Background/Purpose: Autologous chimeric antigen receptor (CAR) T-cell therapy is an exciting new potential therapy for autoimmune diseases but limited in scope of application by logistical complexity and cost of treatment. Furthermore, autoimmune patients will benefit from CAR T cell protocols that omit intensive conditioning chemotherapy (CCT) and integrate with their existing treatments. Here, we report 3-12 month follow-up data from our ongoing Phase I trial of FT819, an off-the-shelf iPSC-derived CD19-targeted CAR T-cell therapy, for the treatment of B-cell mediated autoimmune diseases (NCT06308978). FT819 is engineered to improve the safety and efficacy of CAR T cell therapy and incorporates a novel 1XX CAR signaling domain that extends T cell effector function without causing exhaustion. The CAR transgene is integrated into the T cell receptor (TCR) alpha constant locus to promote uniform CAR expression and enhance potency, with bi-allelic disruption of TCR expression to completely prevent graft-versus-host disease.

Methods: All patients enrolled to date were treated with FT819 for moderate to severe systemic lupus erythematosus (SLE) and either received fludarabine-free CCT (bendamustine or cyclophosphamide) or received no CCT and continued their standard-of-care therapy. Blood samples were collected at protocol-specified timepoints for B cell analysis.

Results: At baseline, patients had a mean SLEDAI score of 16 and reduced proportions of naïve B cells compared with healthy controls (HC, 60.2% vs 70.2%), increased proportions of pathogenically associated double-negative (DN) B cells (18.4% vs 8.7%), and circulating plasmablasts (PB, 8.2% vs 2.0%). Clonal architecture, as determined by sequencing of the BCR heavy chain, showed an increase in class-switched BCRs (73.1% vs 45.8%), larger clone sizes (12.3% vs 6.5% of total reads assigned to the top 10 clones), and a less diverse repertoire (Shannon index: 7.5 vs 8.7). Following treatment in patients receiving CCT, and concurrent with the overall resurgence in total B-cell numbers (6-12 mo), proportions of PB and DN B cells returned to the range observed in HC, while naïve B cells expanded to a proportion higher than that seen in HC. Moreover, the average proportion of large clones fell by 73.2%, with 87% of pre-treatment dominant clones absent by 6 months. Repertoire diversity increased from 6.2 to 9.2, and IgG/IgA fractions dropped by 42.6% while IgM rose 2.5-fold. Importantly, these measures paralleled the reduction in SLEDAI in these patients. In the patient treated with FT819 in the absence of CCT, we observed an overall minor reduction in PB (3.3% vs 2.9%) and DN B cells (33.3% vs 25.8%), but no change in naïve B cells at month 3 follow-up. Additionally, we observed a shift toward IgM positivity that, together with observed improvement in SLEDAI, may suggest ongoing rejuvenation of the B-cell compartment.

Conclusion: Collectively, these findings demonstrate that FT819 can remodel the B-cell compartment toward a naïve and more diverse repertoire, even without CCT, supporting immune reset as a mechanism of clinical remission. This trial is actively enrolling, and updated patient data will be included at the time of presentation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/longitudinal-analysis-of-b-cell-remodeling-in-systemic-lupus-erythematosus-following-ipsc-derived-car-t-cell-therapy/