Trastuzumab with chemotherapy is the standard regimen for HER2-positive GC/GEJC. While, for HER2-negative cases, chemotherapy with or without immune checkpoint inhibitors (ICIs)such as nivolumab or pembrolizumab are regarded as the standard therapy...We will highlight the previous clinical trials of zolbetuximab and provide future perspective of CLDN18.2 targeted therapy. In addition, we will introduce the ongoing development of various CLDN18.2 targeting therapies such as newer monoclonal antibodies, antibody-drug conjugates(ADCs), chimeric antigen receptor T-cell(CAR- T)therapy, and bispecific antibodies.

Therapies like monoclonal antibodies (e.g., zolbetuximab), bispecific antibodies, and antibody-drug conjugates have shown significant potential in improving clinical outcomes...However, challenges such as patient selection, resistance mechanisms, and toxicity management remain critical. This review highlights the therapeutic landscape, clinical advancements, and future directions of targeting Claudin 18.2 in gastric and pancreatic cancer treatment.

Mechanistically, early radiation-induced apoptosis promoted the proliferation of CD8 + T cells, while increased chemokine CCL2 levels from localized and distant tumor sites facilitated CAR-T and endogenous T cell infiltration, leading to systemic tumor suppression. This study proposes a promising approach for treating metastatic pancreatic cancer by combining radiotherapy and CAR-T therapy, elucidating the mechanism of CAR-T cell-enhanced radiotherapy effects ex vivo, and highlighting a novel strategy for combating metastatic pancreatic cancer.

P1, N=29, Recruiting, Sichuan University | Not yet recruiting --> Recruiting

Besides, we analyzed the available clinical results and potential areas for future research on claudin18.2-positive gastric cancer and claudin18.2-targeting therapy. In conclusion, claudin18.2 is an ideal target for gastric cancer treatment, and the claudin18.2-targeting therapy has changed the treatment pattern of gastric cancer.

AZD6422 was safe and efficacious in patient-derived, CLDN18.2-positive murine models of gastrointestinal cancers. Our data support further clinical development of AZD6422 for patients with these cancers.

At the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, the final results of the phase 3 SPOTLIGHT trial were presented, demonstrating a significant survival benefit from the addition of the CLDN18.2-specific antibody zolbetuximab to chemotherapy in the first-line treatment of advanced gastroesophageal adenocarcinomas with ≥ 75% CLDN18.2 expression...In addition, several early-phase trials presented at ASCO 2024 investigate other CLDN18.2-targeting approaches in CLDN18.2-positive refractory advanced solid tumors, including the CLDN18.2-targeting antibody-drug conjugates LM-302 and IBI343, the bispecific anti-CLDN18.2/CD3 antibody IBI38, and the chimeric antigen receptor T cell therapy satricabtagene autoleucel. These novel approaches could potentially expand the benefit of CLDN18.2-targeting therapies to a broader range of tumor types and to tumors expressing lower levels of CLDN18.2.

P1, N=30, Recruiting, Second Affiliated Hospital of Guangzhou Medical University | Trial completion date: Aug 2026 --> Aug 2036 | Trial primary completion date: Aug 2024 --> Aug 2026

Satri-cel demonstrates therapeutic potential with a manageable safety profile in patients with CLDN18.2-positive advanced gastrointestinal cancer. ClinicalTrials.gov identifier: NCT03874897 .

Therefore, the synergistic secretion of CXCL10 and IL15 in these CAR-T cells enhances T cell recruitment and adaptability within tumor tissues, improving tumor control. This approach may offer a promising strategy for advancing CAR-T therapies in the treatment of solid tumors.

P1, N=20, Recruiting, CARsgen Therapeutics Co., Ltd. | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026

In patients with metastatic PC after progression on previous therapy, CT041 demonstrated a tolerable safety profile and encouraging anticancer efficacy signals. Response benefit observed here needs to be ascertained in the future.

In vivo, we established a xenograft GC model and observed the antitumor effects and off-target toxicity of CAR-T cells. These results support that synthetic anti-CLDN18.2 CAR-T cells have antitumor effect and anti-CLDN18.2-PD1/CD28 CAR could provide a promising design strategy to improve the efficacy of CAR-T cells in advanced gastric cancer.

P1, N=134, Completed, Peking University | Recruiting --> Completed

P1, N=12, Recruiting, Peking University

This manuscript briefly describes the Claudia protein, the dual roles of Cluadin18 in cancers, and summarizes the ongoing clinical trials targeting Claudin18.2 with a view to integrating the research progress of Claudin18.2 targeted therapy. In addition, this manuscript introduces the clinical research progress of Claudin18.2 positive pancreatic cancer, including monoclonal antibodies, bispecific antibodies, antibody-drug conjugates, CAR-T cell therapy, and hope to provide feasible ideas for the clinical treatment of Claudin18.2 positive pancreatic cancer.

Data from two phase III trials testing the anti-claudin 18.2 antibody zolbetuximab have established claudin 18.2-positive advanced-stage gastric cancers as an independent therapeutic subset that derives benefit from the addition of this agent to chemotherapy...This new development has resulted from drug developers moving beyond traditional targets, such as driver gene alterations or growth factors. In this Review, we highlight the biological rationale and explore the clinical activity of therapies that target claudin 18.2 in patients with advanced-stage gastric cancer and explore the potential for expansion of claudin 18.2-targeted therapies to patients with other claudin 18.2-positive solid tumours.

