iPSC-derived anti-BCMA CAR/CD16/IL-15RF-expressing CD38-eliminated NK cells FT576

An allogeneic, off-the-shelf, natural killer (NK) cell product derived from a clonal master induced pluripotent stem cell (iPSC) line, and engineered and multiplex-edited to express a chimeric antigen receptor (CAR) specific for the tumor-associated antigen (TAA) B-cell maturation antigen (BCMA; tumor necrosis factor receptor superfamily member 17; TNFRSF17), a high-affinity, non-cleavable CD16 (hnCD16) Fc receptor and a recombinant fusion of IL-15 and IL-15 receptor alpha (IL-15RF), and to eliminate CD38 expression, with potential immunostimulatory and antineoplastic activities. Upon administration, iPSC-derived anti-BCMA CAR/CD16/IL-15RF-expressing CD38-eliminated NK cells FT576 recognize, bind to and induce selective cytotoxicity in BCMA-expressing tumor cells, leading to tumor cell lysis and the release of tumor neoantigens. Additionally, FT576 NK cells secrete inflammatory cytokines and chemokines, thereby enhancing T-cell activity and recruitment to the tumor site. BCMA, a receptor for both a proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF), is a member of the tumor necrosis factor receptor superfamily (TNFRSF). BCMA is found on the surfaces of plasma cells, is overexpressed on malignant plasma cells and plays a key role in plasma cell proliferation and survival. IL-15RF promotes the survival of NK cells and enhances the cytotoxic effect of the NK cells and the activated anti-tumor T cells. When used in combination with monoclonal antibodies, the hnCD16 Fc receptor of FT576 binds to the Fc portion of tumor cell-bound monoclonal antibodies, leading to NK cell activation, cytokine secretion and enhanced antibody-dependent cellular cytotoxicity (ADCC). CD16, also known as Fc-gamma receptor III, is normally expressed on the surface of NK cells, neutrophils, monocytes and macrophages, and plays a key role in initiating ADCC. It is often downregulated in certain cancers, thereby inhibiting the anti-tumor immune response. The lack of CD38 in FT576 NK cells prevents NK cell fratricide upon co-administration with a CD38-targeting monoclonal antibody as CD38 is normally expressed on the surface of activated NK cells. This enhances ADCC mediated by CD38-targeting monoclonal antibodies.