LUPUS NEPHRITIS

Repurposing CAR T cells to treat SLE

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.”

References

Original article

  1. 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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Correspondence to Monica Wang.

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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

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