Modeling and Addressing On-Target/Off-Tumor Toxicity of Claudin 18.2 Targeted Immunotherapies
Claudin 18.2 (CLDN18.2) has become a key target for treating upper gastrointestinal (GI) cancers. Therapies such as Zolbetuximab, a recently approved naked antibody, and CT041, a second-generation chimeric antigen receptor (CAR) T cell therapy, are based on this target. However, both treatments have reported gastrointestinal toxicities linked to on-target/off-tumor effects.
Clinical Evidence of Toxicity
Cases of erosive gastritis have been observed in patients receiving Zolbetuximab, indicating a significant side effect tied to CLDN18.2 targeting therapies.
Clinical treatment with Zolbetuximab has been associated with gastric erosive lesions.
Preclinical Insights and CAR T Cell Development
Researchers have developed fully human VH-only single domain CARs targeting CLDN18.2 and studied their effects in gastric cancer models. They found that a CAR with lower affinity reduces on-target/off-tumor toxicity while maintaining strong anti-tumor activity.
A lower affinity CAR mitigates on-target/off-tumor toxicity while preserving anti-tumor efficacy in gastric cancer models.
In a preclinical mouse model reflecting the CT041 CAR T cell therapy derived from a single-chain variable fragment (scFv), the on-target/off-tumor gastric toxicity was thoroughly characterized, providing further insights for safer immunotherapy design.
Challenges in Solid Tumor Immunotherapy
- Extending immunotherapies to solid tumors must overcome the “antigen dilemma,” where the target antigen is present on both tumor and normal tissues from the same organ.
- Addressing on-target/off-tumor toxicities is essential for the safe application of CAR T cell therapies.
Implications for Future Therapy Development
The study emphasizes the importance of fine-tuning CAR affinity to balance efficacy and safety, paving the way for improved immunotherapies against solid tumors expressing CLDN18.2.
Successfully extending immunotherapies to solid tumors requires addressing the antigen dilemma, especially when the tumor antigen is also expressed on normal tissue.
Author’s summary: Refining CAR affinity for CLDN18.2 offers a promising approach to reduce gastric toxicity without compromising the effectiveness of immunotherapies in gastrointestinal cancer.