Biliary Tract Cancer: Implicated Immune-Mediated Pathways and Their Associated Potential Targets

Tariq, Noor-ul-Ain; Vogel, Arndt; McNamara, Mairéad G.; Valle, Juan W

doi:10.1159/000488997

Cited by 8 publications

(7 citation statements)

References 57 publications

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“…29,82 TME composition is an important determinant of patient prognosis in BTC. [83][84][85] and the accumulation of immunosuppressive cell types e.g. tumor associated macrophages (TAMs) and regulatory T-cells (T-regs), poor infiltration of cytotoxic CD8 + T-cells, or defective MHC class 1 expression is linked with poor prognosis as well as gemcitabine resistance.…”

Section: Discussionmentioning

confidence: 99%

IMbrave 151: a randomized phase II trial of atezolizumab combined with bevacizumab and chemotherapy in patients with advanced biliary tract cancer

Hack¹,

Verret²,

Mulla

et al. 2021

Ther Adv Med Oncol

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Background: Biliary tract cancers (BTCs) are heterogenous, highly aggressive tumors that harbor a dismal prognosis for which more effective treatments are needed. The role of cancer immunotherapy in BTC remains to be characterized. The tumor microenvironment (TME) of BTC is highly immunosuppressed and combination treatments are needed to promote effective anticancer immunity. Vascular endothelial growth factor (VEGF) drives immunosuppression in the TME by disrupting antigen presentation, limiting T-cell infiltration, or potentiating immune-suppressive cells. Many VEGF-regulated mechanisms are thought to be relevant to repressed antitumor immunity in BTC, making dual targeting of VEGF and programmed cell death protein 1 (PD-1)/PD-L1 pathways a rational approach. Gemcitabine and Cisplatin (Gem/Cis) can also modulate anticancer immunity through overlapping and complementary mechanisms to those regulated by VEGF. Anti-PD-L1/VEGF inhibition, coupled with chemotherapy, may potentiate antitumor immunity leading to enhanced clinical benefit. Methods: IMbrave 151 is a randomized, double-blind, placebo-controlled, multicenter, international phase II study to evaluate atezolizumab (a PD-L1 inhibitor) in combination with chemotherapy (gemcitabine and cisplatin) and bevacizumab (an anti-VEGF monoclonal antibody) as a first-line treatment for advanced BTC. Approximately 150 patients with previously untreated, advanced BTC will be randomized to either Arm A (atezolizumab + bevacizumab + Gem/Cis) or Arm B (atezolizumab + placebo + Gem/Cis). Randomization is stratified by the presence of metastatic disease, primary tumor location, and geographic region. The primary efficacy endpoint is investigator-assessed progression-free survival (PFS) per RECIST 1.1. Secondary endpoints include objective response rate (ORR), duration of response (DoR), disease control rate (DCR), overall survival (OS), and safety and patient reported outcomes (PROs). Tissue, blood, and stool samples will be collected at baseline and on-treatment in order to perform correlative biomarker analyses. Discussion: IMbrave 151 represents the first randomized study to evaluate combined PD-L1/VEGF blockade on a chemotherapy backbone in BTC. Trial registration: NCT identifier: NCT04677504; EUDRACT number: 2020-003759-14

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Section: Discussionmentioning

confidence: 99%

IMbrave 151: a randomized phase II trial of atezolizumab combined with bevacizumab and chemotherapy in patients with advanced biliary tract cancer

Hack¹,

Verret²,

Mulla

et al. 2021

Ther Adv Med Oncol

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“…In contrast to HCC, the BTC microenvironment has been noted for an immune-excluding desmoplastic-rich stroma, cancer-associated fibroblasts, endothelial cells, and mostly immune cold or suppressive immune subsets (Figure 1). 35,36 Tumor-associated macrophages (TAMs) represent the predominant population of infiltrating immune cells in CCA tumors, and elevated levels are associated with poor prognosis, reduced survival, and metastasis. 37 Job et al 38 recently defined 4 subtypes of iCCA TMEs based on gene expression profiling of iCCA tumors (n5566) and microdissected epithelial/stromal compartments: (1) an immune desert (46%-48%), marked by a lack of CD8 1 T cells, major histocompatibility complex (MHC) class I cells, and myeloid cells; (2) mesenchymal (22%-28%), with an immune-excluded niche rich in fibrous stroma, vascular factors, and chemokines; (3) myeloid (13%-19%), marked by M2 macrophages and CD4 1 /CD8 1 T cells; and (4) inflamed/ immunogenic (9%-13%), rich in both immune-stimulating and immune-suppressive features (Figure 1).…”

