Background/Purpose: Unprecedented clinical data have recently shown that patients with certain highly refractory autoimmune diseases (AI Dz) treated with conditioning chemotherapy (CCT) and autologous anti-CD19 chimeric antigen receptor (CAR) T cells can undergo immunological reset and achieve long-term, drug-free remission. These findings have spurred further clinical investigation into anti-CD19 CAR-targeted cell therapies for AI Dz. However, additional immunological factors, including aberrant plasma and T cells that escape CD19 targeting, may contribute to AI Dz pathology. Furthermore, administration of CCT to patients is associated with significant toxicities, including poor immune reconstitution, prolonged cytopenia, and increased risk of hospitalization, severe infections and secondary cancers. Thus, a next-generation cell therapy should aim to retain B-cell depletion activity, target other diseased cell types, minimize or eliminate the need for administration of CCT to patients, and confer a favorable safety profile to enable outpatient treatment and broad patient reach.

Methods: To meet these challenges, we developed FT522, an off-the-shelf CAR natural killer (NK) cell product candidate that incorporates five synthetic controls of cell function. FT522 is derived from a single engineered induced pluripotent stem cell (iPSC) incorporating a CD38 knockout to enhance metabolic fitness and uniquely enable CD38 targeting; a CAR targeting CD19; an alloimmune defense receptor (ADR) targeting 4-1BB; a high-affinity, non-cleavable CD16 (hnCD16) Fc receptor to maximize antibody-dependent cellular cytotoxicity (ADCC); and an IL-15/IL15 receptor fusion protein (IL15RF) for cytokine-induced support and function.

Results: In a cytotoxicity assay representative of various AI Dz, FT522 exhibited CD19-specific cytotoxicity and rapid, deep, and durable B cell elimination, including in unmatched peripheral blood mononuclear cells (PBMCs) derived from SLE and RA-diagnosed donor populations. In addition, FT522 in combination with rituximab and with daratumumab uniquely displayed potent ADCC against CD19neg/CD20+ and CD19neg/CD38+ cell populations, respectively. Importantly, in a multi-round mixed lymphocyte reaction assay using unmatched PBMCs from SLE-diagnosed donors, FT522 uniquely survived, exhibited functional persistence, and eliminated CD19+ B cells as well as additional cell types expressing 4-1BB, including activated T cells, NK cells and monocytes, whereas both ADR-null anti-CD19 CAR NK and CAR T cells failed to survive and eliminate the targeted cell population.

Conclusion: Collectively, the data highlight the unique potential of FT522 to survive and functionally persist in an allogeneic setting without CCT, and to rapidly target and eliminate both CD19+ B cells as well as other aberrant cell types that contribute to AI Dz pathophysiology. FT522 is currently being investigated in a Phase 1 clinical study in B cell lymphoma, including without administration of CCT to patients. A multi-indication investigational new drug (IND) application is being prepared for the treatment of AI Dz. Available clinical and translational data for FT522 will be presented.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/development-of-a-multiplexed-engineered-off-the-shelf-car-nk-cell-with-unique-multi-pathogenic-cell-targeting-capacity-for-the-treatment-of-autoimmune-diseases-in-the-absence-of-conditioning-chemothe/