An improved understanding of pathogenesis in systemic lupus erythematosus (SLE) has not always translated to advances in patient treatment. Now, Marko Radic and colleagues report that CD19-specific chimeric antigen receptor (CAR) T cells, usually a therapy for patients with leukaemia, can be successfully used to treat SLE in mouse models.
“We used a CAR T cell approach to deplete B cells in mice to test how crucial B cells are in the pathogenesis of lupus,” explains Radic. “This approach was attractive because, if successful, it might offer a viable new treatment option for lupus.” Using retroviral transfection, the researchers inserted a CD19-targeted CAR into purified CD8+ T cells. This CAR included the variable fragment (Fv) of the CD19-specific 1D3 antibody, as a single-chain heterodimer of the light and heavy chains (scFv), the CD28 transmembrane and cytoplasmic signalling domains, and a CD3ζ C terminus engineered to prevent T cell exhaustion.
In two mouse models of lupus (NZB/W and MRL-lpr strains), CAR T cell transfer induced efficient and stable B cell depletion. This effect was accompanied by marked improvements in several measures of disease severity, including the elimination of circulating anti-DNA antibodies, as well as a significant increase in lifespan.
An analysis of immunoglobulin light chain transcript levels indicated that, following CAR T cell transfer, some B cells persisted in the spleen and bone marrow but not in the kidney. Moreover, the treatment prevented the development of glomerulonephritis, as indicated by a reduction in proteinuria and, in the glomerulus, by a decrease in both cellular infiltration and IgG deposition.
“B cell depletion with rituximab was not effective in patients with SLE but CD19-targeted CAR T cells might prove to be more successful as they induce permanent and sustained B cell depletion,” remarks Radic. “We are confident that our research paves the way for the use of CAR T cells to treat patients with severe lupus.”
Kansal, R. et al. Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus. Sci. Transl Med. 11, eaav1648 (2019)
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Wang, M. Repurposing CAR T cells to treat SLE. Nat Rev Nephrol 15, 319 (2019). https://doi.org/10.1038/s41581-019-0144-5
Journal of Immunology Research (2019)