Allogeneic iPSC-derived Anti-MICA/B CAR/CD16/IL-15RF-expressing CD38-eliminated NK Cells FT536
allogeneic ipsc-derived anti-mica/b car/cd16/il-15rf-expressing cd38-eliminated nk cells ft536
A preparation of allogeneic, off-the-shelf (OTS), natural killer (NK) cells 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 alpha 3 domain of the natural-killer group 2, member D receptor protein (NKG2D or KLRK1) ligands MHC class I polypeptide-related sequence A (MICA) and B (MICB), 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, allogeneic iPSC-derived anti-MICA/B CAR/CD16/IL-15RF-expressing CD38-eliminated NK cells FT536 recognize, bind to and induce selective cytotoxicity in MICA/B-expressing tumor cells, leading to tumor cell lysis and the release of tumor neoantigens. Additionally, FT536 NK cells secrete inflammatory cytokines and chemokines, thereby enhancing T-cell activity and recruitment to the tumor site. MICA and MICB are stress-induced NKG2D ligands overexpressed on infected cells and many cancer cell types, but are not expressed on most normal, healthy cells. The shedding of the alpha 1 and alpha 2 domains of MICA and MICB from tumor cell surface allows the tumor cells to evade NKG2D-expressing immune cells, and FT536 specifically targets the alpha 3 domain of MICA/B to overcome this shedding and tumor escape mechanism. 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 FT536 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 FT536 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.