OP0141 LONG TERM SAFETY AND EFFICACY OF CAR-T CELL TREATMENT IN REFRACTORY SYSTEMIC LUPUS ERYTHEMATOSUS - DATA FROM THE FIRST SEVEN PATIENTS

Abstract

Background Despite better treatment modalities some patients with systemic lupus erythematosus (SLE) suffer from severe and treatment-resistant disease. This situation puts patients at high risk for organ failure or even death. Furthermore, many patients with SLE have to take long-term, sometimes even life-long immune suppressive medication to control the disease without being able to enjoy drug-free remission. Recently, we reported that deep B cell depletion using a single infusion with autologous CD19 chimeric antigen receptor (CAR) T cells induced drug-free clinical remission in severe SLE patients with refractory disease [1,2]. This abstract presents the long-term clinical efficacy and safety data of the first seven SLE patients receiving autologous CD19-directed CAR-T cell therapy. Objectives To test whether administration of autologous CD19 chimeric antigen receptor (CAR) T cells is tolerable and effective in patients with severe refractory SLE. Methods Compassionate use program for patients with severe active SLE showing organ involvement and resistance to multiple immune suppressive treatments. Patients received autologous 1x106 CD19-CAR-T cells/kg body weight by single infusion after standard conditioning therapy (cyclophosphamide/fludarabine). The investigational medicinal product MB-CART19.1 was produced as described before [1,2]. All SLE treatments were stopped before CAR-T cell administration. Patients were followed up as in-patients for the first 10 days after CAR T cell administration, then weekly until the end of the first month, then monthly for three months and every three months thereafter. Tolerability was assessed by monitoring for Cytokine-release syndrome (CRS) and Immune-related effector Cell Neurotoxicity Syndrome (ICANS). Preliminary efficacy was assessed by reaching a Lupus Low Disease Activity State (LLDAS) and DORIS remission. Results As per January 2023, seven SLE patients (6 female, 1 male, aged range 19-39) had been treated with CD19 CAR-T cells with a median follow up of 13 months (4 months-22months). Patients had active disease with a median SLEDAI of 10 (range: 8-16), with a median of 4 organs involved (range: 8-16) and a median number of 7 failed treatments (range: 4-15). All patients had active kidney disease. In addition, involvement of the heart, lungs, pleura, joints, skin, muscles and bone marrow were documented. Conditioning was done at the described [1,2] dose with the exception of patients 7, who received only 50% of the dose. All patients received a single infusion of 1x106 autologous CD19-CAR-T cells/kg body weight. No ICANS was observed and CRS if observed were mild (grade I). In vivo, CAR-T cells rapidly expanded peaking at day 9 with a median of 26% of circulating T cells being CAR T cells (range: 11-59%). Expansion of CAR-T cells coincidence with the complete depletion of circulating B cells. B cell aplasia lasted for a median of 120 days (range 58-205). All patients experienced drug-free remission as assessed by DORIS remission criteria and met lupus low activity state (LLDAS) usually within the first three months after CAR T cell therapy. Furthermore, seroconversion with loss of dsDNA antibodies and other autoantibodies was observed. To date, no SLE flare occurred despite complete cessation of treatment. Conclusion Taken together, these data suggest that CD19 CAR T-cell therapy can abrogate disease and delete autoimmunity in patients with severe SLE. After CD19 CAR T-cell therapy SLE patients remain in drug free-remission of SLE even if B cells recur. This remission can be long-lasting as the longest disease -free observation period is now 22 months. References [1] Mougiakakos D et al., CD19-Targeted CAR T Cells in Refractory Systemic Lupus Erythematosus. N Engl J Med 2021;385:567-569. [2] Mackensen A. et al., Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus; Nat Med 2022 Oct; 28(10):2124-2132. ![Figure][1] Acknowledgements The study was supported by the Deutsche Forschungsgemeinschaft (FOR2886, CRC1181 and TRR221), the Bundesministerium für Bildung und Forschung (BMBF; MASCARA), the European Union (ERC Synergy grant 4D Nanoscope, ERC Consolidator grant INSPIRE) and the IMI-funded project RTCure. We thank S. Miltenyi for fruitful discussions, D. Werner and J. Hofer for assistance. Disclosure of Interests None Declared. [1]: pending:yes