CLDN18 (Claudin 18)

Overexpression of CLDN18.2 was associated with unfavorable clinical prognosis and adverse pathological features in intrahepatic cholangiocarcinoma. These findings suggest that CLDN18.2 could serve as a potential prognostic biomarker for intrahepatic cholangiocarcinoma.

Our results demonstrate that universal CAR-CLDN18.2-γδ T cell is promising for the treatment of CLDN18.2-positive solid tumor and provide insights for the development of more universal CAR-γδ T-cell strategies for tumor immunotherapy.

Future directions emphasize the need to overcome resistance mechanisms and refine treatment strategies to improve efficacy while reducing adverse effects. This review aims to elucidate the current landscape of immunotherapy and targeted therapy in gastric cancer and to explore their potential in shaping the future of clinical management for this devastating disease.

The preserved expression of CLDN18.2 in metastatic tumors underscores its potential utility as a target for therapeutic approaches. Our findings emphasize the importance of evaluating CLDN18.2 status in both primary and metastatic tumors to refine therapeutic strategies.

Recently, zolbetuximab, an anti-claudin 18.2 monoclonal antibody, was the first of these agents to get FDA approval. Here, we review zolbetuximab's place in therapy along with other agents being explored.

Our findings indicate that chemotherapy can drive immunosuppressive TME modifications specific to CLDN18.2-positive GC.

Human epidermal growth factor receptor 2 (HER2) was the first molecular biomarker to be used in gastric cancer with trastuzumab being the first approved targeted therapy for HER2-positive gastric cancer. Programmed death-ligand 1 positivity and microsatellite instability can guide the use of immunotherapies, such as pembrolizumab and nivolumab. More recently, zolbetuximab has been approved for patients with claudin 18.2-positive diseases in some countries. More targeted therapies, including savolitinib for MET-positive patients, are currently under clinical investigation...Novel testing and analysis techniques, such as artificial intelligence-assisted image analysis and multiplex immunohistochemistry, and emerging therapeutic strategies, including combination therapies that integrate immune checkpoint inhibitors with targeted therapies, offer potential solutions to some of these challenges. This article reviews recent progress in gastric cancer testing, outlines current challenges, and explores future directions for biomarker testing and targeted therapy for gastric cancer.

CLDN18-positive cases demonstrated significantly improved survival at the cohort's median overall survival (23 months, p < 0.05), suggesting that claudin expression could serve as a both a diagnostic and prognostic marker. Our findings indicate that 32.5 % of PDAC tumors in this cohort are positive for CLDN18, suggesting that a significant proportion of patients with PDAC could benefit from zolbetuximab and other CLDN18.2 targeted immunotherapies if pancreatic cancer therapeutic trials prove successful.

Although CLDN18.2 expression in PM mirrored that in primary lesions, the levels were generally reduced. When zolbetuximab is used for GC patients with peritoneal involvement, it is preferable to assess the expression of CLDN18.2 in the disseminated lesions.

In vitro, 4A7 demonstrated significantly enhanced binding activity, as well as robust antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), outperforming IMAB362, a clinical investigational antibody...4A7 shows great promise as a next-generation therapeutic for Claudin18.2-positive cancers, offering improved efficacy and reduced immunogenicity. This study not only highlights 4A7's potential to address unmet clinical needs but also provides a foundation for future innovations in monoclonal antibody-based cancer therapy.

Over the past decade, therapies for metastatic or advanced GEA/ESCC have expanded, with several new therapeutic targets alongside trastuzumab for metastatic HER2-positive GEA...Experts from the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM) have formed a consensus to optimize biomarker detection and usage in clinical practice. Their recommendations aim to improve personalized treatment strategies for GEA and ESCC patients, integrating new diagnostic insights into routine care.

Like the cervical counterpart, primary EmGA has a distinctive morphologic appearance, harbors frequent TP53 mutations, and can be associated with adverse outcomes despite low-grade morphology and/or low-stage at presentation. They may be represented in all 4 TCGA molecular groups.

