Tumor cells targeted by FT538 NK cells via natural cytotoxicity and ADCC

FT538 is an investigational, off-the-shelf, induced pluripotent stem cell (iPSC)-derived natural killer (NK) cell therapy developed by Fate Therapeutics (Fate Therapeutics, 2024). It is engineered with three key modifications: a high-affinity, non-cleavable CD16 (hnCD16) receptor to maximize antibody-dependent cellular cytotoxicity (ADCC), an IL-15/IL-15 receptor fusion (IL-15RF) for enhanced persistence, and a CD38 knockout (CD38KO) to prevent fratricide and improve metabolic fitness (Cichocki et al., 2020, Blood). The 'target' in this context refers to the population of tumor cells susceptible to FT538-mediated destruction through two primary pathways: natural cytotoxicity and ADCC. Natural cytotoxicity is triggered by the engagement of innate activating receptors on the NK cell, such as NKG2D and DNAM-1, with stress-induced ligands expressed on the tumor surface. ADCC is facilitated by the hnCD16 receptor binding to the Fc region of monoclonal antibodies that have opsonized the tumor cells, allowing FT538 to be used in combination with therapies like daratumumab or rituximab (NCT04614636, ClinicalTrials.gov). This dual mechanism allows FT538 to target a wide variety of malignancies, including multiple myeloma, acute myeloid leukemia, and various solid tumors, by overcoming common mechanisms of immune evasion (Björklund et al., 2022, Frontiers in Immunology).

Other names

FT538-sensitive tumor cellsNK cell-susceptible cancer cellsMalignant cells targeted by iPSC-NK cells

FT538 targets tumor cells through a dual mechanism: (1) Natural cytotoxicity, where innate activating receptors (e.g., NKG2D, DNAM-1) recognize ligands on the tumor cell surface, and (2) Antibody-Dependent Cellular Cytotoxicity (ADCC), where the engineered high-affinity, non-cleavable CD16 (hnCD16) receptor binds to the Fc region of monoclonal antibodies targeting tumor antigens (Fate Therapeutics, 2024; Cichocki et al., 2020).