iPSC-derived anti-CD19 CAR/CD16/IL-15RF/ADR-expressing CD38-eliminated NK cells FT522

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) CD19, a high-affinity, non-cleavable CD16 (hnCD16) Fc receptor, a recombinant fusion of IL-15 and IL-15 receptor alpha (IL-15RF), an alloimmune defense receptor (ADR) that targets the immune co-stimulatory receptor 4-1BB (CD137; tumor necrosis factor receptor superfamily member 9; TNFRSF9), and to eliminate CD38 expression, with potential immunostimulatory and antineoplastic activities. Upon administration, iPSC-derived anti-CD19 CAR/CD16/IL-15RF/ADR-expressing CD38-eliminated NK cells FT522 recognize, bind to and induce selective cytotoxicity in CD19-expressing tumor cells, leading to tumor cell lysis and the release of tumor neoantigens. Additionally, FT522 NK cells secrete inflammatory cytokines and chemokines, thereby enhancing T-cell activity and recruitment to the tumor site. CD19 antigen is a B-cell specific cell surface antigen expressed in all B-cell lineage malignancies. IL-15RF promotes the survival of NK cells and enhances the cytotoxic effect of the NK cells and the activated anti-tumor T cells. The ADR targets 4-1BB-expressing alloreactive immune cells and leads to the killing of the alloreactive immune cells, further enhancing potency and extending the persistence of the FT522 NK cells. When used in combination with monoclonal antibodies, the hnCD16 Fc receptor of FT522 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 FT522 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.