A phase I study of autologous mesenchymal stromal cells for severe steroid-dependent nephrotic syndrome

Abstract

BACKGROUNDSevere forms of idiopathic nephrotic syndrome (INS) require prolonged immunosuppressive therapies and repeated courses of high-dose glucocorticoids. Mesenchymal stromal cells (MSCs) have promising immunomodulatory properties that may be employed therapeutically to reduce patient exposure to medications and their side effects.METHODSWe performed a phase I open-label trial assessing safety and feasibility of autologous bone marrow-derived MSCs (BM-MSCs) in children and young adults with severe forms of steroid-dependent nephrotic syndrome. Following autologous BM-MSC preparation and infusion, oral immunosuppression was tapered. Safety, efficacy, and immunomodulatory effects in vivo were monitored for 12 months.RESULTSSixteen patients (10 children, 6 adults) were treated. Adverse events were limited and not related to BM-MSC infusions. All patients relapsed during follow-up, but in the 10 treated children, time to first relapse was delayed (P = 0.02) and number of relapses was reduced (P = 0.002) after BM-MSC infusion, compared with the previous 12 months. Cumulative prednisone dose was also reduced at 12 months compared with baseline (P < 0.05). No treatment benefit was observed in adults.In children, despite tapering of immunosuppression, clinical benefit was mirrored by a significant reduction in total CD19+, mature, and memory B cells and an increase in regulatory T cells in vivo up to 3-6 months following BM-MSC infusionCONCLUSIONTreatment with autologous BM-MSCs is feasible and safely reduces relapses and immunosuppression at 12 months in children with severe steroid-dependent INS. Immunomodulatory studies suggest that repeating MSC infusions at 3-6 months may sustain benefit.TRIAL REGISTRATIONEudraCT 2016-004804-77.FUNDINGAIFA Ricerca Indipendente 2016-02364623.

Keywords: Clinical Trials; Immunotherapy; Nephrology.

Figure 1. Study design.

*For this child, a subsequent telephone call gave information relating to safety, relapses, and immunosuppression at these time points.

Figure 2. Autologous BM-MSC treatment efficacy in relapse-free survival and withdrawal of immunosuppressive drugs.

(A) Relapse-free survival curve in the 12 months before (dotted line) and after (solid line) BM-MSC infusion shown overall (purple, left panel), in children (blue, central panel), and in adults (red, right panel). Unmatched Cox’s regression and a stratified Cox’s regression for matched pairs between the year before versus the year after of first MSC infusion was carried out. HR, hazard ratio. (B) Number of patients on immunosuppressive agents (prednisone, mycophenolate mofetil, calcineurin inhibitors) at baseline (full plots) and at +12 months (shaded plots) from BM-MSC infusion, shown overall (purple, left panel), in children (blue, central panel), and in adults (red, right panel). Bars represent the sum of patients in each group. Data were compared by Fisher’s exact test. **P < 0.01. ^†One adult patient was lost to follow-up at +8 months, as detailed in Supplemental Table 2. MMF, mycophenolate mofetil; CNI, calcineurin inhibitors (cyclosporine or tacrolimus).

Figure 3. Autologous BM-MSC treatment efficacy in number of relapses and number of immunosuppressive drugs needed to maintain remission.

(A) Single-patient representation of number of relapses in the 12 previous months (full dots, n_tot = 16) and in the 12 months after BM-MSC infusions (shaded dots, n_tot = 15) shown overall (purple, left panel), in children (blue, central panel), and in adults (red, right panel). Data were compared by Wilcoxon’s test. **P < 0.01. NS, not significant. ^†One adult patient was lost to follow-up at +8 months, as detailed in Supplemental Table 2. (B) Single-patient representation of number of immunosuppressive drugs at baseline (full dots, n_tot = 16) and at +12 months after BM-MSC infusions (shaded dots, n_tot = 15) shown overall (purple, left panel), in children (blue, central panel), and in adults (red, right panel). Data were compared by Wilcoxon’s test. *P < 0.05, **P < 0.01. NS, not significant. ^†One adult patient was lost to follow-up at +8 months, as detailed in Supplemental Table 2.

Figure 4. Pediatric immunomonitoring results.

(A) Total CD19⁺ B cells and B cell subpopulations at baseline and at 1, 3, 6, 9, and 12 months from BM-MSC infusions. Numbers of available samples at different time points are indicated in parentheses (n). Differences between groups were compared using the paired Wilcoxon’s test. *P < 0.05; **P < 0.01. (B) Total, memory, and HLA-DR⁺ memory Treg cells at baseline and at 1, 3, 6, 9, and 12 months from BM-MSC infusions. Numbers of available samples at different time points are indicated in parentheses (n). All box-and-whisker plots represent the median and the 25th and 75th centiles; error bars represent the smallest and the largest values. Within-group differences were compared using paired Wilcoxon’s signed-rank test. *P < 0.05; **P < 0.01.