Safety, immunological effects and clinical response in a phase I trial of umbilical cord mesenchymal stromal cells in patients with treatment refractory SLE

Abstract

Background: Reports of clinical improvement following mesenchymal stromal cell (MSC) infusions in refractory lupus patients at a single centre in China led us to perform an explorative phase I trial of umbilical cord derived MSCs in patients refractory to 6 months of immunosuppressive therapy.

Methods: Six women with a SLEDAI >6, having failed standard of care therapy, received one intravenous infusion of 1×106 MSCs/kg of body weight. They maintained their current immunosuppressives, but their physician was allowed to adjust corticosteroids initially for symptom management. The clinical endpoint was an SRI of 4 with no new British Isles Lupus Activity Guide (BILAG) As and no increase in Physician Global Assessment score of >0.3 with tapering of prednisone to 10 mg or less by 20 weeks.

Results: Of six patients, five (83.3%; 95% CI 35.9% to 99.6%) achieved the clinical endpoint of an SRI of 4. Adverse events were minimal. Mechanistic studies revealed significant reductions in CD27IgD double negative B cells, switched memory B cells and activated naïve B cells, with increased transitional B cells in the five patients who met the endpoint. There was a trend towards decreased autoantibody levels in specific patients. Two patients had increases in their Helios+Treg cells, but no other significant T cell changes were noted. GARP-TGFβ complexes were significantly increased following the MSC infusions. The B cell changes and the GARP-TGFβ increases significantly correlated with changes in SLEDAI scores.

Conclusion: This phase 1 trial suggests that umbilical cord (UC) MSC infusions are very safe and may have efficacy in lupus. The B cell and GARP-TGFβ changes provide novel insight into mechanisms by which MSCs may impact disease.

Trial registration number: NCT03171194.

Keywords: Autoimmunity; B-Lymphocytes; Lupus Erythematosus, Systemic.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Clinical and patient-reported outcomes. (A) Line plot of the change in SELENA-SLEDAI scores over the course of the trial. This is the overall score combining lab and clinical criteria. The primary endpoint was the SLE Responder Index (SRI) 4 at 24 weeks). There was overall a significant decline in SELENA-SLEDAI scores of 5/6 patients meeting the SRI-4 endpoint (p

Figure 2

B cell subset changes over time by flow cytometry. (B) Cell subset changes over time as determined by flow cytometry. Significant differences in B cell subsets occurred over the trial period as also noted in online supplemental table 2. The cell markers used are listed in the methods and are previously published. Most significant changes were in decreased double negative B cells including DN2, increased transitional B cells and decreased activated naive B cells. IgD−CD27+=SM+PB, IgD−CD27−=DN1+DN2+(DN3 +4), IgD+CD27=(T1 +T2)+(rN +T3)+aN. aN, activated naïve; DN, double negative; rN, resting naïve; SM, switched memory; T, transitional; PB, plasmablasts; USM, unswitched memory.

Figure 3

Cell changes over time. (A) Treg changes over time are presented. Participant 1 had a significant increase over time in Tregs both Helios+and Helios− looking at percentage change and fold change over baseline. Participant 2 had a significant increase with time compared with baseline in both Treg subsets, though the percentage change was small given the low percentage of Tregs at baseline (B). A representative flow block is shown in figure part C demonstrating the increase in Tregs over time from 0% to 8% in participant 1. (D–F) GARP serum measures. Figure part D shows measures of circulating serum GARP-LAP (latency-associated peptide) complexes as measured by a sandwich ELISA assay as previously described. Random SLE patients in the MUSC cohort (n=30) had significantly less (p=0.0226) circulating GARP-LAP complex than age/sex/race matched controls (n=16) y-axis is od 450. (E) Plots GARP–LAP complexes via ELISA versus patient SLEDAI score at the time of blood draw (n=21) for the MUSC lupus cohort. The y-axis is OD 450 reading via ELISA. There is a significant correlation between SLEDAI score and GARP–LAP complexes in patients with SLEDAI scores >10. Figure part F is a sandwich ELISA measure of soluble serum GARP expressed as ng/mL of serum in the MSC treated patients over time demonstrating near 0 levels of serum GARP at baseline with significant increases at week 4, decreasing at week 8 prior to rebounding at week 24 in 3/5 patients. Mann-Whitney U test was used to determine significance (week 0–week4- p=0.003). GARP, glycoprotein A repetition predominant; LAP, latency-associated peptide; MUSC, Medical University of South Carolina; MSC, mesenchymal stromal cell; OD, optical density.