byJustin Jackson, Phys.org

Credit: Pixabay/CC0 Public Domain

Researchers at the First Affiliated Hospital of the University of Science and Technology of China claim that an in vivo CD8 T-cell-targeted lipid nanoparticle carrying CD19 CAR mRNA (HN2301) generated transient CAR T cells that rapidly depleted B cells and reduced disease activity in five patients with treatment resistant systemic lupus erythematosus.

Lupus is a chronic autoimmune disease in which the immune system produces antibodies that attack the body's own tissues. The condition can inflame and damage organs including the kidneys, joints, skin, and nervous system. Current treatments rely on corticosteroids and immunosuppressants to reduce inflammation. Relapses and treatment resistance are common, leaving a substantial need for therapies that can induce lasting remission.

Autologous CD19 CAR T-cell therapy has shown efficacy in autoimmune disease, with costs and conditioning chemotherapy cited as obstacles to wider use. In vivo CAR T-cell-generation approaches using lipid nanoparticles orlentiviral vectorshave been previously described, with so far unclear clinical efficacy and safety in autoimmune disease.

In a letter to the editor, "In Vivo CD19 CAR T-Cell Therapy for Refractory Systemic Lupus Erythematosus,"publishedin TheNew England Journal of Medicineas a Correspondence, researchers describe outcomes of a feasibility assessment in patients with systemic lupus erythematosus using a CAR T-cell therapy.

Five patients with systemic lupus erythematosus that previously showed resistance to multiple conventional therapies were enrolled. All patients except Patient 4 also had lupus nephritis. HN2301 was administered on a three-dose exploratory schedule. Dosing included 2 mg for Patients 1 and 2 and 4 mg for Patients 3, 4, and 5.

CD8+CD19 CAR T cells became detectable in peripheral blood six hours after infusion. Levels of CAR T cells and CAR mRNA peaked six hours after each infusion and returned to baseline within two to three days. Off-target expression of CAR on non-CD8+T cells measured less than 10%. Up-regulation of CD69 was observed on CD8+T cells and not on CD4+T cells.

Within six hours after the first treatment, circulating B cells substantially decreased at the 2 mg dose and were completely depleted to less than 1 B cell per microliter at the 4 mg dose, with depletion maintained for seven to 10 days.

No grade 3 or 4 cytokine release syndrome occurred and no cases of immune effector cell–associated neurotoxicity syndrome were observed. Increases in C-reactive protein and interleukin-6 were recorded, and three patients received a single dose of tocilizumab for cytokine release syndrome.

No clinically significant elevation of liver-enzyme levels occurred, and no cytopenia was reported other than a transient decrease in lymphocytes. In Patients 4 and 5, anti-nucleosome and anti-double-stranded DNA antibodies appeared to decrease substantially, with initially low complement levels normalizing.

At three months after HN2301 treatment, Systemic Lupus Erythematosus Disease Activity Index 2000 scores decreased in all five patients. The data shown and reporting time fall far short of being able to establish an immune reset.

Authors conclude that in vivo CAR T-cell therapy can generate functionally active CD19 CAR T cells in patients withsystemic lupus erythematosusthat deplete B cells and affect disease-associated autoantibodies anddisease activity. More data and longer follow-up periods are needed to define the durability of this feasibility signal.

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More information: Qian Wang et al, In Vivo CD19 CAR T-Cell Therapy for Refractory Systemic Lupus Erythematosus, New England Journal of Medicine (2025). DOI: 10.1056/nejmc2509522 Journal information: New England Journal of Medicine