Chimeric antigen receptor (CAR) T cell therapy, while highly efficacious for the treatment of certain haematological malignancies, remains ineffective in solid cancers. This can be attributed to various factors, including immunosuppression in the tumour microenvironment (TME), heterogeneous expression of targetable tumour antigens and limited trafficking of CAR T cells into the tumour. Recent advances in CRISPR/Cas9 gene editing for primary T lymphocytes have presented new avenues for the precise engineering of armoured CAR T cells. CRISPR/Cas9 mediated knockout to ‘delete’ immunosuppressive pathways or use of CRISPR/Cas9 KI to “Armour” CAR T cells are promising strategies to address their limitations in the solid tumour setting.
Using a combination of syngeneic murine CAR T and xenograft human CAR T cell models, our lab have developed several CRISPR/Cas9 based approaches that enhance the efficacy of CAR T cell therapy and are clinically applicable given CRISPR-edited CAR T cells are currently under clinical investigation. These approaches include those designed to activate endogenous immunity, which we believe is a key element of success for CAR T cell therapy in the setting of solid tumours.