0501: Phase 1b Study of SBT777101, an Engineered CAR-T-Regulatory Cell Product, in Patients With Rheumatoid Arthritis: Interim Demographics and Safety

Background/Purpose: Regulatory T cells (T_regs) modulate inflammation, maintain self-tolerance, and promote tissue repair, and thus hold promise as a versatile therapeutic tool. Autologous polyclonal T_regs have a favorable safety profile but equivocal efficacy in autoimmune disorders.

Engineered T_regs offer a novel approach by introduction of a chimeric antigen receptor (CAR) specific for tissue- or disease-associated antigens. SBT777101 is an autologous T_reg product transduced with a CAR specific for citrullinated proteins (Cit-P), which are present in the inflamed synovium of participants with rheumatoid arthritis (RA, Figure 1). Unlike cytotoxic CAR-T therapies, SBT777101 may restore balance to the immune system without cell destruction. Potential mechanisms of action include bystander suppression of antigen presenting cells and effector T cells, IL2 consumption, and immunomodulatory cytokine production to promote immune homeostasis and tissue repair.

REGULATE-RA is an ongoing first-in-human, phase 1 study to evaluate the safety and tolerability of autologous CAR-T_reg therapy targeting Cit-P in patients with refractory RA. Exploratory endpoints include the assessment and characterization of SBT777101’s pharmacokinetic (PK) profile, pharmacodynamic (PD) parameters, mechanism of action (MOA), and preliminary efficacy.

Methods: The study includes RA participants aged 18-70 with moderate-to-severe active disease (DAS28-CRP≥3.2). Participants must have demonstrated an inadequate response to, or intolerance of, at least 3 biologic or targeted synthetic disease-modifying antirheumatic drugs with differing MOA.

SBT777101 is prepared by transduction of autologous T_regs with a Cit-P-specific CAR and is administered in a 3+3 dose-escalation design (figure 2).

Participants are monitored for adverse events and clinical response over a 48-week study period. PK, PD, and MOA are evaluated in peripheral blood and, where available, synovial biopsies. All participants are encouraged to enter a 15-year long-term follow-up study for safety evaluation.

Results: Prior to patient enrollment, a manufacturing process for SBT777101 was established and shown to produce consistent yield, functionality, and molecular signatures from both healthy donors and RA participants. For dosed participants, the yield and molecular signatures of manufactured products have remained consistent with the preclinical manufacturing results.

As of April 2025, four participants have received infusions of SBT777101, and no dose-limiting toxicities have been observed. Four additional participants are enrolled but are not yet dosed. Patient characteristics are summarized in Table 1.

All four dosed participants tolerated the infusion, with no cytokine release syndrome, neurotoxicity, or other immune-mediated toxicities detected. Clinical assessments and biomarker analyses are ongoing to assess changes in disease activity, systemic inflammation and T_reg activity.

Conclusion: To date, CAR-T_reg therapy targeting Cit-P demonstrates a favorable safety profile in this early phase study. Ongoing enrollment and follow-up will provide additional insights into characterization, pharmacodynamics and efficacy outcomes.