Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials.
Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials.
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DOI：
10.1016/s0140-6736(20)30167-7
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发表时间：
2020-05-23
期刊：
影响因子：
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通讯作者：
Geissler EK
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作者：
Sawitzki B;Harden PN;Reinke P;Moreau A;Hutchinson JA;Game DS;Tang Q;Guinan EC;Battaglia M;Burlingham WJ;Roberts ISD;Streitz M;Josien R;Böger CA;Scottà C;Markmann JF;Hester JL;Juerchott K;Braudeau C;James B;Contreras-Ruiz L;van der Net JB;Bergler T;Caldara R;Petchey W;Edinger M;Dupas N;Kapinsky M;Mutzbauer I;Otto NM;Öllinger R;Hernandez-Fuentes MP;Issa F;Ahrens N;Meyenberg C;Karitzky S;Kunzendorf U;Knechtle SJ;Grinyó J;Morris PJ;Brent L;Bushell A;Turka LA;Bluestone JA;Lechler RI;Schlitt HJ;Cuturi MC;Schlickeiser S;Friend PJ;Miloud T;Scheffold A;Secchi A;Crisalli K;Kang SM;Hilton R;Banas B;Blancho G;Volk HD;Lombardi G;Wood KJ;Geissler EK
使用基于细胞的药品（CBMP）代表了减少器官移植中一般免疫抑制的最新方法。我们在肾移植试验中测试了多种调节性CBMP，以确定调节性CBMP与减少免疫抑制治疗联合使用时的安全性。ONE研究包括在法国、德国、意大利、英国和美国的8家医院进行的7项以药物为主导的单组试验（60周随访）。纳入的患者为18岁及以上的活体供肾移植受者。参考组试验（RGT）是一个标准治疗组，给予巴利昔单抗、减量类固醇、吗替麦考酚酯和他克莫司。汇总并分析了6项非随机1/2A期细胞治疗组（CTG）试验，其中患者接受了6种含有调节性T细胞、树突状细胞或巨噬细胞的CBMP之一;患者选择和免疫抑制反映了RGT，但巴利昔单抗诱导用CBMP替代，并允许霉酚酸酯逐渐减量。这些试验均未进行随机化，也未对涉及的个体进行设盲。主要终点是移植后60周内活检证实的急性排斥反应（BCAR）;不良事件编码是集中的。RTG和CTG试验注册于ClinicalTrials.gov、NCT 01656135、NCT 02252055、NCT 02085629、NCT 02244801、NCT 02371434、NCT 02129881和NCT 02091232。这七项试验于2012年12月11日至2018年11月14日进行。在评估合格性的782例患者中，130例（17%）患者入组，104例接受治疗并纳入分析。在RGT中接受治疗的66例患者中，73%为男性，中位年龄为47岁。在6项CTG试验中接受治疗的38例患者中，71%为男性，中位年龄为45岁。RGT中接受者的标准治疗免疫抑制导致12%的BCAR率（预期范围为3.2 - 18.0）。6项平行CTG试验的总体BCAR率为16%。15例（40%）接受CBMP的患者成功地从吗替麦考酚酯中脱离，并维持他克莫司单药治疗。所有6项CTG试验的合并不良事件数据和BCAR发作显示，与RGT相比，没有安全性问题。与RGT相比，CTG试验中登记的感染事件较少。调节性细胞治疗在活体供肾移植受者中是安全可行的，并且感染并发症较少，但第一年的排斥率相似。因此，免疫细胞疗法是一种潜在的有用的治疗方法，在肾移植受体，以尽量减少一般免疫抑制的负担。第七个欧盟框架方案。
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 biopsyconfirmed 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.