Enhancing NK Cell Therapy in Multiple Myeloma: The Role of CD38-Deficient FT538 in Preventing Fratricide and Augmenting ADCC with Daratumumab

Monoclonal antibodies are a potent treatment for various cancers, but their effectiveness can be further enhanced by improving their interaction with natural killer (NK) cells to boost antibody-dependent cellular cytotoxicity (ADCC). NK cells are crucial for both innate anti-tumor activity and ADCC. CD38-targeting antibodies like daratumumab are effective against multiple myeloma (MM), but they can also lead to NK cell depletion due to fratricide when NK cells, which express high levels of CD38, are activated.

A novel approach involves the use of FT538, a ready-to-use NK cell therapy derived from induced pluripotent stem cells (iPSCs) that lack CD38 expression, thus avoiding fratricide induced by anti-CD38 antibodies. These cells are modified to express an IL-15 receptor alpha fusion protein to enhance their longevity and a high-affinity CD16 to increase their ADCC capability.

To facilitate the clinical application of FT538, a clinical-grade iPSC line was developed. This line was created by reprogramming donor fibroblasts into iPSCs using a non-integrating method and genetically edited to introduce IL-15RF and hnCD16 while eliminating CD38. The resulting iPSC lines were checked for precise genetic edits, absence of off-target effects, and the ability to differentiate into functional NK cells.

Differentiated FT538 cells exhibit a mature NK cell phenotype with the expression of various NK cell receptors. In vitro assays confirmed that FT538 cells are resistant to fratricide induced by daratumumab, unlike peripheral blood NK cells. Furthermore, FT538 cells maintain their cytotoxic capacity upon repeated exposure to MM target cells and daratumumab, unlike non-engineered NK cells. The combination of IL-15RF expression and CD38 knockout in FT538 cells, along with the enhanced hnCD16-mediated ADCC, results in significant cytotoxicity against MM tumor spheroids.

These findings suggest that FT538, an engineered NK cell product with uniform expression of hnCD16 and IL-15RF and devoid of CD38, could be a promising therapy for MM when combined with daratumumab and other anti-CD38 monoclonal antibodies.