Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials

Sawitzki, Birgit ; Harden, Paul N. ; Reinke, Petra ; Moreau, Aurelie ; Hutchinson, James A.

; Game, David S. ; Tang, Qizhi ; Guinan, Eva C. ; Battaglia, Manuela ; Burlingham, William J. ; Roberts, Ian S. D. ; Streitz Diplom, Mathias ; Josien, Regis ; Böger, Carsten A. ; Scottà, Cristiano ; Markmann, James F. ; Hester, Joanna L. ; Juerchott, Karsten ; Braudeau, Cecile ; James, Ben ; Contreras-Ruiz, Laura ; van der Net, Jeroen B. ; Bergler, Tobias ; Caldara, Rossana ; Petchey, William ; Edinger, Matthias ; Dupas, Nathalie ; Kapinsky, Michael ; Mutzbauer, Ingrid ; Otto, Natalie M. ; Öllinger, Robert ; Hernandez-Fuentes, Maria P. ; Issa, Fadi ; Ahrens, Norbert

; Meyenberg, Christoph ; Karitzky, Sandra ; Kunzendorf, Ulrich ; Knechtle, Stuart J. ; Grinyó, Josep ; Morris, Peter J. ; Brent, Leslie ; Bushell, Andrew ; Turka, Laurence A. ; Bluestone, Jeffrey A. ; Lechler, Robert I. ; Schlitt, Hans J.

; Cuturi, Maria C. ; Schlickeiser, Stephan ; Friend, Peter J. ; Miloud, Tewfik ; Scheffold, Alexander

; Secchi, Antonio ; Crisalli, Kerry ; Kang, Sang-Mo ; Hilton, Rachel ; Banas, Bernhard

; Blancho, Gilles ; Volk, Hans-Dieter ; Lombardi, Giovanna ; Wood, Kathryn J. ; Geissler, Edward K.

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Background
Use of cell-based medicinal products (CBMPs) represents a state-of-the-art approach for reducing general immunosuppression in organ transplantation. We tested multiple regulatory CBMPs in kidney transplant trials to establish the safety of regulatory CBMPs when combined with reduced immunosuppressive treatment.

Methods
The ONE Study consisted of seven investigator-led, single-arm trials done internationally at eight hospitals in France, Germany, Italy, the UK, and the USA (60 week follow-up). Included patients were living-donor kidney transplant recipients aged 18 years and older. The reference group trial (RGT) was a standard-of-care group given basiliximab, tapered steroids, mycophenolate mofetil, and tacrolimus. Six non-randomised phase 1/2A cell therapy group (CTG) trials were pooled and analysed, in which patients received one of six CBMPs containing regulatory T cells, dendritic cells, or macrophages; patient selection and immunosuppression mirrored the RGT, except basiliximab induction was substituted with CBMPs and mycophenolate mofetil tapering was allowed. None of the trials were randomised and none of the individuals involved were masked. The primary endpoint was biopsy-confirmed acute rejection (BCAR) within 60 weeks after transplantation; adverse event coding was centralised. The RTG and CTG trials are registered with ClinicalTrials.gov, NCT01656135, NCT02252055, NCT02085629, NCT02244801, NCT02371434, NCT02129881, and NCT02091232.

Findings
The seven trials took place between Dec 11, 2012, and Nov 14, 2018. Of 782 patients assessed for eligibility, 130 (17%) patients were enrolled and 104 were treated and included in the analysis. The 66 patients who were treated in the RGT were 73% male and had a median age of 47 years. The 38 patients who were treated across six CTG trials were 71% male and had a median age of 45 years. Standard-of-care immunosuppression in the recipients in the RGT resulted in a 12% BCAR rate (expected range 3·2–18·0). The overall BCAR rate for the six parallel CTG trials was 16%. 15 (40%) patients given CBMPs were successfully weaned from mycophenolate mofetil and maintained on tacrolimus monotherapy. Combined adverse event data and BCAR episodes from all six CTG trials revealed no safety concerns when compared with the RGT. Fewer episodes of infections were registered in CTG trials versus the RGT.

Interpretation
Regulatory cell therapy is achievable and safe in living-donor kidney transplant recipients, and is associated with fewer infectious complications, but similar rejection rates in the first year. Therefore, immune cell therapy is a potentially useful therapeutic approach in recipients of kidney transplant to minimise the burden of general immunosuppression.

Funding
The 7th EU Framework Programme.

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