Background/Purpose: Evaluate cCAR safety in SLE, LN and autoimmune conditions. Determine whether a single dose eliminates autoantibodies with well tolerated long-term, medication-free remission in open label proof of concept.

Methods: BCMA-CD19 cCAR approved by Zhongshan People’s Hospital and Peking University Shenzhen Hospital IRBs for autoimmune patients. Initially compassionate use in 2 lymphoma patients with 20-year history of SLE (Patient 1 Sept 2019). After initial SLE patients safely in remission, IRB approved cCAR for use in LN (11 LN patients June 22 to April 23). 18 patients in safety dataset (includes NMOSD, donor specific antibodies in transplant).

Lupus patients: After apheresis, prior to cyc/fludarabine conditioning all lupus medications discontinued. Patients dosed 1.5-3×10⁶ cCAR cells/kg (LN target 3×10⁶/kg) and then monitored, IVIG given PRN. LN: required to fail multiple lines of therapy, be refractory and active disease on kidney biopsy (class III to V). All LN, SLE patients met ACR criteria.

Baseline Characteristics: Lupus age range: 17-58. 10 of 13 female. SLEDAI-2K baseline mean = 10. All LN patients at screening treated with HCQ, glucocorticoids, immunosuppressant (MMF, CYC); majority with belimumab. At screening, mean 24-hour urine microprotein 1.7g and urine/creatine ratio 1.0. Patients avg 3.9 elevated autoantibodies (2.5 >3X ULN, many >20X ULN). Majority had low C3.

Results: Safety: cCAR well tolerated; no CRES/iCANs, no CRS >Grade 1, no fever >40^o C. All LN patients received target dose and only infection other than Covid was a Grade 1 UTI.8 patients tested positive for Covid (at time >80% local population tested positive), 3 hospitalized as precaution, none in ICU. No other URIs reported. No GI infections or diarrhea AEs suggesting no concerning IgA related AEs.

B cells/Ig: B cells eliminated in 1-10 days; IgM, IgA, IgG eliminated in 1-2 months. WBC normal in 7-21 days. B cells returned to normal in all patients (mean 90 days, range 40 to 150). All patients treated >150 days normal IgM. Flow cytometry, BCR sequences confirm immune reset achieved. Given B cells, IgM normal within 150 days, expect all patients to fully regain humoral immunity.

Efficacy: All elevated autoantibodies eliminated, including those derived from long-lived plasma cells, most in first month. All C3, C4 normal within 21 days. All patients had significant medication-free symptom improvement (11 of 13 in first month). All 3 patients at >1 year (up to 44 months) in medication-free remission (no symptoms). Renal function significantly improved in LN patients within first 6 months.

Conclusion: Proof of concept achieved. cCAR safely eliminated all autoantibodies, reset B cell and humoral immune system, and delivered long-term, medication-free remission in a single dose. Monitoring patients to ensure humoral immunity fully recovers. Will update with full dataset, further research is needed.

Acknowledgements: Patients and their families.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/novel-bcma-cd19-compound-car-t-ccar-targets-b-cells-and-plasma-cells-achieving-immune-reset-and-eliminates-all-autoantibodies-in-systemic-lupus-erythematosus-sle-and-lupus-nephritis-ln-patients/