Harnessing Dual-Targeted NK Cells: FT576's Innovative Approach in Advanced Multiple Myeloma Therapy

Multiple myeloma, a B-cell malignancy, is typically addressed with chemotherapy and immunotherapy. New strategies focus on monoclonal antibodies and CAR T cell therapies, with daratumumab being a leading FDA-approved monoclonal antibody targeting CD38. However, challenges arise from CD38's presence on NK cells, causing self-harm and reducing their effectiveness.

Researchers are also exploring BCMA, a TNF-superfamily member, as a promising CAR target for MM. Early clinical trials show potential, but there's room for improvement in managing relapses and enhancing treatment for recurring patients. Evidence hints that a combined approach targeting both CD38 and BCMA may offer superior outcomes.

A novel adoptive NK cell therapy has been developed, featuring engineered NK cells with multiple attributes: a BCMA-specific CAR for precise MM targeting, a high-affinity CD16 to boost ADCC when paired with anti-CD38 antibodies, CD38 deletion to prevent NK cell depletion, and an IL-15/IL-15Rα fusion protein to prolong NK cell survival.

These NK cells are derived from a master pluripotent stem cell line, ensuring consistent production of uniform cells (FT576) that can be scaled for extensive treatment needs. In vitro tests show that FT576 NK cells are resistant to daratumumab-induced self-harm, unlike regular NK cells. They also exhibit superior cytotoxicity against MM cells and can expand significantly without external cytokines.

The engineered NK cells maintain their ADCC capabilities, enhancing cytotoxicity when combined with daratumumab. They also demonstrate direct cytotoxicity against MM spheroids, achieving high levels of cell death in 3D culture models. Ongoing preclinical research aims to further the development of FT576 as a pioneering cellular therapy combining anti-BCMA CAR and antibody targeting for MM treatment.