Background: Through the targeting and depletion of B cells, anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has demonstrated profound responses in patients affected with autoimmune disease, including in refractory systemic lupus erythematosus (SLE). While patient-specific CAR T cells hold great promise as a potentially curative therapeutic option, several obstacles hamper its range of application, including limited access to authorized treatment centers, prolonged pre-apheresis and post-apheresis timelines, the challenge of controlling T-cell product consistency, high costs to the healthcare system, and the inability to create the quantity of CAR T cells needed to support a broad patient base. Furthermore, in many autoimmune diseases, the T-cell compartment is qualitatively and quantitively impaired, which can hinder CAR T-cell production and function. To circumvent these challenges, we have developed an off-the-shelf CAR19 T cell product candidate (FT819) derived from a clonal master cell bank engineered from an induced pluripotent stem cell (iPSC) line. This can be used as a renewable source for the mass production of CAR T cells made available off-the-shelf for broad patient access. FT819 is engineered with the following features designed to improve the safety and efficacy of CAR T cell therapy: a novel 1XX CAR signaling domain, which has been shown to extend T cell effector function without eliciting exhaustion; integration of the CAR transgene directly into the T cell receptor alpha constant (TRAC) locus, which has been shown to promote uniform CAR expression and enhanced T cell potency; and complete bi-allelic disruption of T cell receptor (TCR) expression for the prevention of graft-versus-host disease (GVHD).

Objectives: To evaluate the safety, tolerability, and clinical disease activity of one cycle of FT819.

Methods: A multicenter, Phase 1, study designed to evaluate the safety, pharmacokinetics, and anti-B-cell activity of FT819 in participants with active SLE is ongoing (NCT NCT06308978). SLE diagnosis is dependent on fulfilling 2019 EULAR/ACR classification criteria and at least one positive antibody (ANA ≥ 1:160, dsDNA Ab positive, or Smith Ab positive). Active SLE is defined by SLEDAI-2K of 8 or more and either 1 BILAG A or 2 BILAG B in at least one major organ system. Participants are enrolled in 2 stages: dose-escalation (3 + 3 study design) and dose-expansion. Regimen A is a single dose of FT819 following treatment with fludarabine-free preconditioning chemotherapy consisting of either cyclophosphamide (CY) or bendamustine. We report herein results from the first 3 patients enrolled in Regimen A.

Results: At the time of abstract submission, three patients were enrolled and treated with a single dose of FT819 (3.6 x10 ⁸ viable cells) following fludarabine-free preconditioning with follow-up ranging between 2 months and 8 months. The median age was 28 years (range, 22-29). All patients entered with a renal BILAG A with biopsy-proven lupus nephritis. All patients reported a median of 8 prior therapies (range 7-8) to treat their SLE, including rituximab. Two patients previously received CY during their disease course. At the time of study entry, all patients continued baseline hydroxychloroquine therapy, and two patients continued low dose corticosteroids. Patients received fludarabine-free preconditioning chemotherapy consisting of Cy alone (n=2) or bendamustine alone (n=1) prior to FT819 dosing. Rapid and deep peripheral depletion of B cells was observed in all patients. No FT819-related severe adverse events and no cytokine release syndrome, neurotoxicity, or dose limiting toxicities were reported. Improvements were observed in SLEDAI-2K, PGA, and FACIT-fatigue scores in all patients, in addition to improved proteinuria in patients with lupus nephritis. All patients demonstrated trends toward improvement in serum dsDNA Ab. The first patient has reached 6-month follow-up, achieving DORIS clinical remission and Low Lupus Disease Activity State with discontinuation of corticosteroid therapy by Month 3. Patient outcomes of current and additional subjects will be highlighted at the time of presentation.

Conclusion: Preliminary data from the first three patients in this clinical trial indicate favorable safety profile, effective B cell depletion with reconstitution of more naïve B cells, and promising initial efficacy. These findings support the continued evaluation of FT819 in SLE and expansion to other B-cell mediated autoimmune diseases, including ANCA-associated vasculitis, idiopathic inflammatory myositis, and systemic sclerosis. This initial report highlights the entry of off-the-shelf anti-CD19 CAR T-cell therapy into the clinical trial landscape, with on-demand drug product availability for patients with moderate to severe SLE, including those with active renal involvement.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: Vaneet Sandhu Fate Therapeutics, Fate Therapeutics, Parastoo Fazeli: None declared, Jennifer Medlin: None declared, Debra Zack Fate Therapeutics, Rebecca Elstrom Fate Therapeutics, Andrew BitMansour Fate Therapeutics, Bertha Villa Fate Therapeutics, Lilly Wong Fate Therapeutics, John Goulding Fate Therapeutics, Nicholas Brookhouser Fate Therapeutics, Trever Greene Fate therapeutics, Cara Bickers Fate therapeutics, Carol Wong Fate therapeutics, Julie Stewart Fate therapeutics, Tom Lee Fate therapeutics, Jode Goodridge Fate therapeutics, Marie Hu: None declared, Veronika Bachanova: None declared, Jeffrey S. Miller: None declared, Matthew Lunning: None declared, Bahram Valamehr Fate Therapeutics, Fate Therapeutics.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.