Section: Biliary Tract Cancermentioning

confidence: 99%

T-Cell Subsets as Potential Biomarkers for Hepatobiliary Cancers and Selection of Immunotherapy Regimens as a Treatment Strategy

Kumar-Sinha

Sahai

2022

Journal of the National Comprehensive Cancer Network

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Patients with advanced hepatocellular or biliary cancers have a dismal prognosis with limited efficacy from standard systemic therapies. The benefit of precision medicine has so far been limited to a subset of biliary cancers, including FGFR rearrangements; hotspot mutations in IDH1/2, BRAF, and BRCA1/2; and other rare alterations. In contrast, hepatocellular carcinoma, an inflammation-driven cancer with an immune-infiltrated microenvironment, provides a promising opportunity for immunotherapy, compared with the highly desmoplastic immune desert or excluded stromal microenvironment in biliary cancers. The immune contexture in hepatobiliary cancers is mostly immunosuppressive, protumorigenic, and exhausted, which together with low tumor mutation burden and decreased neoantigens provides challenges for immunotherapy. A better understanding of the spatiotemporal profile of T cells within the tumor microenvironment and the dynamic interplay of immune modulators in the context of standard or experimental therapies is crucial to define additional markers of response and design evidence-based combinatorial regimens. This review considers recent literature in this area and highlights promising leads and emerging trends.

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“…In BTC, the evidence for the use of ACT is limited to case reports or small case series of patients treated in single-arm phase II studies. 100 Another potential target for cancer immunotherapy is CD40, a costimulatory protein found on antigen presenting cells, required for their activation and for presenting the antigens to T cells. Agonistic anti-CD40 has been shown to induce T-cell antitumour responses in mice, 100 which encourages its clinical testing as a cancer treatment.…”

Section: Immunotherapy: Checkpoint Modulators (Ctla4 Pd1/pdl1 Cd40) A...mentioning

confidence: 99%

Medical treatment for cholangiocarcinoma

Adeva

Sangro

Salati

et al. 2019

Liver International

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Most of the patients with cholangiocarcinoma (CCA) present with advanced (inoperable or metastatic) disease, and relapse rates are high in those undergoing potentially curative resection. Previous treatment nihilism of patients with advanced disease has been replaced by active clinical research with the advent of randomized clinical trials (RCTs) and a much greater effort at understanding molecular mechanisms underpinning CCA. Three RCTs have recently been reported evaluating adjuvant chemotherapy following curative resection; only one of these has the potential to change practice. The BILCAP study failed to meet its primary endpoint by intention‐to‐treat analysis; however, a survival benefit was seen in a preplanned sensitivity analysis (predominantly adjusting for lymph nodes status). This, along with the numerical difference in median overall survival has led to the uptake of adjuvant capecitabine by many clinicians. In patients with advanced disease, the only level 1 data available supports the use of cisplatin and gemcitabine for the first‐line treatment of patients with advanced disease; there is no established second‐line chemotherapy. Previous forays into targeted therapy have proven unfruitful (namely targeting the epithelial growth factor receptor and vascular endothelial growth factor pathways). An increasing number of genomic subtypes are being defined; for some of these on‐target therapeutic options are under active investigation. The most developed are studies targeting IDH‐1 (isocitrate dehydrogenase) mutations and FGFR‐2 (fibroblast growth factor receptor) fusions, with promising early results. Several other pathways are under evaluation, along with early studies targeting the immune environment; these are too premature to change practice to date. These emerging treatments are discussed.

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Biliary Tract Cancer: Implicated Immune-Mediated Pathways and Their Associated Potential Targets

Cited by 8 publications

References 57 publications

IMbrave 151: a randomized phase II trial of atezolizumab combined with bevacizumab and chemotherapy in patients with advanced biliary tract cancer

IMbrave 151: a randomized phase II trial of atezolizumab combined with bevacizumab and chemotherapy in patients with advanced biliary tract cancer

T-Cell Subsets as Potential Biomarkers for Hepatobiliary Cancers and Selection of Immunotherapy Regimens as a Treatment Strategy

Medical treatment for cholangiocarcinoma

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