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

Abstract

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.

Conflict of interest statement

Declaration of interests

BS, PR, AM, JAH, DSG, QT, ECG, MB, WJB, ISDR, MS, RJ, JFM, CB, BJ, LC-R, RC, IM, NMO, MPH-F, CM, SK, LAT, JAB, RJL, HJS, MCC, SS, S-MK, BB, GB, H-DV, GL, KJW, and EKG report grants from the EU (FP7 ONE Study) during the conduct of the study. PR and H-DV report grants from the BMBF, outside the submitted work. JAH reports other support from Trizell, personal fees from Finvector Oy during the conduct of the study. DSG reports non-financial support and other from Sandoz, non-financial support and other from Chiesi, non-financial support and other from Astellas, outside the submitted work. QT has a patent US14/382,537 issued and she is a co-founder of Sonoma. MB is one inventor of a patent for in-vitro generation and expansion of CD4+CD25+ T regulatory cells by rapamycin (# WO 2006/090291A2). The patent was licensed for non-exclusive usage to Miltenyi Biotech to develop a commercial kit for the ex-vivo expansion of Treg cells with rapamycin. ND reports other from Beckman Coulter Life Sciences, during the conduct of the study; other from Beckman Coulter Life Sciences, outside the submitted work. MK reports other from Beckman Coulter Life Sciences, during the conduct of the study; other from Beckman Coulter Life Sciences, outside the submitted work. MPH-F reports other from UCB Pharma, outside the submitted work. LAT reports personal fees from Third Rock Ventures, personal fees from Rheos Medicine, outside the submitted work; LAT is employed by Rubius Therapeutics. JAB has a patent US 7722862 B2 issued, a patent US 20080131445 A1, 9,012,1 issued, and a patent US 20150110761 A1 issued and is a founder and current CEO of Sonoma Biotherapeutics, which works on Tregs as therapeutics. HJS reports grants and personal fees from Novartis Pharma, grants and personal fees from Chiesi, outside the submitted work. TM reports other from Beckman Coulter Life Sciences, during the conduct of the study and outside the submitted work. RH reports personal fees and non-financial support from Chiesi, outside the submitted work. EKG reports grant support from Trizell and speaking fees from Novartis Pharma and Chiesi, outside the submitted work. All other authors declare no competing interests.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Trial profile

RGT=reference group trial. CTG=cell therapy group. pTreg=polyclonal T regulatory cells. ATDCs=autologous tolerogenic dendritic cells. darTreg=donor-antigen reactive Treg. Mreg=regulatory macrophages.

Figure 2. Primary endpoint (BCAR) data

(A) Kaplan-Meier estimates of the cumulative BCAR-free survival probability in the RGT (n=66) and CTG (n=38) intention-to-treat analysis sets (88% vs 84% at 60 weeks). (B) Kaplan-Meier estimates of the cumulative BCAR-free survival probability in the RGT (n=47) and CTG (n=32) per-protocol analysis sets (83% vs 81% at 60 weeks). Censored patients are indicated with ticks. RGT=reference group trial. CTG=cell therapy group. BCAR=biopsy-confirmed acute rejection.

Figure 3. Normalised safety data

(A) Incidence of treatment-emergent serious adverse events by MedDRA primary system organ class. (B) Incidence of treatment-emergent infections (all adverse events) by study site. (C) Incidence proportion of treatment-emergent infections (all adverse events) over time. (D) Incidence of treatment-emergent infections (all adverse events) by MedDRA high-level group term. (E) Incidence of treatment-emergent viral infections (all adverse events) by MedDRA high-level term. All adverse events coded using MedDRA version 20.1. Treatment-emergent events are events with onset date equal to or after first dose of any study drug. All events coded to the MedDRA preferred term transplant rejection were excluded as rejection was measured as the primary efficacy endpoint. RGT=reference group trial. CTG=cell therapy group. MedDRA=Medical Dictionary for Regulatory Activities.

Figure 4. Leucocyte subset alterations in patients with end-stage renal disease and time-dependent changes after kidney transplantation

(A) PCA revealing the differences in leucocyte subsets between whole blood samples from end-stage renal disease (n=70) and healthy controls (n=98). (B) Box-and-whiskers plots of absolute numbers from leucocyte subpopulations with highest influence at the PCA shown in A. (C) Time-dependent changes from visit 1 before transplantation (V01) to visit 10 at 60 weeks post-transplant (V10) of monocyte, B cell, CD4+, and CD8+ T cell subset composition (stacked bars of mean proportions) in whole blood samples of patients in the RGT (n=59). Statistical analysis by Kruskal-Wallis-Test. PCA=principal component analysis. PC=principal component. mDCs=myeloid dendritic cells.

Figure 5. Differences in post-transplant changes between patients in the RGT and CTG trials

(A) Differences in post-transplant changes in regulatory T cells. Box and whisker plots of absolute numbers and proportions of CD4+CD25highCD127low Tregs as well as the percentage of CD4+ T cells with demethylated Treg-specific demethylated region in whole blood samples collected pre-transplant (V01) and at the end of the observation period (60 weeks post-transplant, V10) from patients in the RGT (n=59) and CTG trials (n=38). (B) Differences in post-transplant changes in CD8+ T cell subpopulations. Box and whisker plots of absolute numbers of CD8+CD28+, CD8+CD45RA+CCR7-TEMRA and CD8’CD57’ chronically activated cells in whole blood samples collected pre-transplant (V01) and at the end of the observation period (60 weeks post-transplant, V10) from patients in the RGT (n=59) and CTG trials (n=38). (C) Differences in post-transplant changes in marginal zone-like B cells and dendritic cell subpopulations. Box and whisker plots of absolute numbers and proportions of marginal zone-like B cells, CD16+ myeloid dendritic cells, and plasmacytoid dendritic cells in whole blood samples collected pre-transplant (V01) and at the end of the observation period (60 weeks post-transplant, V10) from patients in the RGT (n=59) and CTG trials (n=38). Statistical analysis by Wilcoxon matched-pairs signed rank and Dunn’s multiple comparison test. RGT=reference group trial. CTG=cell therapy group. *p<0·05. †p<0·01. ‡p<0·001. §p<0·0001.