3 research outputs found
Journal Club: AntiâCD19 Chimeric Antigen Receptor T Cell Therapy for Refractory Systemic Lupus Erythematosus
Objective Despite substantial advances in the treatment of systemic lupus erythematosus (SLE), some patients do not respond to the current stateâofâthe art therapies. This study assessed the tolerability and efficacy of CD19 chimeric antigen receptor (CAR) T cells in a small series of seriously ill and treatmentâresistant patients with SLE. Methods Five patients with SLE (four female patients and one male patient) with a median age of 22 (range 18â24) years, a median disease duration of 4 (range 1â9) years, and active disease (median Systemic Lupus Erythematosus Disease Activity Index score of 16 [range 8â16]) refractory to several immunosuppressive drug treatments were enrolled in a compassionateâuse CARâT cell program. Autologous T cells from patients with SLE were transduced with a lentiviral antiâCD19 CAR vector, expanded, and reinfused at a dose of 1âĂâ106 CAR T cells per kilogram of body weight into the patients after lymphodepletion with fludarabine and cyclophosphamide. Results CAR T cells expanded in vivo and led to deep depletion of B cells, improvement of clinical symptoms, and normalization of laboratory parameters, including seroconversion of antiâdoubleâstranded DNA antibodies. Remission of SLE according to definition of remission in SLE criteria was achieved in all five patients after 3 months, and the median Systemic Lupus Erythematosus Disease Activity Index score after 3 months was 0 (range 2). Drugâfree remission was maintained during longer followâup (median of 8 [range 12] months after CARâT cell administration) and even after the reappearance of B cells, which was observed after a mean (±SD) of 110â±â32âdays after CARâT cell treatment. Reappearing B cells were naive and showed nonâclassâswitched B cell receptors. CARâT cell treatment was well tolerated, with only mild cytokine release syndrome. Conclusion These data suggest that CD19 CARâT cell therapy was feasible, tolerable, and effective in this small case series of refractory SLE. Nevertheless, larger placeboâcontrolled trials are warranted
CaMK4 controls follicular helper T cell expansion and function during normal and autoimmune T-dependent B cell responses
Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by dysregulated B cell compartment responsible for the production of autoantibodies. Here, we show that T cell-specific expression of calcium/calmodulin-dependent protein kinase IV (CaMK4) leads to T follicular helper (Tfh) cells expansion in models of T-dependent immunization and autoimmunity. Mechanistically, CaMK4 controls the Tfh-specific transcription factor B cell lymphoma 6 (Bcl6) at the transcriptional level through the cAMP responsive element modulator α (CREMα). In the absence of CaMK4 in T cells, germinal center formation and humoral immunity is impaired in immunized mice, resulting in reduced anti-dsDNA titres, as well as IgG and complement kidney deposition in the lupus-prone B6.lpr mouse. In human Tfh cells, CaMK4 inhibition reduced BCL6 expression and IL-21 secretion ex vivo, resulting in impaired plasmablast formation and IgG production. In patients with SLE, CAMK4 mRNA levels in Tfh cells correlated with those of BCL6. In conclusion, we identify CaMK4/CREMα as a driver of T cell-dependent B cell dysregulation in autoimmunity