Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality

L Poirot(2) S Das(1) J Sumin(1) S Dharani(1) P Duchateau(2) J Valton(2)

1:Cellectis Inc, New York, NY, USA; 2:Cellectis, Paris, France

Adoptive cell therapy based on chimeric antigen receptor-engineered T (CAR-T) cells has proven lifesaving for many cancer patients. However, its therapeutic efficacy is restricted to only a few malignancies, with solid tumors proving to be especially recalcitrant to safe therapy. Poor intra-tumor infiltration by T cells and T cell dysfunction due to an immunosuppressive microenvironment are key barriers against CAR-T cell success against solid tumors. Furthermore, boosting CAR-T cells uncontrollably would raise safety concerns. We present here T cell engineering strategies that illustrate how endogenous genes can be repurposed to improve persistence and potency of allogenic CAR-T cells in a tumor-specific manner using TALEN®-based gene editing.