Background/Purpose: Anti-CD19 chimeric antigen receptor (CAR) T cell therapy shows promise in autoimmune disease. However, autologous CAR T-cell therapy is limited by prolonged pre- and post-apheresis timelines, access to authorized treatment centers, T cell product inconsistency, high costs, and production capacity to support a broad patient (pt) base. Derived from a clonal master induced pluripotent stem cell (iPSC) bank for mass production of CAR T cells for on-demand and broad utilization, FT819 is an off-the-shelf CD19-targeting CAR T cell product engineered with features designed to improve safety and efficacy via a 1XX CAR signaling domain that extends T cell effector function without exhaustion; integration of CAR transgene directly into the T cell receptor (TCR) alpha constant locus promotes uniform CAR expression and enhanced potency; and complete bi-allelic disruption of TCR expression for the prevention of graft-versus-host disease (GVHD). Methods: A Phase 1 dose-escalation study evaluating the safety, pharmacokinetics, and anti-B-cell activity of FT819 in pts with B-cell mediated autoimmune diseases (NCT06308978) is ongoing. All pts enrolled to date have SLE (EULAR/ACR 2019 classification with at least one antibody: ANA 1:160, anti-dsDNA, or anti-smith), whose severity is defined by SLEDAI-2K ≥ 8 + 1 BILAG A/2 BILAG B scores. FT819 was administered as a single dose under 2 regimens (Reg): Reg A, fludarabine-free conditioning chemotherapy (CCT) with single-dose cyclophosphamide or bendamustine daily for 2 days prior to FT819; and Reg B, no CCT with continued stable dose of maintenance therapy, including mycophenolate (MMF). Results: As of the data cutoff date, pts treated in Reg A and Reg B had follow-up ranging from 1-12 months (mo). All pts tolerated FT819 without dose-limiting toxicity. Expected cytopenias after CCT were observed in Reg A. No Grade >2 CRS, ICANS, GvHD, or death was reported.
Pts in Reg A experienced rapid and deep peripheral B cell depletion, with greater depletion observed at dose level 2 (DL; DL1 = 3.6 x 108 viable cells (VC)/dose; DL2 = 9 x 108 VC/dose). Reconstitution of the B cell compartment, predominantly naïve, was noted within 1-3 mo post-FT819. Pts from both Regimens experienced sustained improvements in SLEDAI-2K, PGA, and FACIT-fatigue scores and UPCr improved in pts with lupus nephritis (LN). Pts with LN achieved either a primary efficacy renal response or complete renal response (CRR) by last follow up.
In the first pt in Reg A, steroids were discontinued at 3 mo, Definition of Remission in SLE (DORIS) achieved at 6 and 12 mo, and CRR at 9 mo. In the first pt in Reg B (BILAG A cardiorespiratory), MMF was continued without CCT, and Low Lupus Disease Activity State was achieved at 3 mo. Additional pt outcomes of current and additional pts will be highlighted at the time of presentation. Conclusion: Preliminary patient data indicates a favorable safety profile, effective B cell depletion, and promising initial efficacy. These findings support the continued evaluation of FT819 in SLE as well as other B-cell mediated autoimmune diseases (ANCA-associated vasculitis, idiopathic inflammatory myositis, and systemic sclerosis) included in the FT819 protocol.
