allogeneic PD-L1 tumor-targeted high-affinity natural killer cells

A preparation of natural killer (NK) cells that are derived from NK-92 cells, a human cytotoxic cell line composed of allogeneic NK cells derived from a 50-year old male patient with rapidly progressive non-Hodgkin's lymphoma (NHL), that are genetically engineered to express the high-affinity CD16/FcgammaRIIIa (158V) allele, endoplasmic reticulum (ER)-retained interleukin (IL)-2 and a chimeric antigen receptor (CAR) specific for programmed death-ligand 1 (PD-L1), with potential immunomodulating, cytolytic and antineoplastic activities. Upon infusion of the PD-L1 tumor-targeted high-affinity (ha) NK cells, the NK cells recognize and bind to tumor cells, preferentially to PD-L1-expressing tumor cells and human peripheral myeloid-derived suppressor cells (MDSCs). This leads to the secretion and release of perforins, granzymes, cytokines and chemokines, and results in cancer cell lysis and apoptosis. In addition, the incorporation of the high-affinity CD16 allele allows the NK cells to lyse tumor cells via antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by tumor-antigen-specific immunoglobulin G1 (IgG1) antibodies through binding of CD16 with the Fc region of human IgG1 antibodies. IL-2 replenishes the granular stock of NK cells, leading to enhanced perforin- and granzyme-mediated lysis of tumor cells.