Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials.
Journal
Lancet (London, England)
ISSN: 1474-547X
Titre abrégé: Lancet
Pays: England
ID NLM: 2985213R
Informations de publication
Date de publication:
23 05 2020
23 05 2020
Historique:
received:
15
11
2019
revised:
15
01
2020
accepted:
20
01
2020
entrez:
25
5
2020
pubmed:
25
5
2020
medline:
11
6
2020
Statut:
ppublish
Résumé
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. 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. 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. 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. The 7th EU Framework Programme.
Sections du résumé
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.
Identifiants
pubmed: 32446407
pii: S0140-6736(20)30167-7
doi: 10.1016/S0140-6736(20)30167-7
pmc: PMC7613154
mid: EMS150701
pii:
doi:
Substances chimiques
Immunosuppressive Agents
0
Banques de données
ClinicalTrials.gov
['NCT02091232', 'NCT02085629', 'NCT01656135', 'NCT02129881', 'NCT02244801', 'NCT02252055', 'NCT02371434']
Types de publication
Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1627-1639Subventions
Organisme : British Heart Foundation
ID : RG/13/12/30395
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 211122/Z/18/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/K025538/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 211122
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N027930/1
Pays : United Kingdom
Commentaires et corrections
Type : ErratumIn
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.
Références
N Engl J Med. 2007 Dec 20;357(25):2562-75
pubmed: 18094377
Am J Transplant. 2008 Jan;8(1):103-10
pubmed: 18021284
Am J Transplant. 2017 Oct;17(10):2659-2667
pubmed: 28332287
Am J Transplant. 2013 Nov;13(11):3010-20
pubmed: 24102808
Front Immunol. 2018 Oct 02;9:2242
pubmed: 30356862
PLoS One. 2013 Jul 29;8(7):e70152
pubmed: 23922945
Am J Transplant. 2017 Apr;17(4):856-879
pubmed: 28117944
Transpl Int. 2008 Aug;21(8):728-41
pubmed: 18573142
Cytometry A. 2016 Jun;89(6):543-64
pubmed: 27144459
Transpl Int. 2017 Aug;30(8):765-775
pubmed: 28543878
Front Immunol. 2018 Feb 26;9:354
pubmed: 29535728
J Am Soc Nephrol. 2015 Aug;26(8):1795-805
pubmed: 25556168
Transpl Int. 2008 Aug;21(8):742-54
pubmed: 18573141
Hepatology. 2016 Aug;64(2):632-43
pubmed: 26773713
Nat Commun. 2018 Jul 20;9(1):2858
pubmed: 30030423
Int Immunol. 2015 Oct;27(10):505-11
pubmed: 26306497
Sci Rep. 2018 May 9;8(1):7428
pubmed: 29743501
Transplant Res. 2013 Oct 25;2(1):17
pubmed: 24160259
Clin Exp Immunol. 2013 Dec;174(3):424-32
pubmed: 23962178
Am J Transplant. 2015 Dec;15(12):3143-56
pubmed: 26211927
Mol Ther Methods Clin Dev. 2018 Jan 31;8:198-209
pubmed: 29552576
Kidney Int. 2015 Jun;87(6):1116-24
pubmed: 25738251
Front Immunol. 2018 Feb 19;9:274
pubmed: 29520275
Cell Metab. 2019 Dec 3;30(6):1075-1090.e8
pubmed: 31801055
Curr Opin Organ Transplant. 2019 Aug;24(4):441-450
pubmed: 31169530
Am J Transplant. 2017 Nov;17(11):2945-2954
pubmed: 28675676
Transpl Int. 2015 Aug;28(8):891-900
pubmed: 25752992
Eur J Immunol. 2017 Aug;47(8):1324-1334
pubmed: 28586095
Lancet. 2017 May 27;389(10084):2152-2162
pubmed: 28561006
Kidney Int. 2018 Jun;93(6):1452-1464
pubmed: 29792274
Am J Transplant. 2016 Jul;16(7):2187-95
pubmed: 26790369
Transplantation. 2018 Nov;102(11):1795-1814
pubmed: 30028786