Safety and Preliminary Efficacy of Mesenchymal Stromal Cell (ORBCEL-M) Therapy in Diabetic Kidney Disease: A Randomized Clinical Trial (NEPHSTROM)

Abstract

Significance statement: Mesenchymal stromal cells (MSCs) may offer a novel therapy for diabetic kidney disease (DKD), although clinical translation of this approach has been limited. The authors present findings from the first, lowest dose cohort of 16 adults with type 2 diabetes and progressive DKD participating in a randomized, placebo-controlled, dose-escalation phase 1b/2a trial of next-generation bone marrow-derived, anti-CD362 antibody-selected allogeneic MSCs (ORBCEL-M). A single intravenous (iv) infusion of 80×10 6 cells was safe and well-tolerated, with one quickly resolved infusion reaction in the placebo group and no subsequent treatment-related serious adverse events (SAEs). Compared with placebo, the median annual rate of decline in eGFR was significantly lower with ORBCEL-M, although mGFR did not differ. The results support further investigation of ORBCEL-M in this patient population in an appropriately sized phase 2b study.

Background: Systemic therapy with mesenchymal stromal cells may target maladaptive processes involved in diabetic kidney disease progression. However, clinical translation of this approach has been limited.

Methods: The Novel Stromal Cell Therapy for Diabetic Kidney Disease (NEPHSTROM) study, a randomized, placebo-controlled phase 1b/2a trial, assesses safety, tolerability, and preliminary efficacy of next-generation bone marrow-derived, anti-CD362-selected, allogeneic mesenchymal stromal cells (ORBCEL-M) in adults with type 2 diabetes and progressive diabetic kidney disease. This first, lowest dose cohort of 16 participants at three European sites was randomized (3:1) to receive intravenous infusion of ORBCEL-M (80×10 6 cells, n =12) or placebo ( n =4) and was followed for 18 months.

Results: At baseline, all participants were negative for anti-HLA antibodies and the measured GFR (mGFR) and estimated GFR were comparable between groups. The intervention was safe and well-tolerated. One placebo-treated participant had a quickly resolved infusion reaction (bronchospasm), with no subsequent treatment-related serious adverse events. Two ORBCEL-M recipients died during follow-up of causes deemed unrelated to the trial intervention; one recipient developed low-level anti-HLA antibodies. The median annual rate of kidney function decline after ORBCEL-M therapy compared with placebo did not differ by mGFR, but was significantly lower by eGFR estimated by the Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease equations. Immunologic profiling provided evidence of preservation of circulating regulatory T cells, lower natural killer T cells, and stabilization of inflammatory monocyte subsets in those receiving the cell therapy compared with placebo.

Conclusions: Findings indicate safety and tolerability of intravenous ORBCEL-M cell therapy in the trial's lowest dose cohort. The rate of decline in eGFR (but not mGFR) over 18 months was significantly lower among those receiving cell therapy compared with placebo. Further studies will be needed to determine the therapy's effect on CKD progression.

Clinical trial registration number: ClinicalTrial.gov NCT02585622 .

Graphical abstract

Figure 1

Summary of NEPHSTROM trial design. Study flowchart of the NEPHSTROM cohort trial (A) and the overall NEPHSTROM clinical trial treatment plan and follow-up (B). Figure 1 can be viewed in color online at www.jasn.org.

Figure 2

Frequency of peripheral blood leukocytes during the study period. Percentages of CD4⁺ T cells (A), CD8⁺ T cells (B), B cells (C), Lin⁻HLADR⁺ dendritic cells (D), monocytes (E), cytotoxic NK cells (F), and natural killer T cells (G) within CD45⁺ peripheral blood leukocytes in participants randomized to ORBCEL-M or placebo during the follow-up. Values are expressed as median (IQR). *P < 0.05 between the ORBCEL-M and placebo groups (ANCOVA). §P < 0.05 versus preinfusion in the group (Wilcoxon test). Lin⁻: CD3, CD14, CD16, CD19, CD20, and CD56.

Figure 3

Frequency of peripheral blood Tregs and Treg subpopulations during the study period. Percentages of Tregs (A), CD45RA⁻RO⁺ memory Tregs (B), Helios⁺CD95⁺HLA-DR⁻ memory Tregs (C), and CD45RA⁺RO⁻-naïve Tregs (D) within peripheral blood CD3⁺CD4⁺ T cells in participants randomized to ORBCEL-M or placebo during the follow-up. Values are expressed as median (IQR). Tregs, regulatory T cells. *P < 0.05 between the ORBCEL-M and placebo groups (ANCOVA). Tregs, regulatory T cells.

Figure 4

Frequency of peripheral blood monocyte subpopulations during the study period. Percentages of HLADR⁺CD33⁺CD14⁺CD16⁻ monocytes (A), HLADR⁺CD33⁺CD14⁻CD16⁺ monocytes (B), and HLADR⁺CD33⁺CD14⁺CD16⁺ monocytes (C) within CD45⁺ peripheral blood leukocytes in participants randomized to ORBCEL-M or placebo during the follow-up period. Values are expressed as median (IQR). *P < 0.05 between the ORBCEL-M and placebo groups (ANCOVA).

Figure 5

Proinflammatory mediators. Serum concentrations of TNFR1 (A), NGAL (B), VCAM-1 (C), and EGF (D) in participants randomized to ORBCEL-M or placebo during the follow-up. Values are expressed as median (IQR). §P < 0.05 versus preinfusion in the group (Wilcoxon test). TNFR1, soluble tumor necrosis factor 1; NGAL, neutrophil gelatinase-associated lipocalin; VCAM-1, vascular cell adhesion molecule 1; EGF, epidermal growth factor.

Figure 6

Progression of diabetic kidney disease in the two study groups. Risk of diabetic kidney disease progression in participants randomized to ORBCEL-M or placebo for change in the 2-year risk of achieving end stage kidney failure from baseline to 18 months on the basis of the validated Tangri 4-variable kidney failure risk equation. Total number of participants at baseline, ORBCEL-M n=12 and placebo n=4, and at 18 months ORBCEL-M n=10 (2 died before the end of the study) and placebo n=4.