Advances in molecular biomarkers research and clinical application progress for gastric cancer immunotherapy

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Abstract

Gastric cancer is characterized by high morbidity and mortality worldwide. Early-stage gastric cancer is mainly treated with surgery, while for advanced gastric cancer, the current treatment options remain insufficient. In the 2022 NCCN Guidelines for Gastric Cancer, immunotherapy is listed as a first-line option for certain conditions. Immunotherapy for gastric cancer mainly targets the PD-1 molecule and achieves therapeutic effects by activating T cells. In addition, therapeutic strategies targeting other molecules, such as CTLA4, LAG3, Tim3, TIGIT, and OX40, have also been developed to improve the treatment efficacy of gastric cancer immunotherapy. This review summarizes the molecular biomarkers of gastric cancer immunotherapy and their clinical trials.

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Most cited references 93

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Microenvironmental regulation of tumor progression and metastasis.

Daniela F Quail, Johanna A Joyce (2013)

Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.

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The Tumor Microenvironment Innately Modulates Cancer Progression

Dominique C. Hinshaw, Lalita A Shevde (2019)

Cancer development and progression occurs in concert with alterations in the surrounding stroma. Cancer cells can functionally sculpt their microenvironment through the secretion of various cytokines, chemokines, and other factors. This results in a reprogramming of the surrounding cells, enabling them to play a determinative role in tumor survival and progression. Immune cells are important constituents of the tumor stroma and critically take part in this process. Growing evidence suggests that the innate immune cells (macrophages, neutrophils, dendritic cells, innate lymphoid cells, myeloid-derived suppressor cells, and NK cells) as well as adaptive immune cells (T cells and B cells) contribute to tumor progression when present in the tumor microenvironment (TME). Crosstalk between cancer cells and the proximal immune cells ultimately results in an environment that fosters tumor growth and metastasis. Understanding the nature of this dialog will allow for improved therapeutics that simultaneously target multiple components of the TME, increasing the likelihood of favorable patient outcomes.

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Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.

Yung-Jue Bang, Eric Van Cutsem, Andrea Feyereislova … (2010)

Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2; also known as ERBB2), was investigated in combination with chemotherapy for first-line treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer. ToGA (Trastuzumab for Gastric Cancer) was an open-label, international, phase 3, randomised controlled trial undertaken in 122 centres in 24 countries. Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation. Participants were randomly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab. Allocation was by block randomisation stratified by Eastern Cooperative Oncology Group performance status, chemotherapy regimen, extent of disease, primary cancer site, and measurability of disease, implemented with a central interactive voice recognition system. The primary endpoint was overall survival in all randomised patients who received study medication at least once. This trial is registered with ClinicalTrials.gov, number NCT01041404. 594 patients were randomly assigned to study treatment (trastuzumab plus chemotherapy, n=298; chemotherapy alone, n=296), of whom 584 were included in the primary analysis (n=294; n=290). Median follow-up was 18.6 months (IQR 11-25) in the trastuzumab plus chemotherapy group and 17.1 months (9-25) in the chemotherapy alone group. Median overall survival was 13.8 months (95% CI 12-16) in those assigned to trastuzumab plus chemotherapy compared with 11.1 months (10-13) in those assigned to chemotherapy alone (hazard ratio 0.74; 95% CI 0.60-0.91; p=0.0046). The most common adverse events in both groups were nausea (trastuzumab plus chemotherapy, 197 [67%] vs chemotherapy alone, 184 [63%]), vomiting (147 [50%] vs 134 [46%]), and neutropenia (157 [53%] vs 165 [57%]). Rates of overall grade 3 or 4 adverse events (201 [68%] vs 198 [68%]) and cardiac adverse events (17 [6%] vs 18 [6%]) did not differ between groups. Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer. F Hoffmann-La Roche. Copyright 2010 Elsevier Ltd. All rights reserved.

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Author and article information

Contributors

Hongzhen Cai: 1910301129@pku.edu.cn

Man Li: 1910301332@pku.edu.cn

Ruiyi Deng: 1910301104@pku.edu.cn

Mopei Wang: wangmopei@bjmu.edu.cn

Yanyan Shi: shiyanyan@bjmu.edu.cn

Journal

Journal ID (nlm-ta): Biomark Res

Journal ID (iso-abbrev): Biomark Res

Title: Biomarker Research

Publisher: BioMed Central (London )

ISSN (Electronic): 2050-7771

Publication date (Electronic): 30 August 2022

Publication date PMC-release: 30 August 2022

Publication date Collection: 2022

Volume: 10

Electronic Location Identifier: 67

Affiliations

[1 ]GRID grid.411642.4, ISNI 0000 0004 0605 3760, Research Center of Clinical Epidemiology, , Peking University Third Hospital, ; Beijing, 100191 People’s Republic of China

[2 ]GRID grid.11135.37, ISNI 0000 0001 2256 9319, Peking University Health Science Center, ; Beijing, 100191 People’s Republic of China

[3 ]GRID grid.411642.4, ISNI 0000 0004 0605 3760, Department of Medical Oncology and Radiation Sickness, , Peking University Third Hospital, ; Beijing, 100191 People’s Republic of China

Article

Publisher ID: 413

DOI: 10.1186/s40364-022-00413-0

PMC ID: 9426247

PubMed ID: 36042469

SO-VID: 5272594b-cb0f-4964-8e6d-e31c8b397c5d

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 9 June 2022

Date accepted : 20 August 2022

Funding

Funded by: Peking University Medicine Fund of Fostering Young Scholars’ Scientific & Technological Innovation

Award ID: BMU2021PY002

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: No. 81700496

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Keywords: gastric cancer,immunotherapy,anti-pd-1,biomarker,checkpoint inhibitor

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Keywords: gastric cancer, immunotherapy, anti-pd-1, biomarker, checkpoint inhibitor

Advances in molecular biomarkers research and clinical application progress for gastric cancer immunotherapy

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Abstract

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Cancer Immunotherapy

Most cited references 93

Microenvironmental regulation of tumor progression and metastasis.

The Tumor Microenvironment Innately Modulates Cancer Progression

Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.

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