Modeling and Addressing On-Target/Off-Tumor Toxicity of Claudin 18.2 Targeted Immunotherapies
Claudin 18.2 (CLDN18.2) has become a promising target for upper gastrointestinal (GI) cancer therapies, including treatments like Zolbetuximab, a naked antibody recently approved, and CT041, a second-generation CAR T cell therapy showing encouraging clinical results. However, both therapies have been linked to gastrointestinal toxicities.
Clinical Observations of Toxicity
Evidence from patients treated with CLDN18.2-targeted immunotherapies shows occurrences of erosive gastritis.
Clinical Zolbetuximab treatment has been associated with cases of gastric erosive lesions.
Preclinical Modeling and CAR Development
The authors developed and characterized fully human VH-only single domain CARs targeting CLDN18.2. Their research demonstrates that a CAR with lower affinity effectively reduces on-target/off-tumor toxicity while maintaining anti-tumor efficacy in gastric cancer models.
A lower affinity CAR mitigates on-target/off-tumor toxicity while preserving anti-tumor effects in gastric cancer models.
Challenges in Extending Immunotherapies to Solid Tumors
One of the main hurdles is the "antigen dilemma": many solid tumor target antigens are also present on normal tissues from the tumor's origin, increasing the risk of toxicity.
Preclinical Toxicity Characterization
Using a mouse model with CT041-scFv derived CAR T cells, on-target/off-tumor gastric toxicity from CLDN18.2 targeting was successfully demonstrated and characterized.
Summary
Addressing on-target/off-tumor toxicity is crucial for effective and safe use of CLDN18.2-targeted therapies in GI cancers, with affinity-tuning of CARs offering a promising strategy.
Author's summary: Lower affinity CLDN18.2-targeted CAR T cells reduce gastrointestinal toxicity without compromising anti-tumor efficacy, advancing safer immunotherapy options for gastric cancer.