PD-L1, TMB, MSI, and Other Predictors of Response to Immune Checkpoint Inhibitors in Biliary Tract Cancer

Rizzo, Alessandro; Ricci, Angela Dalia; Brandi, Giovanni

doi:10.3390/cancers13030558

Cited by 197 publications

(166 citation statements)

References 74 publications

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“…These three biomarkers have been reviewed extensively in the literature. For the most recent review, the readers can refer to Alessandro Rizzo et al’s article in biliary tract cancer ( 7 ). Here, we do not intend to further review those biomarkers in general.…”

Section: Introductionmentioning

confidence: 99%

FDA-Approved and Emerging Next Generation Predictive Biomarkers for Immune Checkpoint Inhibitors in Cancer Patients

et al. 2021

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A patient’s response to immune checkpoint inhibitors (ICIs) is a complex quantitative trait, and determined by multiple intrinsic and extrinsic factors. Three currently FDA-approved predictive biomarkers (progra1mmed cell death ligand-1 (PD-L1); microsatellite instability (MSI); tumor mutational burden (TMB)) are routinely used for patient selection for ICI response in clinical practice. Although clinical utility of these biomarkers has been demonstrated in ample clinical trials, many variables involved in using these biomarkers have poised serious challenges in daily practice. Furthermore, the predicted responders by these three biomarkers only have a small percentage of overlap, suggesting that each biomarker captures different contributing factors to ICI response. Optimized use of currently FDA-approved biomarkers and development of a new generation of predictive biomarkers are urgently needed. In this review, we will first discuss three widely used FDA-approved predictive biomarkers and their optimal use. Secondly, we will review four novel gene signature biomarkers: T-cell inflamed gene expression profile (GEP), T-cell dysfunction and exclusion gene signature (TIDE), melanocytic plasticity signature (MPS) and B-cell focused gene signature. The GEP and TIDE have shown better predictive performance than PD-L1, and PD-L1 or TMB, respectively. The MPS is superior to PD-L1, TMB, and TIDE. The B-cell focused gene signature represents a previously unexplored predictive biomarker to ICI response. Thirdly, we will highlight two combined predictive biomarkers: TMB+GEP and MPS+TIDE. These integrated biomarkers showed improved predictive outcomes compared to a single predictor. Finally, we will present a potential nucleic acid biomarker signature, allowing DNA and RNA biomarkers to be analyzed in one assay. This comprehensive signature could represent a future direction of developing robust predictive biomarkers, particularly for the cold tumors, for ICI response.

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Section: Introductionmentioning

confidence: 99%

FDA-Approved and Emerging Next Generation Predictive Biomarkers for Immune Checkpoint Inhibitors in Cancer Patients

et al. 2021

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“…Last but not least, the lack of validated predictive biomarkers, in order to determine the patients’ sub-cohorts which will derive benefit from immunotherapy, represents a crucial challenge and should be underscored. To date, no single biomarker, including TME, MMR/MSI status, TMB, and PD-L1, has proved efficient to predict response to immune-targeted therapies and guide treatment decisions in iCC clinical settings [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

“…Immunotherapy approaches have emerged as viable therapeutic options for iCC, albeit available data are limited to sub-analyses of either small single-arm studies or basket trials; the conflicting results, so far, highlight the unmet need for discovery and validation of predictive biomarkers [ 45 ]. In a transcriptome study which categorized 566 cases of iCC, based on their cellular TME features, 11% displayed hot phenotype, whereas 45% showed an immune desert—cold phenotype [ 46 ].…”

Section: Immunological Characterisation Of Iccmentioning

confidence: 99%

The Emerging Role of Immunotherapy in Intrahepatic Cholangiocarcinoma

Fiste

Ntanasis‐Stathopoulos

Gavriatopoulou

et al. 2021

Vaccines

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Biliary tract cancer, and intrahepatic cholangiocarcinoma (iCC) in particular, represents a rather uncommon, highly aggressive malignancy with unfavorable prognosis. Therapeutic options remain scarce, with platinum-based chemotherapy is being considered as the gold standard for the management of advanced disease. Comprehensive molecular profiling of tumor tissue biopsies, utilizing multi-omics approaches, enabled the identification of iCC’s intratumor heterogeneity and paved the way for the introduction of novel targeted therapies under the scope of precision medicine. Yet, the unmet need for optimal care of patients with chemo-refractory disease or without targetable mutations still exists. Immunotherapy has provided a paradigm shift in cancer care over the past decade. Currently, immunotherapeutic strategies for the management of iCC are under intense research. Intrinsic factors of the tumor, including programmed death-ligand 1 (PD-L1) expression and mismatch repair (MMR) status, are simply the tip of the proverbial iceberg with regard to resistance to immunotherapy. Acknowledging the significance of the tumor microenvironment (TME) in both cancer growth and drug response, we broadly discuss about its diverse immune components. We further review the emerging role of immunotherapy in this rare disease, summarizing the results of completed and ongoing phase I–III clinical trials, expounding current challenges and future directions.

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“…CCAs account for approximately 3% of all gastrointestinal cancers worldwide and 10–15% of all primary liver tumors [ 4 , 5 , 6 ]. As suggested by several studies, these subgroups of hepatobiliary tumors not only develop from different anatomical locations, but vary widely in terms of epidemiology, biology, prognosis, and etiology [ 7 , 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Targeted Therapies in Advanced Cholangiocarcinoma: A Focus on FGFR Inhibitors

Rizzo

2021

Medicina

Self Cite

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Despite advanced diseases continuing to be associated with grim prognoses, the past decade has witnessed the advent of several novel treatment options for cholangiocarcinoma (CCA) patients. In fact, CCA has emerged as a heterogeneous group of malignancies harboring potentially druggable mutations in approximately 50% of cases, and thus, molecularly targeted therapies have been actively explored in this setting. Among these, fibroblast growth factor receptor (FGFR) inhibitors have reported important results, as witnessed by the FDA approval of pemigatinib in previously treated metastatic CCA patients harboring FGFR2 fusion or other rearrangements. Herein, we provide an overview of available evidence on FGFR inhibitors in CCA, especially focusing on the development, pitfalls and challenges of emerging treatments in this setting.

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PD-L1, TMB, MSI, and Other Predictors of Response to Immune Checkpoint Inhibitors in Biliary Tract Cancer

Cited by 197 publications

References 74 publications

FDA-Approved and Emerging Next Generation Predictive Biomarkers for Immune Checkpoint Inhibitors in Cancer Patients

FDA-Approved and Emerging Next Generation Predictive Biomarkers for Immune Checkpoint Inhibitors in Cancer Patients

The Emerging Role of Immunotherapy in Intrahepatic Cholangiocarcinoma

Targeted Therapies in Advanced Cholangiocarcinoma: A Focus on FGFR Inhibitors

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