CAR T cells targeting mesothelin for treating intrahepatic cholangiocarcinoma

Authors

• I Shats
• H Wang
• Y Zhou
• C Gu
• R Blind
• X Wang
• X Li

Abstract

In the US and the rest of the world, intrahepatic cholangiocarcinoma (iCCA) is a major type of liver cancer. iCCA is one of the most common cancers in Thailand, where there is an endemic of the liver fluke. We previously reported that mesothelin (MSLN) was highly expressed in over 30% of iCCA and suggested that MSLN might be a promising therapeutic target in iCCA. The MSLN CAR T cells have been developed against several MSLN-expressing solid tumors. However, this strategy has not been extensively evaluated for treating iCCA. The present study aims to evaluate the anti-tumor effect of MSLN CAR T cells based on the humanized rabbit antibodies with various specificities and affinities in iCCA models. We developed MSLN CAR T cells against membrane-proximal epitope (hYP218), membrane-middle epitope (hYP223), membrane-distal epitope (HN1 and hYP158), and membrane-conformation epitope (hYP3). Their anti-tumor activity was evaluated in vitro using MSLN-positive iCCA cell lines. Among CAR T cell constructs, hYP218 CAR T cells targeting membrane-proximal epitope are the most effective against CCA cell lines. A single intravenous injection of hYP218 CAR T cells eliminated tumors in mice within two weeks. In conclusion, the current results demonstrate that MSLN CAR T cells targeting membrane-proximal epitope are very effective against iCCA. Ongoing studies are to establish iCCA tumor models in mice for testing the efficacy of CAR T cells in vivo.

Scientific Focus Area: Cell Biology

This page was last updated on Monday, September 25, 2023