This study systematically reveals the significant gastric toxicity of CLDN18.2-targeted CAR-T cell therapy in gastric cancer through clinical observations and mouse models, proposing that reducing CAR binding affinity can effectively widen the therapeutic window, providing a new strategy for optimizing CAR-T therapy for solid tumors.
Literature Overview
This article titled 'Modeling and addressing on-target/off-tumor toxicity of claudin 18.2 targeted immunotherapies' published in Nature Communications reviews and summarizes the gastric toxicity issues associated with immune therapies targeting CLDN18.2, a gastric cancer-related antigen. The research team validated the 'on-target/off-tumor' mechanism of this toxicity through clinical data and mouse models, and explored the impact of different CAR domains on antigen affinity to optimize the therapeutic window.
Background Knowledge
CLDN18.2 is a transmembrane protein specifically expressed in gastric epithelial cells and is highly expressed in multiple solid tumors such as gastric cancer, pancreatic cancer, and esophageal cancer, making it an important target for tumor immunotherapy. However, due to its continued expression in normal gastric epithelium, immune therapies targeting this antigen, such as Zolbetuximab and CT041 CAR-T cell therapy, often result in gastric toxicity, limiting their clinical application. Currently, how to maintain antitumor efficacy while reducing toxicity to normal tissues remains a major challenge in this field. This study systematically evaluates the impact of different binding domain affinities on toxicity and efficacy through the construction of mouse models, providing a theoretical basis for the design of next-generation CAR-T cell therapies.
Research Methods and Experiments
The research team observed 58 gastric cancer patients receiving Zolbetuximab treatment in the clinic, evaluating gastric mucosal damage through endoscopy, and conducted experimental validation using scFv CAR-T cells derived from CT041 in mouse models. Additionally, the researchers developed fully human VH single-domain CAR-T cells and analyzed their binding kinetics using surface plasmon resonance (SPR), comparing the impact of different affinities on gastric toxicity and antitumor activity.
Key Conclusions and Perspectives
Research Significance and Prospects
This study provides direct evidence for the toxicity mechanisms of solid tumor CAR-T therapy and proposes strategies to improve the therapeutic window by optimizing CAR binding affinity. Future research could further explore how to combine dual-targeting strategies (e.g., AND logic gate) or genetic engineering modifications (e.g., conditional expression, armored modifications) to enhance tissue specificity of CAR-T cells, while also evaluating the impact of different co-stimulatory domains on antibody-dependent cellular cytotoxicity or antitumor responses.
Conclusion
This study systematically revealed the gastric toxicity induced by CLDN18.2-targeted immunotherapy in gastric cancer patients and mouse models, proposing a strategy to alleviate toxicity while maintaining efficacy by reducing CAR binding affinity. The results emphasize the need to evaluate the balance between toxicity and efficacy in preclinical models for CLDN18.2-targeted CAR-T cell therapy to avoid severe adverse reactions. Additionally, this study provides new insights for the design of immunotherapies for solid tumors, including combining low-affinity CARs with enhanced signaling or dual-targeting strategies to achieve higher safety and effectiveness. These findings have significant guiding value for the development of next-generation immunotherapeutic drugs.
