P1.087. Advancing Immunotherapy in Oesophagogastric Cancer: A Systematic Review of CLDN18.2-Targeted CAR T-Cell and T-Cell Engager Strategies

Abstract

Abstract Topic Esophageal Cancer: Adjuvant and Neo-Adjuvant Therapies Background Conventional immunotherapy strategies have shown limited efficacy in oesophagogastric adenocarcinomas compared to other solid tumours. CLDN18.2-targeted chimeric antigen receptor T cells (CAR-T) and bispecific T-cell engagers (TCEs) represent emerging therapeutic strategies for advanced oesophagogastric cancers, yet their safety profiles and efficacy remain poorly characterized. This systematic review integrates early-phase outcomes across CLDN18.2-directed clinical studies. Methods A systematic review was conducted in accordance with PRISMA 2020 guidelines, with searches of PubMed, Embase, the Cochrane Library, and clinical trials registries including ClinicalTrials.gov from inception to 2025 using predefined eligibility criteria. Extracted parameters included 1) safety events—cytokine release syndrome (CRS), cytopenias, gastrointestinal toxicities—2) short-term efficacy outcomes including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and radiological and/or biomarker-based responses. Study designs, dose levels and relevant translational correlates (e.g., CLDN18.2 expression thresholds, pharmacodynamic activation markers) were reviewed to contextualize therapeutic activity across modalities. Only gastric and GEJ adenocarcinomas were included. Results Seven early-phase studies of CLDN18.2-directed CAR-T and T-cell–engager therapies were identified. Meta-analysis was not feasible due to heterogeneity in dose levels, populations, and reporting formats. Across these studies, 396 treated patients were included, predominantly pre-treated (≥2 prior lines), with median ages 52–63 years and a male:female distribution of 230:152. Eligibility often required CLDN18.2 IHC ≥2+ with ≥40% tumour cells, though broader thresholds appeared in early dose-escalation cohorts. CRS was common but mainly low-grade: CAR-T studies showed 76–100% grade 1–2 CRS with rare grade ≥3, while IBI389 reported 57% CRS with 0.9% grade. No neurotoxicity occurred across any program. Hematologic cytopenias were more pronounced with CAR-T. CT041 Phase 2 improved PFS (HR 0.37) with ORR 22% and DCR 41%. LB1908 showed ORR 66.6% and DCR 93.3%, while TCE studies demonstrated ORRs 16–31% with favourable tolerability. Conclusion CLDN18.2-directed CAR T-cell therapies and T-cell engagers demonstrate favorable safety profiles with encouraging short-term efficacy across early-phase studies. Comparative signals suggest TCE's may be safer than CAR-T therapies, showing lower rates of high-grade CRS and toxicity. However, thresholds for CLDN18.2 positivity remain undefined, and inclusion criteria require standardization to ensure consistency across trials and clinical practice. These findings support further evaluation through randomised controlled trials in UK and Western healthcare settings to confirm clinical utility, refine comparative effectiveness, and improve patient access. If validated, these therapies may benefit patients unresponsive to standard immunotherapies.