HLA selected allogeneic mesenchymal stromal cell therapy in renal transplantation: the Neptune study, a phase I open-label single-center study

G.J. Dreyer, K.E. Groeneweg, S. Heidt, D.L. Roelen, M. van Pel, H. Roelofs, V.A.L. Huurman, I.M. Bajema, D.J.A.R. Moes, W.E. Fibbe, F.H.J. Claas, C. van Kooten, T.J. Rabelink, J.W. de Fijter, M.E.J. Reinders

Thursday 5 march 2020

14:00 - 14:10h at Theaterzaal

Parallel session: Parallel sessie XII – Klinische en Basale abstracts

Background: In renal transplantation, new strategies are needed to minimize the side effects of immunosuppressive drugs and to ensure long-term graft survival. Mesenchymal stromal cells (MSC) are an interesting candidate because of their anti-inflammatory, immune-regulatory and reparative properties and may therefore allow tapering of standard immunosuppression. So far, most clinical studies in renal transplantation have used autologous MSCs but to meet the need for acute treatment options, allogeneic MSCs are more suitable. However, allogeneic MSCs hold the risk to elicit an anti-donor immune response which might induce graft dysfunction, or sensitize patients for future transplants.

Methods: In this clinical phase I study 10 patients were included who received two doses of 1.5x10⁶ allogeneic MSCs infused 6 months after renal transplantation. At this point maintenance immunosuppression consisted of low dose calcineurin inhibitor (CNI) (trough levels of 1.5-3 ng/ml), everolimus and prednisone. In order to minimize the risk of an anti-donor immune response we selected allogeneic MSCs without repeated HLA mismatches with the allograft. The primary endpoint was safety, as measured by biopsy proven acute rejection (BPAR) and graft loss 12 months after transplantation. In addition, immune monitoring was performed before and after MSC infusion, including measurements of anti-HLA antibodies (DSA).

Results: No BPAR occurred and patient and graft survival was 100%. Mean tacrolimus trough level after MSCs was 3.04 ng/ml. Of importance, no de novo DSAs were formed against the MSCs or against the kidney graft. There were no major differences in T- and B-cell populations before and after infusion. Plasma cytokine analysis showed no significant changes directly after MSC infusion. CMV and BK viremia were comparable to numbers described in literature and no opportunistic infections occurred.

Conclusions: We demonstrate that selected allogeneic MSCs in combination with low dose CNI, 6 months after transplantation are safe. No dnDSA were formed and clinically there were no signs of rejection, graft loss and no decline in renal function. Immune monitoring in this study did not show specific T- and B-cell responses and no significant changes in cytokines, which demonstrates safety as no major immunological responses occurred. These results underline the potential immune modulatory effects of MSCs. Long term results of immune monitoring and clinical endpoints will be necessary to ensure safety in the long term.