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Updated: Jan 12, 2026
A Syngeneic Mouse B-Cell Lymphoma Model for Pre-Clinical Evaluation of CD19 CAR T Cells
Published on: October 16, 2018
On-target off-tumor toxicity of claudin18.2-directed CAR-T cells in preclinical models
Filippo Birocchi1,2,3, Antonio J Almazan1,2, Aiyana Parker1,2
1Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
Abstract:
Claudin 18.2 (CLDN18.2)-targeted CAR-T cell therapies have shown promising clinical efficacy in gastric cancer. However, early-phase trials have reported gastrointestinal adverse events due to on-target off-tumor recognition of CLDN18.2 in the gastric mucosa. By leveraging shared CLDN18.2 epitopes and expression in humans and mice, we establish an in vivo model that replicates the on-target off-tumor toxicity of CLDN18.2 CAR-T. Our findings confirm that this toxicity is independent of the CAR construct's design, co-stimulatory domain, and tumor model. Additionally, we demonstrate the utility of this model in testing strategies to mitigate on-target toxicity, such as Boolean-logic AND-gate approaches. Our results offer insights into the use of mouse models that recapitulate on-target off-tumor toxicities, with the caveat that although we are often concerned that models will undercall toxicities in humans, they may also overcall the incidence and severity of toxicities, prematurely discarding promising therapeutic agents from further clinical development.
Insights
A new mouse model replicates Claudin 18.2 CAR-T cell therapy toxicities in gastric cancer. This model helps evaluate strategies to reduce gastrointestinal side effects, improving future cancer treatments.
Area of Science:
- Immunology
- Oncology
- Gastroenterology
Background:
- Claudin 18.2 (CLDN18.2)-targeted CAR-T cell therapies show promise for gastric cancer.
- Gastrointestinal adverse events have been observed due to on-target off-tumor recognition of CLDN18.2.
Purpose of the Study:
- To establish and validate an in vivo mouse model that accurately replicates CLDN18.2 CAR-T on-target off-tumor toxicity.
- To assess the utility of this model in evaluating toxicity mitigation strategies.
Main Methods:
- Leveraged shared CLDN18.2 epitopes and expression in humans and mice.
- Developed a CLDN18.2 CAR-T in vivo model.
- Tested toxicity mitigation strategies, including Boolean-logic AND-gate approaches.
Main Results:
- The established mouse model successfully replicated CLDN18.2 CAR-T on-target off-tumor toxicity.
- Toxicity was independent of CAR construct design, co-stimulatory domain, and tumor model.
- The model demonstrated utility in testing toxicity mitigation strategies.
Conclusions:
- The developed mouse model is a valuable tool for studying and mitigating CLDN18.2 CAR-T on-target off-tumor toxicities.
- Caution is advised as mouse models may overcall or undercall toxicities compared to human trials, potentially impacting therapeutic development.