CLDN18.2-positive GC is associated with poor prognosis and worse immunotherapeutic outcomes. The combination of anti-CLDN18.2 therapy, anti-PD-L1/PD-1 therapy, and chemotherapy for GC requires further investigation.

Our studies suggested that ectopic CXCR2 played a significant and promising role in improving the efficiency of CAR-T therapy against primary and metastatic PDAC and partially reversed the immune-suppressive microenvironment.

This experience supports targeting Claudin18.2-positive GC with CAR T-cell therapy and helps to validate ctDNA as a biomarker in CAR T-cell therapy. Clinical Insight: Claudin18.2-targeted CAR T cells can safely provide complete objective and ctDNA response in salvage metastatic GC.

P1, N=96, Recruiting, Peking University | Not yet recruiting --> Recruiting

In gastric or gastroesophageal junction (GEJ) cancers, trastuzumab combined with first-line chemotherapy in human epidermal growth factor receptor 2 (HER2)-positive patients and ramucirumab combined with second-line paclitaxel remarkably prolonged overall survival (OS) compared with chemotherapy alone, according to phase 3 trial results. Global phase Ⅲ trials revealed that the addition of zolbetuximab to first-line chemotherapy prolonged OS in CLDN18.2-positive and HER2-negative GC patients. This review summarizes recent clinical trials of CLDN18.2-targeted therapy.

P1/2, N=110, Active, not recruiting, CARsgen Therapeutics Co., Ltd. | Recruiting --> Active, not recruiting | Phase classification: P1b/2 --> P1/2

After a conditioning regimen of fludarabine, cyclophosphamide, and nab-paclitaxel, patients were administered 1-3 cycles of satri-cel... The safety profile and therapeutic efficacy of satri-cel were shown to be promising in heavily pretreated patients with CLDN18.2-positive advanced GC/GEJ and PC. In the Phase 2 study, the first patient with GC received satri-cel in May 2023. Clinical trial information: NCT04404595.

No data analysis is available as of the submission deadline. Clinical trial information: NCT05862324.

P1, N=12, Not yet recruiting, Peking University

Overall, our study demonstrated that CXCR4 CAR-T cells could traffic more into tumor sites and meanwhile suppress MDSCs migration via STAT3/NF-κB/SDF-1α axis, to obtained better efficacy in CLDN18.2 positive pancreatic cancer. Our findings provide a theoretical rationale for CXCR4 CAR-T cell therapy in PDAC.

P1, N=29, Not yet recruiting, Sichuan University

P1, N=18, Recruiting, Suzhou Immunofoco Biotechnology Co., Ltd | Not yet recruiting --> Recruiting

Patients received a pre-conditioning regimen of fludarabine, cyclophosphamide, and 100mg/m2 nab-paclitaxel before CT041 CAR-T infusion...Results A 57-year-old man with metastatic gastric cancer to the liver (HER2 negative, PD-L1 CPS 10%) progressed after 5 cycles of FOLFOX+Nivolumab and 4 cycles of FOLFIRI/Ramucirumab...Again, he had G1 CRS with fever, which was resolved without tocilizumab...Conclusions Repeated dosing of anti-claudin 18. 2 CAR-T cells (CT041) was safe and deepened tumor response was observed after repeated dosing.

2 and TGFβ levels as determined by IHC. Conclusions Taken together, the selection of CAR-T design which provided therapeutic margin in relevant murine models, addition of armoring and optimization of manufacturing enabled generation of a lead molecule which provides efficacy in relevant cell line and patient derived xenograft models of gastric, pancreatic and esophageal cancers and supports further clinical development of AZD6422.

Patient experienced grade 2 CRS, which was controlled with tocilizumab...Elevating IL-8 and declining TGF-β1 were also observed. The tumor is still under well control until the last follow-up on July 18, 2023.

P1, N=20, Recruiting, CARsgen Therapeutics Co., Ltd. | Not yet recruiting --> Recruiting

We further demonstrated that recurrent tumors following H9 CAR-IL15 T-cell therapy downregulated CLDN18.2 expression, suggesting immune escape through the selection of antigen-negative cells under persistent CAR-T-cell immune pressure. In conclusion, our findings provide preclinical evidence supporting the clinical evaluation of IL-15-expressing CLDN18.2 CAR-T cells in patients with CLDN18.2-positive tumors.

P1, N=34, Terminated, Shanghai East Hospital | N=64 --> 34 | Trial completion date: Jun 2026 --> Jul 2023 | Recruiting --> Terminated | Trial primary completion date: Dec 2023 --> Jul 2023; Both the sponsors and collaborator are considering terminating the study

P1, N=96, Not yet recruiting, Peking University

Table: 1054P Overview of clinical and biomarker results for each individual patient Conclusions IBI345 demonstrated a manageable safety profile and preliminary efficacy in patients with CLDN18.2+ advanced solid tumors. To realize the full potential of this modular CAR-T cell product, the dose and regimen of the P329G Ab and CAR-T cells requires further exploration.

P=N/A, N=9, Recruiting, The Affiliated Hospital of Qingdao University

P1, N=18, Not yet recruiting, Suzhou Immunofoco Biotechnology Co., Ltd

P1, N=20, Not yet recruiting, CARsgen Therapeutics Co., Ltd.

P1, N=63, Recruiting, Peking University | Not yet recruiting --> Recruiting

P1, N=7, Completed, Innovent Biologics (Suzhou) Co. Ltd. | Recruiting --> Completed | N=30 --> 7 | Trial completion date: Dec 2023 --> Jan 2023 | Trial primary completion date: Dec 2023 --> Oct 2022