Harnessing Dual-Targeted NK Cell Therapy: The Advancement of FT576 in Multiple Myeloma Treatment

Multiple myeloma, a disease stemming from mutated plasma cells, is typically treated with chemotherapy and immunomodulatory drugs. New research has concentrated on monoclonal antibodies (mAbs) and CAR T cell therapies, with daratumumab, an anti-CD38 mAb, showing clinical advantages. However, the high presence of CD38 on NK cells can lead to self-harm, reducing the effectiveness of ADCC. Another antigen, BCMA, is being explored for CAR T cell therapy with initial promising results, although improvements are needed for relapse rates and treating recurring patients. The combination of targeting CD38 and BCMA may enhance treatment effectiveness.

Our team has created a novel NK cell immunotherapy for MM, utilizing a ready-to-use NK cell platform with four modifications: a BCMA-specific CAR for MM targeting, a high-affinity non-cleavable CD16 to boost ADCC with anti-CD38 mAbs, CD38 deletion to prevent NK cell depletion, and an IL-15/IL-15 receptor α fusion protein for enhanced NK cell longevity. The BCMA CAR features a unique targeting domain with low nanomolar affinity, ensuring effectiveness even when BCMA levels are low. The NK cells are derived from a master pluripotent stem cell line, ensuring uniformity and scalability for mass production (FT576) to support extensive treatment strategies.

Preclinical tests showed that FT576 NK cells uniformly expressed CD16, CAR, and IL15-RF, and were CD38 negative. They were resistant to daratumumab-induced self-harm, unlike peripheral blood NK cells which were vulnerable. FT576 NK cells also showed superior cytotoxicity against MM1.S cells and greater persistence compared to NK cells without IL-15RF. They were able to expand significantly without external cytokine support and maintained ADCC capability when combined with daratumumab. FT576 NK cells also demonstrated direct cytotoxicity against RPMI-8226 MM spheroids in a 3D culture model, achieving over 99% cytotoxicity. Ongoing preclinical studies aim to progress FT576 as a pioneering cellular therapy combining anti-BCMA CAR with mAb targeting for MM.

The disclosures section indicates that several individuals are employed by Fate Therapeutics, Inc., which may have a vested interest in the research outcomes.