Modeling and addressing on-target/off-tumor toxicity of claudin 18.2 targeted immunotherapies

Area of Science:

• Oncology
• Immunotherapy
• Gastroenterology

Background:

• Extending immunotherapy to solid tumors faces challenges like the "antigen dilemma," where target antigens are also on normal tissues.
• Claudin 18.2 (CLDN18.2) is a key target for upper gastrointestinal cancers, with therapies like Zolbetuximab and CAR T cells showing promise but causing GI toxicities.

Purpose of the Study:

• To investigate the mechanisms of CLDN18.2-targeting immunotherapies and their associated toxicities.
• To develop novel CLDN18.2-targeting CAR T cells with an improved therapeutic window.

Main Methods:

• Analysis of clinical cases of Zolbetuximab-associated gastric erosions.
• Preclinical characterization of on-target/off-tumor toxicity using a mouse model of CLDN18.2-targeting CAR T cell therapy.
• Development and testing of fully-human VH-only single domain CARs with varying affinities.

Main Results:

• Clinical data confirmed gastric erosive lesions associated with Zolbetuximab treatment.
• Preclinical models demonstrated on-target/off-tumor gastric toxicity with CLDN18.2-targeting CAR T cells.
• Lower affinity CLDN18.2 CAR T cells showed reduced toxicity while maintaining anti-tumor efficacy.

Conclusions:

• On-target/off-tumor toxicity in CLDN18.2-targeted therapies is a significant concern.
• CAR T cell affinity is a critical factor in balancing efficacy and toxicity.
• Developing lower-affinity CLDN18.2 CARs may offer a safer therapeutic strategy for upper GI cancers.