Engineering a juxtamembrane-targeting CAR T-cell against mesothelin: a novel binder resilient to shed antigen for enhanced efficacy against ovarian and pancreatic cancer

To develop CAR T cells that target the juxtamembrane region of mesothelin, overcoming challenges posed by antigen shedding in cancer therapies.

CAR T Cell Development: Utilized phage display-derived antibodies specific for the mesothelin stump domain to create CAR T cells (CAR 422) that are unaffected by mesothelin shedding.
Preclinical Evaluation: Assessed the cytotoxicity and in vivo activity of CAR 422 T cells against tumor cells, including those resistant to conventional anti-mesothelin CAR T cells.

CAR 422 T cells demonstrated comparable cytotoxicity and in vivo activity to previously studied anti-mesothelin CAR T cells.
CAR 422 was effective against tumor cells resistant to conventional anti-mesothelin CAR T cells.
Reduced on-target/off-tumor toxicity was observed in a human mesothelin knock-in mouse model.

The study primarily focuses on preclinical models, and clinical efficacy remains to be evaluated in human trials.