An Inducible Caspase-9 Suicide Gene to Increase the Safety of a Novel Off-The-Shelf CAR immunotherapy for prostate cancer

Chimeric antigen receptor (CAR) cell immunotherapy is a revolutionary new pillar of adoptive cell therapy in cancer treatment. Despite the great success of CAR-T therapy in hematological malignancies, many challenges limit the therapeutic efficacy and safety of CAR-T cells in solid and hematological cancers. Even though CAR-T cell therapy represents a valid therapeutic strategy, it may induce severe toxicities, the most common being cytokine release syndrome (CRS) and CAR-T cell-related encephalopathy syndrome (CRES). Moreover, other potential issues involve the unpredictable on-target off-tumor toxicity, uncontrolled expansion, damage of normal organs and malignant transformation. Considering these shortcomings, there is increasing and intense interest in studying a suicide gene technology that can provide a valuable “safety switch” in this at-risk clinical condition, enabling the targeted elimination of inappropriately activated CAR cells. Inducible caspase 9 (iC9) system is a suicide gene able to be activated upon the binding with an inert small biomolecule, as the chemically induced dimerizer AP20187. When exposed to this synthetic drug, the inducible iC9 becomes activated and rapidly drives the apoptotic pathway of cells expressing this construct. In the following study, we evaluated the inclusion of the iC9 gene in the CAR construct as a short-term safety switch of anti-hPSMA CAR/NK92 lymphoma cells to eliminate aberrant cells and enhance the safety and applicability of cellular therapy. The results show that the CAR/NK92 cell inactivation system mediated by the iC9 system is an effective safety system capable of inducing cell apoptosis within short time frames and thus possibly preventing the toxicity of the undesirable effects associated with this therapy.