ALLOGENEIC UMBILICAL-CORD DERIVED MESENCHYMAL STROMAL CELLS MSC(UC) AS TREATMENT FOR SYSTEMIC LUPUS ERYTHEMATOSUS (SLE): SAFETY AND EARLY CLINICAL/BIOLOGICAL RESULTS FROM A PHASE I-II PROOF-OF-CONCEPT CLINICAL STUDY

Background & Aim: Background Preclinical studies show Mesenchymal Stromal Cells (MSC) unique immunomodulatory, proangiogenic, and antifibrotic effects. Few clinical data report MSC use to treat Systemic Lupus (SLE) patients (pts) resistant to standard immunosuppressors and biologics, who suffer from high morbidity and increased mortality. Aims To test the safety and preliminary efficacy of a single intravenous injection of allogeneic umbilical cord-derived (UC) MSC in severe SLE. Methods, Results & Conclusion: Methods A prospective, single-center, Bayesian phase I/II study (NCT03562065) enrolled SLE pts (ACR criteria + antinuclear antibodies), aged 18–70 years (yr) with active disease (SELENA-SLEDAI-2K ≥6) at baseline and refractory to >2 immunosuppressive therapies for at least 3 months (M), including Prednisone ≥ 6 mg daily for ≥ 28 days, to receive a single infusion of 2 or 4.106 MSC(UC)/kg obtained from a single UC. Primary endpoint was the rate of treatment-related (TR) severe adverse events (SAE, grade ≥ 3) in the first 10 days post-MSC(UC) infusion. Secondary endpoints were adequacy of MSC(UC) production, all AE, clinical, HrQol and immune responses at M1 and quarterly for 1 yr post-infusion. Results From Sept 2019 to Feb 2023, 8 (7 female) pts, median age 35 [IQR 27-60] yrs after 12 [6-21] yrs SLE duration, were included with PGA 2 [1.5-2], SELENA-SLEDAI-2K 11.5 [8-14.2], BILAG A (50%), B (38%) or C (12%) and SLICC-ACR 1.5 [0-2.8] prior MSC(UC) infusion (median dose 2 [IQR 2-4]x106/kg). All pts received ≥2.106/kg MSC(UC) (5 assigned to 2.106/kg, 3 to 4.106/kg) with 1 batch released at lower than expected target dose. No SAE and 3 infusion-related AE (2 grade 1, 1 grade 2) in 2 pts occurred in the first 10 days. After 12.4 (min 9.6-max 13) months of follow-up, there were no TR SAE and 3 non-TR SAE after relapse in 1 pt. Improved clinical status (Table) in 7/8 pts at M3 persisted over 1 yr with 2 major and 2 partial clinical responses at M12. Donor-specific anti-HLA antibodies developed de novo in 1 pt at M3. While circulating T, B, NK and monocytes were unmodified by MSC(UC), CD24hiCD38hi transitional and CD27posCD38neg/loCD24hi memory B-cells frequencies, i.e. regulatory B-cell subsets, increased significantly and transiently at M1. Conclusion A single infusion of MSC(UC) was safe in 8 severe SLE pts. This proof of concept study showed clinical improvement. Placebo-controlled trials are needed to confirm clinical efficacy and explore the role of B-cell modifications in clinical benefit. Preclinical studies show Mesenchymal Stromal Cells (MSC) unique immunomodulatory, proangiogenic, and antifibrotic effects. Few clinical data report MSC use to treat Systemic Lupus (SLE) patients (pts) resistant to standard immunosuppressors and biologics, who suffer from high morbidity and increased mortality. To test the safety and preliminary efficacy of a single intravenous injection of allogeneic umbilical cord-derived (UC) MSC in severe SLE. A prospective, single-center, Bayesian phase I/II study (NCT03562065) enrolled SLE pts (ACR criteria + antinuclear antibodies), aged 18–70 years (yr) with active disease (SELENA-SLEDAI-2K ≥6) at baseline and refractory to >2 immunosuppressive therapies for at least 3 months (M), including Prednisone ≥ 6 mg daily for ≥ 28 days, to receive a single infusion of 2 or 4.106 MSC(UC)/kg obtained from a single UC. Primary endpoint was the rate of treatment-related (TR) severe adverse events (SAE, grade ≥ 3) in the first 10 days post-MSC(UC) infusion. Secondary endpoints were adequacy of MSC(UC) production, all AE, clinical, HrQol and immune responses at M1 and quarterly for 1 yr post-infusion.