Dual targeting chimeric antigen receptor cells enhance antitumour activity by overcoming T cell exhaustion in pancreatic cancer

Abstract

Background and PurposeAlthough our previous data indicated that claudin 18 isoform 2 (CLDN18.2)‐targeted chimeric antigen receptor (CAR) T cells displayed remarkable clinical efficacy in CLDN18.2‐positive gastric cancer, their efficacy is limited in pancreatic ductal adenocarcinoma (PDAC). The tumour microenvironment (TME) is one of the main obstacles to the efficacy of CAR‐T and remodelling the TME may be a possible way to overcome this obstacle. The TME of PDAC is characterized by abundant cancer‐related fibroblasts (CAFs), which hinder the infiltration and function of CLDN18.2‐targeted CAR‐T cells. The expression of fibroblast activation protein alpha (FAP) is an important feature of active CAFs, providing potential targets for eliminating CAFs.Experimental ApproachIn this study, we generated 10 FAP/CLDN 18.2 dual‐targeted CAR‐T cells and evaluated their anti‐tumour ability in vitro and in vivo.Key ResultsCompared with conventional CAR‐T cells, some dual‐targeted CAR‐T cells showed improved therapeutic effects in mouse pancreatic cancers. Further, dual‐targeted CAR‐T cells with better anti‐tumour effect could suppress the recruitment of myeloid‐derived suppressor cells (MDSCs) to improve the immunosuppressive TME, which contributes to the survival of CD8+ T cells. Moreover, dual‐targeted CAR‐T cells reduced the exhaustion of T cells in transforming TGF‐β dependent manner.Conclusion and ImplicationsThe dual‐targeted CAR‐T cells obtained enhancement of T effector function, inhibition of T cell exhaustion, and improvement of tumour microenvironment. Our findings provide a theoretical rationale for dual‐targeted FAP/CLDN 18.2 CAR‐T cells therapy in PDAC.