Christopher L. Moore, PhD: No relevant disclosure to display
Introduction/Rationale: CD19 CAR T cells have demonstrated promising efficacy in SLE by deeply depleting B cells, but these autologous cell therapies are expensive to deploy, come with significant toxicity risks, and lack the ability to control additional immune cell functions driving autoreactive B cell generation and lupus pathogenesis.
Methods: We developed GNTI-350, an allogeneic hypoimmune CD19 CAR–engineered regulatory T cell (CAR19 EngTreg) therapy, which leverages stable FOXP3 expression, a CD19 CAR for selective targeting, and a rapamycin-inducible IL-2 signaling complex to sustain Treg function.
Results: Persistence of GNTI-350 is enabled by Immune Evasion Engineering (IEE), a hypoimmune technology that allows MHC-deficient allogeneic cell therapies to evade host NK cell clearance. Human CAR19 EngTregs expressed canonical Treg markers, suppressed T cell proliferation, blocked B cell differentiation into plasma cells, and depleted CD19+ B cells in humanized mice with minimal inflammatory cytokine release versus conventional CD19 CAR T cells. In the SLE123 mouse model, CAR19 mEngTregs persisted >4 months, lowered autoantibodies, improved kidney pathology, and reduced the levels of T follicular helper (Tfh) and germinal center (GC) B cells - potentially showing a reinforcement of T follicular regulatory (Tfr) cell function.
Conclusion: These data show that GNTI-350 can safely achieve a durable immune reset and may provide superior therapeutic benefit over CAR-T approaches to patients with B cell–driven autoimmune diseases.
