“The example case illustrates the principal possibility to resolve SLE via a single infusion of therapeutic T cells that induce deep B cell depletion. This observation highlights the seminal role of B cells in mounting inflammation and tissue damage in SLE,” the authors write. “The elimination of disease-specific autoantibodies without induction of hypogammaglobulinemia or loss of vaccination responses points to the fact that at least some autoantibodies—those directed against DNA and nucleosomes—mostly stem from plasmablasts and not from long-lived bone marrow plasma cells.”
B Cell-Depleting Therapy
Plasmablasts may not represent the principal source of all types of autoantibodies. In SLE, the contribution of plasmablasts and short-lived and long-lived plasma cells in autoantibody production is unknown. Patients with SLE may require a tailored treatment approach targeting plasma cells, such as with daratumumab. This monoclonal antibody recognizes the CD38 surface molecule expressed on several B cell-differentiation stages, including plasma cells and activated T cells.
However, “including the plasma cell compartment in a treatment approach must be weighed against its risks, such as loss of immune memory and abrogation of vaccine responses as well as increased infection risk arising from hypogammaglobulinemia,” the authors write.
CAR-T cells are genetically engineered T cells that express a surface receptor called CAR, comprising domains for extracellular antigen-binding and intracellular T cell activation. CAR-T cells that target the B cell-specific receptor CD19 were designed to eradicate malignant B cells in B cell leukemia and lymphoma. Autoimmune B cells also express CD19, so are susceptible to eradication by CD19-targeted CAR-T cells.
In SLE, CAR-T cell-induced B cell depletion is short, lasting for around three to four months after infusion, and despite B cell reconstitution, not followed by disease recurrence—a complete contrast to cancer.
“CAR-T cells are exhausted or eliminated after CD19 CAR-T cell therapy in SLE because the recurring B cells do not show evidence for an immune escape like the downregulation of CD19 expression observed in cancer cells,” the authors write.
Safety
While generally well tolerated, patients undergoing B cell-depleting therapy may become unresponsive to humoral vaccinations or develop hypogammaglobulinemia with an increased risk of infection. However, the short time to B cell reconstitution after CD19 CAR-T cell therapy limits the development of hypogammaglobulinemia and the time of insufficient vaccination responses.
“Another interesting aspect is the good tolerability of CAR-T cell therapy in the few patients with SLE studied so far,” the authors write. “T cell activation and the resulting cytokine release in conjunction with target-engaged CAR-T cells is substantially milder, resulting in better tolerability of the treatment.”
