A Phase 1 Study of NKX019, an Allogeneic Chimeric Antigen Receptor Natural Killer (CAR-NK) Cell Therapy in Patients with Systemic Lupus Erythematosus

Introduction Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease with clinical manifestations that affects nearly every organ and induces myriad laboratory abnormalities. B-cell dysfunction is central to SLE pathophysiology, including autoantibody production and cytokine secretion. Treatment of SLE consists of immunosuppressive therapy to prevent organ damage and improve quality of life. Recently, CD19-directed chimeric antigen receptor (CAR) T-cell therapy has shown promising early results in patients with SLE and lupus nephritis (LN) via transient B-cell depletion and, possibly, immunologic reset to a more naïve B cell repertoire. More widespread use has been limited by cumbersome infrastructure requirements and treatment delays associated with bespoke manufacturing of CAR T cells, as well as concerns about side effects from chemotherapy used for lymphodepletion (LD). Allogeneic NK cell-based therapies allow off-the-shelf use, obviating the necessity to wait for manufacture of autologous T-cell therapies. NKX019 is a cryopreserved product, composed of expanded NK cells engineered to express a humanized CAR against CD19, fused to co-stimulatory (OX40) and signaling (CD3ζ) domains to enhance target cell killing. NKX019 also expresses a membrane-bound interleukin-15 (IL-15) to serve as an autocrine growth factor and thereby increase NKX019 persistence, with an in vivo half-life of up to 28 days without systemic IL-2 support. Whereas autologous CAR T cells depend on host cytokine surges induced by lymphodepletion, the membrane-bound IL-15 construct also enables the use of NKX019 without fludarabine-containing LD. Preclinical characterization has shown that NKX019, unlike non-engineered NK cells, effectively kills B cells from patients with various autoimmune diseases, including SLE. Lacking a T-cell receptor and the consequent clonal expansion, NKX019 has been safely administered to patients with B-cell malignancies with minimal elevations of inflammatory cytokines and without side effects typically associated with CAR T-cell therapies, such as severe cytokine release syndrome or neurotoxicity (Dickinson 2023). Hence, clinical evaluation of NKX019 is being undertaken in this Phase 1 study in subjects with refractory SLE with or without LN. Methods This is a single center, open-label, non-randomized Phase 1 study of NKX019 in adult (≥18 years) patients with SLE with or without LN (NCT06518668). Patients with SLE must have a score of 8 or more points on the Hybrid Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and those with SLE and LN must have biopsy-proven active LN (Class III or IV with or without Class V using the 2018 International Society of Nephrology and Renal Pathology Society criteria) with proteinuria after at least 2 prior lines of therapy. Patients with prior hematopoietic transplantation or cellular therapy (including CAR T or CAR NK), significant organ dysfunction or severe cytopenias are ineligible. The study will evaluate safety and tolerability, pharmacokinetics (PK), immunogenicity, and activity of NKX019, including changes in autoantibody levels and improvement in SLE disease-related activity. NKX019 is manufactured from NK cells obtained from healthy adult donors. The study will evaluate NKX019 dosed at 1 × 109 viable CAR+ NK cells administered on Days 0, 7, and 14 following single agent cyclophosphamide lymphodepletion. The primary endpoint is incidence of adverse events, dose-limiting toxicities, and clinically significant laboratory abnormalities. Secondary endpoints include standard cellular PK parameters and SLE responses. Subjects will be assessed for response based on SLEDAI or the European Alliance of Associations for Rheumatology (EULAR)/European Renal Association-European Dialysis and Transplantation Association (ERA-EDTA) criteria. Patient screening began in mid-2024. References: Dickinson M, Hamad N, Bryant C, et al. First in human data of NKX019, an allogeneic CAR NK for the treatment of relapsed/refractory (R/R) B-cell malignancies. Presented at: 2023 EHA Congress; June 8-11, 2023; Frankfurt, Germany. Abstract S261.