Background/Purpose: CD19 CAR T therapies have demonstrated promise in systemic lupus erythematosus (SLE) by transiently depleting B cells and resetting the immune system. However, long-term remission may require sustained regulation of autoreactive immune responses, including suppression of T follicular helper (Tfh) cells that drive pathogenic B cell maturation in germinal centers (GCs). Additionally, limitations such as cytokine release syndrome (CRS), neurotoxicity, and the cost of autologous manufacturing restrict applicability of current CAR T approaches in autoimmune settings.

Methods: To overcome these limitations, we developed GNTI-350, an allogeneic CD19 CAR-engineered regulatory T cell (CAR19 EngTreg) therapy designed to achieve robust immune reset by combining the B cell depletion capacity of CAR T cells with the suppressive function of Tregs. GNTI-350 cells are generated using a proprietary platform enabling (1) stable FOXP3 expression for lineage commitment, (2) a CD19-targeted CAR for selective B cell engagement, and (3) a chemically-inducible IL-2–like signaling complex (CISC) that supports Treg function in IL-2–deficient autoimmune settings through rapamycin addition. The platform enables efficient manufacturing with high purity and scalability.

Results: In vitro, CAR19 EngTregs exhibited hallmark Treg markers (FOXP3, CD25, CTLA-4, ICOS) and drove primary B cell depletion, while maintaining low inflammatory cytokine production (IFNγ, TNFα, IL-6) compared to CAR19 T effectors. Additionally, CAR19 EngTregs suppressed T cell proliferation, blocked B cell differentiation, and reduced immunoglobulin production. In vivo studies in the SLE123 model also demonstrated short-term depletion of peripheral B cells followed by a return to baseline levels within one month, mirroring transient clinical CAR19 T effectors. However, GNTI-350 achieved sustained immunologic reset: EngTregs persisted for over 7 months, suppressed Tfh cells, reduced GC B cells, lowered disease-driving autoantibodies, and decreased kidney damage markers. Notably, these data demonstrate CAR19 EngTregs drive dual modulation of B and T cells, mimicking the function of follicular regulatory T cells (Tfr) that naturally restrain GC activity. In this context, GNTI-350 acted as a “super Tfr” by simultaneously suppressing Tfh cells and GC B cells—thereby disrupting the regeneration of pathogenic B cells and autoantibodies.

Conclusion: GNTI-350 is a first-in-class, allogeneic, antigen-targeted Treg therapy with the capacity to act as a potent “super Tfr,” disrupting germinal center pathology by concurrently targeting B cells and Tfh cells. This dual mechanism offers a durable and safe immune reset, distinguishing GNTI-350 as a promising therapeutic candidate for B cell–driven autoimmune diseases such as SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/gnti-350-a-car-treg-therapy-offering-durable-immune-reset-with-improved-safety-for-b-cell-driven-autoimmune-diseases/