Genetically modified CD19-targeting IL-15 secreting NK cells for the treatment of systemic lupus erythematosus

Given the efficacy of B-cell depletion therapy in systemic lupus erythematosus (SLE) treatment and the capacity of engineered natural killer (NK) cells in B-cell elimination, we explored the potential of genetically modified NK cells to target CD19 for the treatment of SLE. Peripheral blood-derived NK cells were engineered with CAR.CD19/interleukin (IL)-15 (XB-19.15) or CAR.CD19 alone. In vitro assays tested cytotoxicity, proliferation (Ki-67), and cytokine release (IL-15/interferon-gamma [IFN-γ]] against CD19+ cells (Raji, Nalm6, SLE B-cell). In vivo models included Nalm6-luc xenografts, humanised CD34+ mice, and SLE peripheral blood mononuclear cells xenografts to assess efficacy, persistence, and safety. A phase 1 trial enrolled 3 patients with refractory SLE receiving XB-19.15 as a proof-of-concept study. XB-19.15 showed superior cytotoxicity, sustained IL-15 secretion, and enhanced proliferation in vitro. In the mouse model, XB-19.15 showed significant dose-dependent tumour regression of Nalm-6 and B-cell depletion of humanised mice with long-term persistence in various lymphoid organs. The total levels of hIgG and anti-dsDNA antibodies were decreased in XB-19.15-treated groups with deep clearance of B-cell and plasma cells of bone marrow and spleen in the SLE xenograft model, indicating potential attenuation of SLE. Three patients received XB-19.15 achieved improvement in disease activity and reset of B-cell repertoires without severe adverse events. XB-19.15 enables potent, durable B-cell depletion and immune resetting in SLE with off-the-shelf utility and favourable safety. Preclinical and early clinical data support further trials to optimise dosing and confirm long-term efficacy.