Harnessing iPSC-Derived CAR-NK Cells: The Advancement of FT596 in Targeting B Cell Malignancies

Innovative stem cell-derived effector cells are being developed for advanced immune therapies, offering advantages such as scalable production and precise genetic modification. Natural killer (NK) cells derived from induced pluripotent stem cells (iPSCs), known as iNK cells, display innate responses to stress indicators and potential to stimulate adaptive immune responses. A product candidate, FT596, is a multi-antigen targeted chimeric antigen receptor (CAR)-iNK cell, designed for enhanced effector functions. It is produced from a master iPSC line that expresses a CD19-targeting CAR, a high-affinity CD16 variant, and a fusion of IL-15 and its receptor for sustained activity.

The CD19-CAR design leverages the polyfunctionality of NK cells, engaging multiple signaling pathways through different receptors. The combination of NKG2D's transmembrane region with the signaling domains of 2B4 and CD3ζ was found to be most effective in eliciting antigen-specific responses. This CAR showed specific recognition and clearance of CD19+ B cell lymphoma cells in cytotoxicity assays.

The integration of IL-15RF in the iNK cells allowed for expansion without additional cytokines, enhancing longevity and functionality both in vitro and in vivo, and promoting functional maturation. The combination of CD19-CAR and IL-15RF resulted in improved CAR performance, and in mouse models, this engineered cell treatment was highly effective against B cell lymphoma.

The co-expression of CD19-CAR and IL15-RF, along with hnCD16, enables the iNK cells to target dual-specificities and combat antigen escape. FT596 demonstrated comparable anti-tumor activity to primary CAR19 T cells and showed enhanced activity when combined with anti-CD20 (rituximab). It effectively eliminated antigen-escaped target cells and showed equivalent or superior tumor clearance in vivo compared to CAR19 T cells, with improved survival and safety profiles.

These findings support the development of FT596 as a potent, multi-antigen targeting engineered immune cell derived from a master iPSC line. It offers a highly effective combination therapy platform for Phase I Studies as a monotherapy and in combination with CD20-targeted monoclonal antibodies for treating relapsed/refractory B-cell lymphoma and leukemia.

Disclosures indicate affiliations and potential conflicts of interest, with several individuals listed as being employed by or having consultancy roles, board memberships, or research funding from companies such as Fate Therapeutics, Inc., Vycellix, Moderna, Dr. Reddys Laboratory, CytoSen, OnKImmune, and GT BioPharma.