Nature Cancer: CDH17 (LI-cadherin), a safe target for CAR-T in the treatment of neuroendocrine tumors and gastrointestinal stromal tumors

Gastrointestinal tumors (GIC, includinggastric cancer , pancreatic cancer ,colorectal cancer ) and neuroendocrine tumors (NETs) are often fatal after metastasis

To date, FDA - approved CAR-T therapies have targeted tumor-associated antigens (TAAs), such as CD19, which are also expressed in certain normal cells, resulting in the elimination of normally antibody-producing B cells, requiring injections of human IgG to rescue

On March 21, researchers at the Perelman School of Medicine at the University of Pennsylvania published their latest study in Nature Cancer, including Carl June

First, to overcome the limitations of the lack of valuable TAAs and cognate monoclonal antibodies, we developed an unbiased phage display screening method to identify camelid-derived single domains that preferentially bind to the cell surface of GI-NETs Antibodies (nanobodies, VHH) and isolated VHH1 that specifically binds to NETs

Based on the findings of the first step, the researchers developed a CDH17-targeting nanobody VHH1-driven CAR-T (CDH17CART)

Source: Nature Cancer

Notably, CDH17 CART does not attack normal intestinal epithelial cells that also express CDH17 to cause toxicity

Further studies revealed that CDH17 was only localized and restricted to the lateral membranes of tight junctions between intestinal epithelial cells, and was not expressed on the apical or basal surfaces (k, n below)

At present, Boehringer Ingelheim’s TRAILR2/CDH17 bispecific antibody BI 905711 has the fastest progress in research on CDH17 targets, which is in Phase I/II clinical stage