Cancers of the oesophagus and stomach are the 8th most common cancers worldwide and have the 6th highest mortality rate of all cancers. This is mainly due to the high rate of metastatic disease at diagnosis, for which effective treatments are lacking, highlighting the dire need for novel therapies that can improve patient survival. Tumour-associated glycoprotein-72 (TAG-72) is highly expressed in adenocarcinomas, including gastro-oesophageal cancers, but not in normal cells, making it a viable target for chimeric antigen receptor(CAR)-cell based therapies. CAR-NK cell therapy offers potential advantages that may overcome some of the limitations associated with autologous CAR-T cell therapy, including graft-versus-host disease and accessibility for patients.
In this study, we utilised unique iPSC-derived CAR-NK cells developed by Cartherics, which have been genetically engineered to express a CAR targeting TAG-72. The expression of TAG-72 in our gastro-oesophageal adenocarcinoma cell lines and patient derived xenografts was assessed using flow cytometry and immunohistochemistry. The efficacy of the CAR-iNK cells was evaluated in vitro through cytotoxicity assays against TAG-72 positive gastro-oesophageal cancer cell lines, followed by in vivo testing in our various xenograft models.
TAG-72 was found to be highly expressed in many of our models, validating its potential as a therapeutic target in gastro-oesophageal adenocarcinoma. In vitro assays demonstrated that iNK cells kill tumour cells in a dose-dependent manner, regardless of the CAR expression. Moreover, iNK cells displayed similar cytotoxicity against both TAG-72 -positive and -negative gastro-oesophageal cancer cell lines. In vivo biodistribution studies indicate that iNK cells can survive in the mouse environment, with detectable levels in both primary and metastatic in vivo models, with promising indications of trafficking inside the tumour-microenvironment. These preliminary findings indicate that CAR-iNK cells may possess strong tumour-targeting capabilities, providing a strong foundation and insights that will guide the optimisation of future in vivo efficacy studies.