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Slamming the brakes on lupus with CAR T cells

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Science Immunology  05 Apr 2019:
Vol. 4, Issue 34, eaax3916
DOI: 10.1126/sciimmunol.aax3916

Abstract

Sustained depletion of B cells with CAR T cells induces disease remission in lupus-prone mice.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by periodic inflammatory flares in multiple organ systems and the formation of autoantibodies. The B cell–depleting anti-CD20 antibody Rituximab failed to improve lupus in two clinical trials, but these patients may have had incomplete or transient B cell depletion. To improve B cell depletion, Kansal et al. engineered CD19-targeted chimeric antigen receptor (CAR) CD8+ T cells and used them to treat lupus-prone mice. A single dose of CAR T cells depleted CD19+ B cells for up to a year, abolished the production of autoantigens, reversed tissue injury, and extended lifespan in two different strains of lupus-prone mice. CAR T cells were long-lived in the circulation and appeared to adopt a central memory T cell phenotype. T cells from the spleens of CAR-treated mice were able to transfer B cell depletion and disease remission to naïve autoimmune mice, confirming that T cells were responsible for disease control. Circulating immunoglobulin G (IgG) and IgM antibody levels remained normal in CAR T treated MRLfas/fas (MRL-lpr) lupus-prone mice, likely because long-lived plasma cells in the bone marrow and some splenic B cells were spared. CAR T cells directly kill B cells, whereas monoclonal antibodies rely on antibody-dependent cellular cytotoxicity for B cell depletion, an immune mechanism that is blunted in patients with SLE. These studies highlight a novel method of inducing sustained B cell depletion that overcomes current limitations in monoclonal antibody therapy and may hold promise for the treatment of patients with severe SLE.

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