Targeted Immunotherapy for Gastric and Gastroesophageal Junction Cancer

Targeted immunotherapy in gastric and gastroesophageal junction cancer has transformed the clinical landscape by focusing on tumour-specific antigens and modulating the host immune response. Beyond conventional chemotherapy, monoclonal antibodies directed against cell-surface proteins, antibody–drug conjugates that deliver cytotoxic payloads, bispecific constructs that recruit T cells to tumour cells, and chimeric antigen receptor T-cell therapies have all entered clinical and preclinical development. Central to these advances is the identification of claudin-18 isoform 2 (CLDN18.2) as a lineage-restricted marker retained in many gastric and junctional adenocarcinomas. Concurrent efforts target human epidermal growth factor receptor 2 (HER2)-negative disease, immune checkpoints such as PD-1/PD-L1, and other tumour-associated antigens. Stratification by biomarker expression, coupled with deeper understanding of the tumour immune microenvironment, is refining patient selection and informing combination regimens that aim to improve progression-free and overall survival while minimising off-target toxicity.

Research from Nature Portfolio

Recent clinical findings have established a new first-line standard for patients with CLDN18.2-positive, HER2-negative advanced disease. In a global randomised trial, the addition of an anti-CLDN18.2 monoclonal antibody to standard capecitabine and oxaliplatin significantly extended progression-free and overall survival compared with chemotherapy alone, without increasing grade 3–4 adverse events. Complementing this, preclinical models have demonstrated that both CD3-engaging bispecific antibodies and antibody–drug conjugates directed to CLDN18.2 exhibit potent cytotoxicity against gastric and pancreatic adenocarcinoma xenografts. These modalities showed on-target tumour growth inhibition in vitro and in vivo, with preliminary tolerability in rodent safety studies, thereby validating CLDN18.2 as a versatile platform for next-generation targeted therapies.

Targeted Immunotherapy for Gastric and Gastroesophageal Junction Cancer publication trend

The graph below shows the total number of articles in targeted immunotherapy for gastric and gastroesophageal junction cancer across all publications each year (not limited to Nature Index journals).

Technical terms

Claudin-18.2 (CLDN18.2): Isoform of a tight junction protein selectively expressed in gastric epithelial cells and retained in many gastric and gastroesophageal junction tumours.

Monoclonal antibody (mAb): Laboratory-generated antibody designed to bind a specific antigen on tumour cells, mediating direct cytotoxicity or immune recruitment.

Bispecific antibody (BsAb): Engineered antibody with two distinct binding domains, typically one targeting a tumour antigen and the other engaging a T-cell receptor (eg, CD3).

Antibody–drug conjugate (ADC): Antibody linked to a cytotoxic agent, delivering the payload selectively to antigen-expressing tumour cells.

Chimeric antigen receptor T cell (CAR-T): Patient-derived T cell genetically modified to express a receptor that recognises a tumour-associated antigen, redirecting T-cell cytotoxicity.

References

1. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nature Medicine (2023).
2. Targeting CLDN18.2 by CD3 Bispecific and ADC Modalities for the Treatments of Gastric and Pancreatic Cancer. Scientific Reports (2019).
3. Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy. Biomarker Research (2022).
4. CAR-T Cell Therapy—An Overview of Targets in Gastric Cancer. Journal of Clinical Medicine (2020).