1205 Treatment of Lupus-prone BXSB Mice with a Modulatable CAR T cell System Targeting CD19

Chimeric antigen receptor (CAR) T cells directed against CD19 have demonstrated efficacy in treating active lupus in both human and mouse lupus. However, a significant limitation of this approach is immunodeficiency due to the long-term depletion of B cells. To address this issue, we studied the potential of a switchable CAR (sCAR) T cell system targeting CD19 to transiently eliminate B cells and provide therapeutic benefit with less immunosuppression. This approach consists of a CAR that, instead of targeting CD19 directly, binds to a soluble antiCD19 Fab switch with a short half-life, thereby allowing sCAR T cell killing only when the antiCD19 switch is present. Treatment of BXSB males with sCAR T plus continuous antiCD19 switch reduced B cell numbers, circulating immunoglobulins, autoantibodies, and nephritis. To document the efficacy of a shorter course of treatment, B6 mice were given three every other day doses of antiCD19 switch. There was depletion of virtually all CD19+ B cells and plasma cells from the bone marrow, spleen, and peritoneum, as well as most CD19- plasma cells in the bone marrow and spleen. When BXSB males with active disease were similarly treated, there was a transient elimination of B cells and disease remission associated with about a 2-month prolonged survival. To address whether recurrence could be prevented by repeated sCAR T+antiCD19 treatment, BXSB males with active lupus were given an additional two cycles of antiCD19 switch at 60 and 138 days. Circulating B cells, IgM and IgG, and anti-chromatin levels were reduced after each switch cycle and increased in the intervening periods. Notably, proteinuria did not recur, and there were no deaths beyond day 8 after the start of treatment compared with 100% mortality in the sCAR T+PBS controls. These studies inform on the potential effectiveness and limitations of therapeutic depletion of B cells in SLE and suggest a possible strategy for employing CAR T cells to minimize immunosuppression.