Inclusion of the inducible Caspase 9 suicide gene in CAR construct to increase the efficacy and safety of an off-the-shelf CAR-NK cancer immunotherapy

The project aims to produce a safe, cheap, and universal off-the-shelf platform for prostate cancer adoptive immunotherapy. Despite the exciting results obtained with the study of the second-generation NK92/CAR anti-hPSMA, this approach needs improvement to enhance the efficacy of the NK92/CAR cells in vivo and to improve the safety profile. In this study, we investigate the inclusion of the inducible caspase 9 (iC9) suicide gene in the CAR construct design as a safety switch-off of the system and of the IL-2 cassette to sustain NK92/CAR cell proliferation. Our preliminary results demonstrate that NK92/CAR anti-hPSMA cells represent a universal, off-the-shelf and cost-effective adoptive cell therapy. The inclusion of the iC9 suicide gene results in a safe NK92/CAR product that can be activated in the case of uncontrolled cell proliferation, therapy-associated toxicity or even in the presence of cells that escape the irradiation. This study demonstrates the validation of a safety system that can be introduced in different cell types targeting different tumoral antigens. Our prospect is the clinical administration of NK92/CAR cells with the inclusion of a suicide gene without prior irradiation to enhance the anti-tumour effect without losing the safety control of the therapy.