Furthermore, drug sensitivity analysis revealed that the MaGPS signature scores were significantly associated with the sensitivity to 38 different drugs, highlighting potential targeted therapies related to MaGPS. The MaGPS model, based on bulk RNA-seq, scRNA-seq, and spatial transcriptomics data, effectively evaluated the prognosis of pancreatic cancer and provided valuable insights for better therapeutic targets.

S100P and IMP3 expression levels were significantly elevated in high-grade lesions, particularly within the I+B-type BilIN group, with no notable differences in G- or GI-type BilIN. Immunophenotypic profiling with lineage-specific markers effectively subclassified BilIN, enhancing the understanding of its histogenesis and progression.

Targeting IDO1 represents a promising strategy to overcome immunosuppressive barriers in gastrointestinal cancers, improving the efficacy of CLDN18.2-CAR-T therapy. These findings highlight the potential for integrating IDO1 inhibition into CAR-T treatment regimens to address resistance in treatment-refractory cancers.

The combination of anti-PD-1 therapy increased TNF-α and IFN-γ secretion and further boosted the cytotoxic efficacy of CD8+ T cells. Excellent therapeutic efficacy is found simultaneously on cell-derived allografts and patient-derived xenografts based on this spatiotemporally manipulated strategy, presenting a therapeutic option for enhancing responsiveness to immunotherapy for CLDN18.2-positive individuals.

Examining how to improve upon outcomes will be of benefit. Additionally, there are GAC subsets who may also have benefit from zolbetuximab but need more close examination such as those with moderate CLDN18.2 expressed tumors, low CLDN18.2 expressed tumors, and CLD18-ARHGAP fusion patients.

Finally, two biomarkers (EDNRB and MME) were identified by intersecting genes, obtained from USA and Taiwan cohorts. The proposed biomarkers can significantly improve patient outcomes by enabling earlier detection, precise diagnosis, and tailored treatment, ultimately contributing to better survival rates and quality of life for patients.

CLDN18.2 is not expressed in normal prostate tissue or PC, suggesting that it is unlikely to serve as a prognostic marker or a potential target for immunotherapy in PC.

Outpatient zolbetuximab administration proved safe and feasible in a community setting when implemented with appropriate protocols and support systems. This implementation model could serve as a template for delivering complex cancer therapies in resource-limited settings.

Analyzing biophysical properties of the receptor suggests that TAC receptors with high TCR affinities are suboptimal compared to receptor constructs that show lower TCR affinities with notably fast off-rates. This work demonstrates that balancing TCR recruitment is critical when designing effective TAC T cell receptors, a concept that may apply more broadly to other therapeutic approaches relying on TCR signaling.

P1/2, N=20, Completed, LaNova Australia Pty Limited | Terminated --> Completed

P1/2, N=113, Active, not recruiting, Triumvira Immunologics, Inc. | Recruiting --> Active, not recruiting

The correlations between the expression of CLDN18.2 and clinicopathological characteristics and prognosis suggest that early-stage patients could benefit more from future anti-CLDN18.2 treatment and that CLDN18.2 may function as a pivotal regulatory molecule in patients with GBC. The underlying mechanism may be related to immune activation caused by high CLDN18.2 expression.

The aim of this review is to summarize the current biomarker landscape of patients with metastatic gastroesophageal tumors, its direct clinical impact on daily decision-making, and to evaluate current findings on biomarker co-expression. Furthermore, possible treatment strategies with multiple biomarker expression are discussed.

P1, N=176, Completed, Keymed Biosciences Co.Ltd | Recruiting --> Completed | Trial completion date: Oct 2024 --> Apr 2024

© 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

We found that high expression of CLDN18 in ascites epithelial cells correlated with a favorable prognosis, whereas ascites epithelial cells with high MYC expression and strong interactions between tumor cells and T cells were adverse prognostic factors for CT041 treatment. These findings may provide theoretical evidence for the screening of populations that can benefit from CAR T therapy and improve the efficacy of CAR T therapy.

Other biomarkers with targeted therapies are being studied including fibroblast growth factor receptor, trophoblast cell surface antigen-2, and epidermal growth factor receptor. Additionally, epidemiological distinctions are starting to drive therapy such as in EBV in GAC.

