OP0017 BCMA CD19 COMPOUND CHIMERIC ANTIGEN RECEPTOR T CELLS (cCAR) PROVIDES COMPLETE HUMORAL RESET, ELIMINATES ALL ELEVATED AUTOANTIBODIES, IMPROVES SYMPTOMS AND RENAL FUNCTION IN LUPUS NEPHRITIS (LN) PATIENTS
Authors: Y. Ma, Y. Yuan, S. He, W. Zhang, H. Zhang, V. Destefano, M. Wada, K. Pinz, G. Deener, N. Hagag, Y. Ma, M. Wang, F. LI, M. Hong, T. Lan, C. Zou, M. Wang, L. Ding, Y. Liang, W. Wang
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Lupus nephritis (LN) is a severe renal manifestation of systemic lupus erythematosus (SLE) caused by deposition of autoantibody immune complexes (type-3 hypersensitivity) which damage glomerular structures and may lead to end stage kidney disease. Autoantibody depletion has been attempted by targeting B cells, however no such treatment provides a complete humoral reset addressing both B and long-lived plasma cells. <h3>Objectives:</h3> cCAR was assessed for safety, efficacy, including improvement of renal function, and the potential to completely reset humoral immunity in an open label phase I clinical trial of LN patients receiving 3X10<sup>6</sup>/kg body weight cCAR target dose. <h3>Methods:</h3> 10 refractory LN patients who had failed multiple lines of therapy underwent a renal biopsy to confirm Class III to V LN, consented to the cCAR trial and received target dose after conditioning. T cells from peripheral blood obtained via apheresis were transfected to create cCAR. Cessation of all SLE medications (immunosuppressants, hydroxychloroquine, steroids and biologics) prior to conditioning and monitored after cCAR. IVIG prn per investigator discretion. <i>Baseline Characteristics</i>: 10 LN patients enrolled from June 2022 to February 2023. Patient age range: 16-46 with a mean 8 years since diagnosis (3 &gt;10 years) and 7 of 10 were female. Renal biopsy: Class IV/V most common (6 of 10), 2 Class IV, 1 Class V and 1 Class III/IV. Mean baseline eGFR 134 (3 &lt; 90). Mean 24-hr protein at screening (on SLE meds) was 1722 mg/day and increased to 2955 mg/day at baseline (after conditioning, SLE meds discontinued). Urine protein/creatine ratio (UPCR) 1.0 at screening, 1.8 at baseline. Mean SLEDAI-2K at screening 10.2. Patients had 37 elevated autoantibodies at baseline (3.7/patient). <h3>Results:</h3> <i>Safety</i>: Overall cCAR has been well tolerated. There have been no severe adverse events (SAE) attributed to cCAR, no CRES, no ICANS and no CRS &gt; 1. Other than Covid, only one Grade 1 urinary tract infection (UTI) infection reported. All patients recovered B cells and IgM within 150 days and patients on track to recover IgA and IgG within 1 year. First patient revaccinated recovered normal vaccine titers. <i>Efficacy</i>: B cells were entirely depleted in peripheral blood within 10 days post cCAR. IgM and IgA entirely depleted by day 42. Flow cytometry and B cell receptor (BCR) sequencing data confirm full humoral reset achieved. All elevated autoantibodies eliminated and did not return when B cells, Ig recovered. Mean SLEDAI-2K was 1.2 at 6 months (3 patients with &gt;10 years since diagnosis scored 4 on proteinuria or hematuria at last measure, may not be due to active disease given all elevated autoantibodies eliminated). After mean 9 months of follow up on no SLE meds, mean 24-hour urine was 574 mg/day (-67% decline from screening) and UPCR was 0.39 (-59% decline). Improvement in 24-hr urine and UPCR was much more profound in patients &lt;10 years of diagnosis with eGFR ≥90 compared to those with &gt;10 years since diagnosis or eGFR &lt;90. Platelets normalized in patient with thrombocytopenia at screening. Complete remission achieved at 6 months in patients &lt;10 years since diagnosis and with eGFR ≥90 at screening. <h3>Conclusion:</h3> These data on the 10 LN patients treated with cCAR demonstrate that the proof of concept intervention is well tolerated, provides a complete humoral reset that results in elimination of all elevated autoantibodies, medication-free symptom and renal function improvement. Patients will be followed to ensure remission/improvement is maintained. May need to treat with cCAR within 10 years of diagnosis and prior to Stage 3 chronic kidney disease (CKD) in order to achieve complete remission and complete renal response. The full dataset will be updated at the meeting. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> Patients and their families. <h3>Disclosure of Interests:</h3> Yupo Ma Employee of iCell Gene Therapeutics Inc., Yong Yuan: None declared, Shanzhi He: None declared, Wenli Zhang: None declared, Hongyu Zhang: None declared, Vincent DeStefano Employee of iCell Gene Therapeutics Inc., Masayuki Wada Employee of iCell Gene Therapeutics Inc., Kevin Pinz Employee of iCell Gene Therapeutics Inc., Greg Deener Employee of iCell Gene Therapeutics Inc., Nabil Hagag Employee of iCell Gene Therapeutics Inc., Yu Ma Employee of iCAR Bio Therapeutics Ltd, Min Wang: None declared, Fugui Li: None declared, Ming Hong: None declared, Ting Lan: None declared, Chanjuan Zou: None declared, Mingxia Wang: None declared, Ling Ding: None declared, Yingwen Liang: None declared, Weijia Wang: None declared.