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

B cell–intrinsic TLR9 expression is protective in murine lupus

“…This was important because multiple hematopoietic cell lineages express TLR9 and could modulate disease. These cell lineages include B cells (18)(19)(20), neutrophils (21,22), macrophages (23,24), DCs (25,26), and plasmacytoid DCs (pDCs) (26,27).…”

B Cell Abnormalities in Systemic Lupus Erythematosus and Lupus Nephritis—Role in Pathogenesis and Effect of Immunosuppressive Treatments

“…Bortezomib is currently being tested in a Phase 2 trial for SLE (NCT02102594) and ixazomib (a second-generation oral PI with less neurological side effects) is being investigated in LN patients (NCT02176486). The application of chimeric antigen receptor T cells (CAR-T) technology can potentially confer more profound and sustained B cell depletion, and is shown to be highly effective in a murine lupus model [118].…”

Immunotherapy Deriving from CAR-T Cell Treatment in Autoimmune Diseases

“…A single use of CD19-targeted CAR-T cells was highly effective to treat lupus, manifested as complete and sustained CD19+ B cell depletion, terminated autoantibody production, reversed disease phenotype, and prolonged survival time, and the treatment effect was sustained for up to one year. Transferring splenic T cells from the mice after CD19+ B cell depletion by CAR-T cell treatment to lupus prone mice alleviated disease severity in adoptive autoimmune mice [45]. The persistence and function of CD19-targeted CAR-T cells were quite long in vivo after a single administration, reaching up to one year, and meanwhile, persistent B cell depletion was observed.…”