Comment on: “Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus”.
Mackensen A et al. Nature Medicine 2002; 28: 2124.
Commented by: Frédéric A. Houssiau. Service de Rhumatologie, Cliniques Universitaires Saint-Luc, Bruxelles. Pôle de Pathologies Rhumatismales Inflammatoires et Systémiques, Institut de Recherche Expérimentale et Clinique, UCLouvain.
This article by the group of Georg Schett in Erlangen will likely not change our daily practice in 2023. Yet, this paper sheds a new light on the therapy of autoimmune disorders. The concept is to apply CAR (Chimeric Antigen Receptor) T cell therapy to treat selected refractory lupus cases.
In brief, CAR T cells are in vitro genetically modified autologous T cells which express a chimeric receptor containing an extracellular and an intracellular domain. The extracellular domain (expressed on the surface of the T cells) is usually a fusion protein containing the variable part (one VH and one VL chain) of a monoclonal antibody targeting an antigen. The intracellular domain of the receptor acts as a signal transducer and weapons T cells to kill the target cells bearing the antigen recognized by the CAR extracellular domain. This CAR T cell technology has been approved for the treatment of several haematological malignancies, such as aggressive B-cell lymphomas or acute B-cell lymphoblastic leukaemias. According to the extracellular domain of the CAR, the corresponding CAR T cells can kill B cells, plasma cells, T cells, myeloid cells and – tomorrow – solid cancer cells expressing tumor antigens. Targeting auto-immune B cells is the bold step taken by Erlangen’s group. The hypothesis behind is straightforward: standard B cell depletion therapy (with monoclonal antibodies such as rituximab or obinutuzumab) indeed fails to completely eliminate tissue-based B cells which might be responsible for relapses. By using a more efficient B cell depletion procedure, also effective in immunological niches, long lasting remission – and even cure – might be expected.
In their Nature Medicine paper, the authors report on the efficacy and safety of CAR T cell therapy in 5 young refractory lupus patients. Autologous T cells were transduced with a lentiviral vector containing the sequence for a single-chain variable fragment derived from an antihuman CD19 hybridoma clone. After in vitro expansion, anti-CD19 CAR T cells were infused in patients, who had been previously conditioned by lymphodepletion chemotherapy with fludarabine and cyclophosphamide. As expected, CAR T cells expanded in vivo and CD19 B cells promptly disappeared from the circulation. Symptoms improved and DORIS remission – and even drug-free remission – was achieved in all 5 patients at 3 months. Serum complement C3 was normalized and serum anti-DNA antibodies completely disappeared. Despite B cells reconstitution after a mean of 110 days (mainly CD21+CD27– naive B cells but only a few or no CD21+CD27+ memory B cells, nor CD38+CD20– plasmablasts), no relapses were observed after 5 to 17 months of follow-up. Vaccination responses were not significantly affected. A low-grade cytokine release syndrome (fever) was observed in 3 out of 5 patients. None developed immune effector cell-associated neurotoxicity syndrome.
Several caveats must be raised, not the least being the possibility that lymphodepletion with fludarabine and cyclophosphamide per se was responsible for the clinical and biological benefit, although these patients had already received several lines of immunosuppression without success. Other issues need to be addressed, such as feasibility of a “tailor-made” therapy, cost of the procedure, patient’s selection or potential long-term adverse events. At last, whether CD19 CAR T cells are the most appropriate CAR T design is questionable since long-lived plasma cells do not express CD19.
Despite these caveats, this preliminary report might open a new research field in systemic autoimmunity.