Figure 4.

Other advanced genetic modification strategies. Other non-CAR structure-based genetic modifications have also been explored to improve NK cytotoxicity and in vivo persistence. For example, the introduction of high-affinity non-ADAM17 cleavable CD16 (hnCD16) or CD64 significantly enhances the affinity of NK cells to the tumor-targeting antibodies (Abs), thereby improving antibody-dependent cell-mediated cytotoxicity (ADCC). TCR NK cells achieve similar tumor control as redirected T-cells while retaining their NK cell function. Targeting TGF-β signaling or transducing activating receptors (DNAM-1, NKG2D) can tilt NK cells toward activation. Strategies to improve in vivo persistence mainly focus on maintaining the viability and quantity of NK cells. Under low cytokine concentration, possible methods to maintain cell vitality include the deletion of CISH or the expression of c-MPL or EPOR. Prolonged persistence can also be achieved by deleting the endogenous CD38 or MHC-I of NK cells so that the infused NK cells are undetectable to the daratumumab (DARA) or the recipient’s T-lymphocytes.