The determination of serum autoantibody panel has clinical value in screening and prediction of gastric cancer, and can be used as an auxiliary index in clinical diagnosis. The combination of 7-TAAs and Helicobacter pylori can effectively improve the screening specificity and positive predictive value. The detection results of different proteins were related to the stage of disease, the degree of tumor differentiation and the depth of invasion.

Variability in criteria used to define claudin 18.2 positivity, as well as methodological differences, could explain the variation in the proportion of positive cases described, as well as the inconsistency of the association with clinical, molecular, and survival variables. The upcoming anticlaudin 18.2 therapy in advanced gastric cancer should prompt pathology laboratories to adjust their staining protocols and evaluation criteria in their series of patients, to further establish the association of claudin expression with clinical and molecular variables.

P=N/A, N=18, Completed, The First Affiliated Hospital of Zhengzhou University; The First Affiliated Hospital of Zhengzhou University | Not yet recruiting --> Completed

Claudin 18.2, nectin-4, and HER3 are potential therapeutic targets in SBA, and nectin-4 positivity is independently associated with an unfavorable prognosis. These proteins may represent new therapeutic targets for SBA.

Trastuzumab had been the standard treatment for HER2-positive AGC for a decade, and subsequently, trastuzumab deruxtecan, an antibody-drug conjugate (ADC), emerged with an impressive response. Recently, the addition of pembrolizumab to first-line chemotherapy plus trastuzumab has become a novel standard treatment...Learning from past trials, further development of novel HER2-targeted therapies is underway, expanding their scope to HER2-expressing AGC. Meanwhile, selecting optimal treatment is a challenging issue in cases with HER2-low AGC overlapping with other biomarkers like CLDN18.2.

The high expression of Claudin 18.2 in neoplastic tissue and absence in normal cells suggested that this protein had an attractive role in PDA as both a diagnostic and a prognostic-therapeutic marker. High expression of Claudin 18.2 in neoplastic tissue was associated with more favorable prognostic parameters and the high percentage of positive samples obtained suggests that Zolbetuximab may be suitable for a large number of patients.

Advanced neoantigen prediction and identification of optimal T-cell activation targets could facilitate the clinical application of TIL and T-cell receptor-T therapies in GI cancers. Cell-based therapies might have the potential to transform the treatment landscape for GI cancers.

P2, N=190, Recruiting, AstraZeneca | N=123 --> 190 | Trial primary completion date: May 2025 --> Dec 2025

131I-HLX58-Der demonstrated no toxic effects on hepatorenal function, routine blood tests, or major organs in mice when compared to the control group. These findings validate the potential of RADCs targeting CLDN18.2 in treating CLDN18.2-expressing solid tumors.

Multiple immunohistochemistry is a powerful technique for exploring the intricate immune microenvironment of hepatocellular carcinoma, enabling the precise identification of diverse cell subsets and their spatial distribution within the tumor microenvironment. This methodology provides valuable insights into the complex interactions and spatial organization of immune cells in the context of hepatocellular carcinoma progression. Low GPC3 expression in HCC patients indicates potential benefits from combined targeted and immunotherapy. Different levels of GPC3 expression levels can predict the effectiveness of targeted combination immunotherapy in HCC patients. Additionally, different GPC3 expression patterns in HCC patients correspond to unique tumor immune microenvironments, which have implications for guiding HCC treatment approaches.

In conclusion, CLDN18.2-positive colorectal adenocarcinomas are frequently MMR deficient, BRAF V600E mutated, and demonstrate distinct histologic features. Future studies addressing the efficacy of zolbetuximab therapy in this subset of colorectal cancers are needed.

Tumor heterogeneity can be categorized into spatial heterogeneity, which refers to variations within the primary tumor (intra-tumoral) or between primary and metastatic sites, and temporal heterogeneity, which encompasses changes over time. This review addresses the tumor heterogeneity in predictive biomarker expression in GC, focusing on HER2, PD-L1, MMR, the Epstein-Barr virus, claudin 18.2, and FGFR2b.

P2, N=240, Recruiting, AstraZeneca | Trial completion date: Mar 2026 --> Jan 2027 | Trial primary completion date: Sep 2025 --> Jan 2026