2000036652) were included and their immune-related gene expression profiles were analyzed using RNA from baseline tumor samples. Immune-related signature correlating with clinical outcome was identified according to the 12 ICC patients, and its predictive value was validated in an ICC cohort with 26 patients. Multiplexed immunofluorescence (mIF) and flow cytometry (FCM) analysis were performed to evaluate the immune-related molecules with therapeutic outcomes.ResultsGEM-based chemotherapy induced immunogenic cell death of cholangiocarcinoma cells, together with increased CD274 expression. In an ICC cohort, we found that upregulation of immune-checkpoint molecules and immune response-related pathways were significantly related to better clinical outcome. On the contrary, baseline immune-cell proportions in tumor tissues did not show any correlation with clinical benefit between responders and non-responders. Immune-related signature (including six genes) correlating with clinical outcome was identified according to the 12 ICC patients, and its predictive value was validated in a small ICC cohort with 26 patients.ConclusionImmune-related RNA signature predicts the outcome of PD-1 inhibitor-combined GEMCIS therapy in advanced intrahepatic cholangiocarcinoma, which could be tested as a biomarker for immune-chemotherapy in the future.

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Current Progress and Future Perspectives of Immune Checkpoint Inhibitors in Biliary Tract Cancer

Cited by 6 publications

References 57 publications

Genomic alterations in biliary tract cancer predict prognosis and immunotherapy outcomes

Genomic alterations in biliary tract cancer predict prognosis and immunotherapy outcomes

Current options and future directions of systemic therapy for advanced biliary tract cancer

Immune-related RNA signature predicts outcome of PD-1 inhibitor-combined GEMCIS therapy in advanced intrahepatic cholangiocarcinoma

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