Predictive Biomarkers of Immune Checkpoint Inhibition in Gastroesophageal Cancers

Sundar, Raghav; Smyth, Elizabeth; Peng, Siyu; Yeong, Joe Poh Sheng; Tan, Patrick

doi:10.3389/fonc.2020.00763

Cited by 43 publications

(40 citation statements)

References 95 publications

(102 reference statements)

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“…Pathways regulating the immune system are called immune checkpoints: different cancer types use these immune checkpoints as a mechanism of immune evasion, leading to tumor progression [ 117 , 118 ]. The dependence of cancer on these pathways has been therapeutically exploited with the development of specific immune checkpoint inhibitors (ICI) such as anti-programmed cell death 1 (anti-PD-1) and anti-PD-1 ligand (anti-PD-L1) antibodies.…”

Section: Immunotherapy and Tme In Gastric Cancermentioning

confidence: 99%

“…By blocking the PD-1 axis with anti-PD-1 or anti-PD-L1 monoclonal antibodies, anti-tumor immune responses can be restored, leading to tumor regression. Briefly, PD-1 is a negative co-stimulatory transmembrane protein expressed on T-cells, B-cells, and NK cells; its binding to PD-L1 (which is expressed on tumor cells) and PD-L2 leads to peripheral T effector cell modulation as well as to tumor cell apoptosis and increased conversion of T effector cells to Treg cells [ 118 ].…”

Section: Immunotherapy and Tme In Gastric Cancermentioning

confidence: 99%

See 1 more Smart Citation

Tumor-Associated Macrophages and Inflammatory Microenvironment in Gastric Cancer: Novel Translational Implications

Rihawi

Ricci

Rizzo

et al. 2021

IJMS

115

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Gastric cancer (GC) represents the fifth most frequently diagnosed cancer worldwide, with a poor prognosis in patients with advanced disease despite many improvements in systemic treatments in the last decade. In fact, GC has shown resistance to several treatment options, and thus, notable efforts have been focused on the research and identification of novel therapeutic targets in this setting. The tumor microenvironment (TME) has emerged as a potential therapeutic target in several malignancies including GC, due to its pivotal role in cancer progression and drug resistance. Therefore, several agents and therapeutic strategies targeting the TME are currently under assessment in both preclinical and clinical studies. The present study provides an overview of available evidence of the inflammatory TME in GC, highlighting different types of tumor-associated cells and implications for future therapeutic strategies.

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Section: Immunotherapy and Tme In Gastric Cancermentioning

confidence: 99%

Section: Immunotherapy and Tme In Gastric Cancermentioning

confidence: 99%

Tumor-Associated Macrophages and Inflammatory Microenvironment in Gastric Cancer: Novel Translational Implications

Rihawi

Ricci

Rizzo

et al. 2021

IJMS

115

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“…MSI-H tumors have also been associated with a good response to immunotherapy [ 15 , 59 , 60 ]. Based on these findings, the FDA approved pembrolizumab for the treatment of MSI-H tumors that had progressed following prior treatment, irrespective of tumor site [ 61 ].…”

Section: Biomarkers Of Response To Immunotherapy In Gastric Cancermentioning

confidence: 99%

“…Based on these findings, the FDA approved pembrolizumab for the treatment of MSI-H tumors that had progressed following prior treatment, irrespective of tumor site [ 61 ]. In GC, studies have also demonstrated that dMMR and MSI-H tumors generally have a favorable response to immune-checkpoint blockade [ 36 , 59 ]. A multi cohort study of pembrolizumab monotherapy in advanced GC showed that MSI-H tumors had greater ORR (57.1%) compared to MSS patients (9%) and also a significant disease control rate (DCR) of 71.4% was achieved [ 30 , 36 ].…”

Section: Biomarkers Of Response To Immunotherapy In Gastric Cancermentioning

confidence: 99%

How to Best Exploit Immunotherapeutics in Advanced Gastric Cancer: Between Biomarkers and Novel Cell-Based Approaches

Ghidini

Petrillo²,

Botticelli

et al. 2021

JCM

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Despite extensive research efforts, advanced gastric cancer still has a dismal prognosis with conventional treatment options. Immune checkpoint inhibitors have revolutionized the treatment landscape for many solid tumors. Amongst gastric cancer subtypes, tumors with microsatellite instability and Epstein Barr Virus positive tumors provide the strongest rationale for responding to immunotherapy. Various predictive biomarkers such as mismatch repair status, programmed death ligand 1 expression, tumor mutational burden, assessment of tumor infiltrating lymphocytes and circulating biomarkers have been evaluated. However, results have been inconsistent due to different methodologies and thresholds used. Clinical implementation therefore remains a challenge. The role of immune checkpoint inhibitors in gastric cancer is emerging with data from monotherapy in the heavily pre-treated population already available and studies in earlier disease settings with different combinatorial approaches in progress. Immune checkpoint inhibitor combinations with chemotherapy (CT), anti-angiogenics, tyrosine kinase inhibitors, anti-Her2 directed therapy, poly (ADP-ribose) polymerase inhibitors or dual checkpoint inhibitor strategies are being explored. Moreover, novel strategies including vaccines and CAR T cell therapy are also being trialed. Here we provide an update on predictive biomarkers for response to immunotherapy with an overview of their strengths and limitations. We discuss clinical trials that have been reported and trials in progress whilst providing an account of future steps needed to improve outcome in this lethal disease.

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“…In these tumors, dMMR has been described in 7-22% of cases; it represents a driver molecular event for tumorigenesis and tumor progression [6]. Several studies support the better prognosis of dMMR/MSI high (MSI-H) GEC patients, along with the higher response rate to immune-checkpoint inhibitors (ICI) [7][8][9][10]. During recent years, significant achievements have been made in the understanding of the biology of dMMR in GEC [7,11,12].…”

Section: Introductionmentioning

confidence: 99%

Mismatch Repair System Genomic Scars in Gastroesophageal Cancers: Biology and Clinical Testing

Lopez

Venetis

Sajjadi

et al. 2020

Gastrointestinal Disorders

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Alterations in the mismatch repair (MMR) system result in genomic instability, neoantigen production, and immune response in cancer. There is evidence that gastroesophageal tumors with MMR deficiency may be susceptible to immune-checkpoint inhibitors treatment, especially in those presenting at advanced-stage disease. Although a number of biomarkers have been developed in histology-agnostic settings to assess MMR status, there is evidence that a tumor-specific testing approach would improve the selection of patients for immunotherapy. However, no testing methods have been developed specifically for gastroesophageal cancers so far. Here, we discuss the state of the art, current advances, and future perspectives of MMR-related biomarkers’ biologic and clinical role in gastroesophageal cancers.

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Predictive Biomarkers of Immune Checkpoint Inhibition in Gastroesophageal Cancers

Cited by 43 publications

References 95 publications

Tumor-Associated Macrophages and Inflammatory Microenvironment in Gastric Cancer: Novel Translational Implications

Tumor-Associated Macrophages and Inflammatory Microenvironment in Gastric Cancer: Novel Translational Implications

How to Best Exploit Immunotherapeutics in Advanced Gastric Cancer: Between Biomarkers and Novel Cell-Based Approaches

Mismatch Repair System Genomic Scars in Gastroesophageal Cancers: Biology and Clinical Testing

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