Definition

A preparation of off-the-shelf (OTS), allogeneic and ex vivo expanded natural killer cells (NKs) that are engineered to express membrane-bound IL-15 (mbIL15) and a chimeric antigen receptor (CAR) encoding for human natural-killer group 2, member D receptor protein (NKG2D; KLRK1; natural killer cell activating receptor group 2D) that is coupled to the co-stimulatory domain of OX40 (CD134), and to the zeta chain of the TCR/CD3 complex (CD3-zeta; CD3zeta), with potential immunomodulating and antineoplastic activities. Upon transfusion of the allogeneic NKG2D-OX40-CD3zeta-CAR-mbIL-15-expressing NKs NKX101, these cells specifically target and bind to tumor cells expressing NKG2D ligands (NKG2DL). This induces secretion of pro-inflammatory cytokines and results in the lysis of NKG2DL-expressing tumor cells. In addition, these cells target, bind to and kill NKG2DL-expressing tumor-associated endothelial cells in the neovasculature and immunosuppressive cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) that express NKG2D ligands. IL-15 is a pro-survival cytokine that potentiates the immune response against tumor cells. NKG2D ligands are overexpressed in a variety of cancer cells.