Harnessing iPSC-Derived CAR-NK Cells: The Advancement of FT596 in B Cell Malignancy Therapy

The abstract discusses the development of a novel immune therapy using induced pluripotent stem cell (iPSC)-derived effector cells, specifically focusing on natural killer (NK) cells. These iPSC-derived NK cells, or iNK cells, are highlighted for their innate reactivity and potential to stimulate adaptive immune responses. The multi-antigen targeted chimeric antigen receptor (CAR)-iNK cell product, named FT596, is engineered with a CD19-targeting CAR, a high-affinity CD16, and a fusion of IL-15 and its receptor alpha for self-sustaining cytokine support.

The CD19-CAR design leverages the polyfunctionality of NK cells, utilizing the transmembrane region of NKG2D and intracellular signaling domains of 2B4 and CD3ζ for effective antigen-specific responses. This CAR-iNK cell has demonstrated high efficacy in cytotoxicity assays against CD19+ B cell lymphoma cells. The inclusion of IL-15RF in the design allows for cytokine-independent expansion and enhanced longevity and functionality of the iNK cells.

FT596, when combined with hnCD16, exhibits dual-specificity, enabling it to combat antigen escape through the use of monoclonal antibodies. In assays, FT596 showed comparable anti-tumor activity to primary CAR19 T cells and enhanced activity when combined with anti-CD20 (rituximab). It was particularly effective in eliminating CD19-escaped target cells.

In vivo studies showed that FT596 matched the tumor clearance of primary CAR19 T cells and demonstrated improved survival and safety profiles in a human CD34 engrafted NSG mouse model. The abstract concludes that FT596 represents a potent, persistent, and scalable engineered immune cell therapy, supporting the rationale for a Phase I Study as a monotherapy and in combination with CD20-targeted monoclonal antibodies for the treatment of relapsed/refractory B-cell lymphoma and leukemia.