Potential lung attack and lethality generated by EpCAM-specific CAR-T cells in immunocompetent mouse models

Area of Science:

• Immunology
• Oncology
• Cell Therapy

Background:

• Current evaluation of human CAR-T cells uses immune-deficient models, which poorly mimic clinical adverse effects.
• Epithelial cell adhesion molecule (EpCAM) is a promising target for CAR-T therapy due to its presence on various carcinomas.

Purpose of the Study:

• To develop and evaluate an anti-mouse EpCAM CAR-T therapy in immunocompetent models.
• To assess the safety and efficacy of EpCAM CAR-T cells, including potential toxicities.

Main Methods:

• Development of murine EpCAM CAR-T cells.
• In vitro and in vivo testing of anti-tumor efficacy in immunocompetent mice.
• Evaluation of dose-dependent toxicities and pathological examination.

Main Results:

• Murine EpCAM CAR-T cells demonstrated significant anti-tumor efficacy in vitro and in vivo.
• Dose-dependent toxicities, including cytokine-release syndrome (CRS) and mortality, were observed.
• Severe pulmonary immunopathology resulted from EpCAM expression in normal lung tissue.

Conclusions:

• EpCAM CAR-T therapy exhibits potent anti-tumor activity but carries risks of lethal toxicity.
• Basal EpCAM expression in normal organs like the lung can lead to severe adverse events.
• Careful evaluation is necessary before clinical application of EpCAM CAR-T for solid tumors.