Research ArticleAutoimmunity

Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus

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Science Translational Medicine  06 Mar 2019:
Vol. 11, Issue 482, eaav1648
DOI: 10.1126/scitranslmed.aav1648

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CAR T cells: Not just for cancer

CD19-targeted chimeric antigen receptor (CAR) T cell therapy is revolutionizing treatment for hematologic malignancies. As CD19 is a marker on all B cells, not just malignant ones, Kansal et al. reasoned that CD19-targeted CAR T cells could possibly be used to deplete autoreactive B cells in lupus. They generated CD19-targeted CAR constructs and showed that CD8+ T cells from two different lupus strains could be transfected. Transfer of the CD19-CAR T cells into mice ablated autoantibodies and CD19+ cells. In both models, survival was remarkably extended, and target organs were spared. These exciting results could pave the way for using CD19-targeted T cells to treat patients with lupus.

Abstract

The failure of anti-CD20 antibody (Rituximab) as therapy for lupus may be attributed to the transient and incomplete B cell depletion achieved in clinical trials. Here, using an alternative approach, we report that complete and sustained CD19+ B cell depletion is a highly effective therapy in lupus models. CD8+ T cells expressing CD19-targeted chimeric antigen receptors (CARs) persistently depleted CD19+ B cells, eliminated autoantibody production, reversed disease manifestations in target organs, and extended life spans well beyond normal in the (NZB × NZW) F1 and MRLfas/fas mouse models of lupus. CAR T cells were active for 1 year in vivo and were enriched in the CD44+CD62L+ T cell subset. Adoptively transferred splenic T cells from CAR T cell–treated mice depleted CD19+ B cells and reduced disease in naive autoimmune mice, indicating that disease control was cell-mediated. Sustained B cell depletion with CD19-targeted CAR T cell immunotherapy is a stable and effective strategy to treat murine lupus, and its effectiveness should be explored in clinical trials for lupus.

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