Background: GC012F (AZD0120) is a CD19/B cell maturation antigen (BCMA) dual-targeting CAR-T developed on the novel FasTCAR-T platform with next-day manufacturing, designed to improve depth and duration of B-cell depleting response. We present here early results from a dose escalation investigator initiative trial (IIT) (NCT05858684) to determine the safety, cellular kinetics (CK), and preliminary efficacy of GC012F in patients with refractory systemic lupus erythematosus (SLE).

Objectives: To evaluate the safety and preliminary efficacy of GC012F in patients with refractory SLE.

Methods: Ten SLE patients with SLEDAI-2K score ≥ 8 who had previously failed at least two kinds of immunosuppressants and one biologics were enrolled in this open-label, IIT study, conducted in Renji hospital, Shanghai. Standard lymphodepleting regimen (fludarabine 25 mg/m^2/day and cyclophosphamide 250 mg/m^2/day for 3 days, Day -5 to -3) was given before CAR-T cell infusion. Patients were administered a single infusion of GC012F at doses of 1.0×10^5 CAR-T cells/kg, 2.0×10^5 CAR-T cells/kg, or 3.0×10^5 CAR-T cells/kg using a 3 + 3 design for dose escalation. Safety parameters included cytokine-release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) as assessed by ASTCT 2019, and adverse effects evaluated according to CTCAE 5.0. Cellular kinetics (CK) data were monitored by quantitative polymerase chain reaction and flow cytometry. Efficacy was evaluated by the measure of autoantibodies, complement, SLEDAI-2K score, DORIS, KDIGO-2024 complete response (CR) and partial response (PR).

Results: As of Nov 12, 2024, ten Chinese patients with refractory active SLE (SLEDAI-2K score range 8-20) were enrolled and received GC012F infusion between June 2023 and April 2024 (4 patients at 1.0×10^5 cells/kg, 3 patients at 2.0×10^5 cells/kg, and 3 patients at 3.0×10^5 cells/kg). Patients were mostly young with a median age of 26.5 years (range: 19-42). All patients had biopsy proven lupus nephritis (Grade III: n=1, IV: n=5, V: n=1, III+V: n=1, IV+V: n=2), with a median disease duration of 6 years (range: 2-19). The median follow-up time after CAR-T infusion was 313.5 days (range: 211-487). No DLTs were observed. 7 patients across the 3 dose groups experienced Grade 1 (n= 6) or 2 (n= 1) CRS. The median time to onset of CRS was 7 days (range: 6-14) and the median duration was 1 day (range: 1-4). The Grade 2 CRS event was observed at dose of 3×10 ⁵ CAR-T cells/kg, with onset on day 7 and resolved on day 8 after treatment with dexamethasone and tocilizumab. No ICANS and ≥Grade 3 CRS were reported. Infections were observed in 8 patients, most of which were Grade 1 or 2 in severity. One patient (1.0×10^5 cells/kg) experienced grade 3 nasosinusitis and pneumonia, that resolved after antibiotics treatment. CK analysis revealed robust cell expansion, with a median peak concentration (Cmax) of 20,180 copies/μg DNA (11,482-50,316), and a median Tmax of 10 days (7-11). Complete B cell depletion was observed in all patients (shown as 0 cells/μL). The nadir of B cell concentration was observed on Day 10 (median, range: 7-10), with recovery starting on Day 84 (84-168). The majority of the recovered B cells were naïve B cells. All patients stopped immunosuppressants and biologics prior to CAR-T infusion, and stopped or used glucocorticoids (prednisone 5- 20mg/day) and/ or stable hydroxychloroquine after infusion for SLE per disease activity. At month 9, out of 10 patients, 7 patients stopped glucocorticoids and 4 of them also discontinued hydroxychloroquine, the other 3 patients were treated with prednisone 5mg/day. All patients achieved normalization of complement level after CAR-T infusion. 7 out of 10 patients achieved persistent serological conversion of ANA, ENA panel and anti-dsDNA antibodies. As of Jan 2025, 9 out of 10 patients achieved DORIS remission at month 9. All patients showed significant reduction of proteinuria, and among them, 6 achieved CR at month 9; 4 achieved PR per KDIGO 2024. 3 out of 4 patients with residual proteinuria consented for repeated renal biopsy at month 6-9, showing little active inflammation with dissolved immunocomplex deposition and effacement of podocyte foot processes in the kidney. These findings suggested that the remaining proteinuria is likely due to previous kidney damage rather than lupus activity and were not scored in the SLEDAI-2K. The one patient who did not consent for repeated biopsy scored 4 in SLEDAI-2K.

Conclusion: GC012F, a CD19/BCMA dual-targeting CAR-T, induced disease remission in refractory SLE patients with early favorable safety profile. A multicenter phase1/2 study (NCT06530849) is ongoing to further evaluate the safety and efficacy of GC012F in a broader range of patients with SLE.

REFERENCES: NIL.

Acknowledgements: We would like to thank all the participants and their families for their support.

Disclosure of Interests: Chunmei Wu: None declared, Yakai Fu: None declared, Jia Liu Gracell Biotechnologies Ltd, Yan Ye: None declared, Ran Wang: None declared, Gui Li Gracell Biotechnologies Ltd, Peiying Li: None declared, Lihong Weng Gracell Biotechnologies Ltd, Lianjun Shen Gracell Biotechnologies Ltd, Shuang Ye: None declared, Qiong Fu: None declared.

© 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.