Chimeric-antigen Receptor (CAR) T cells and bi-specific T cell engagers (BiTEs) are forms of immune therapies that harness the power of T cells to fight against cancer. However, despite the clinical success of these approaches in blood cancers, tumour antigen heterogeneity remains a major challenge in treating solid tumours.
Using CRISPR/Cas9 combined with AAV6-mediated Homology-directed repair (HDR) technology, we engineered HER2 (human epidermal growth factor receptor 2)-targeting CAR T cells to secret an anti-mEpCAM (mouse epithelial cellular adhesion molecule)/CD3 BiTE under the control of the NR4A2 promoter. These CAR T cells (1) exhibited superior tumour suppression with increased activation of endogenous T cells compared to control CAR T cells without BiTE, and (2) had a five-times improved safety profile compared to CAR T cells with a constitutive expression of BiTE.
In conclusion, a new generation of CAR T cells armed with BiTE which targets a second antigen was developed using CRISPR/HDR technology. This could not only prompt a tumour-localised secreting of BiTEs/nanobodies of desire but also allow the usage of BiTEs/nanobodies that were too toxic when given systemically.