Regulatory T cells for minimising immune suppression in kidney transplantation: phase I/IIa clinical trial.
Regulatory T cells for minimising immune suppression in kidney transplantation: phase I/IIa clinical trial.
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DOI：
10.1136/bmj.m3734
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发表时间：
2020-10-21
期刊：
影响因子：
--
通讯作者：
Reinke P
中科院分区：
文献类型：
--
作者：
Roemhild A;Otto NM;Moll G;Abou-El-Enein M;Kaiser D;Bold G;Schachtner T;Choi M;Oellinger R;Landwehr-Kenzel S;Juerchott K;Sawitzki B;Giesler C;Sefrin A;Beier C;Wagner DL;Schlickeiser S;Streitz M;Schmueck-Henneresse M;Amini L;Stervbo U;Babel N;Volk HD;Reinke P
为了评估肾移植后通过输注自体自然调节T细胞(NTreg)来重塑患者的免疫平衡是否安全、可行，并使疗效有限、不良反应和高直接和间接成本的终身高剂量免疫抑制得以逐渐减少，同时在有用的概念验证疾病模型中解决nTreg治疗的几个关键挑战，例如容易且坚固的制造、过度免疫抑制的危险、与标准护理药物的相互作用以及炎症环境中的功能稳定性。研究人员发起、单中心、nTreg剂量递增，I/IIa期临床试验(ONEnTreg13)。Charité-University医院，德国柏林，在One Study财团(由欧盟资助)内。活体供肾移植受者(ONEnTreg13，n=11)和相应参照组试验(ONErgt11-CHA，n=9)。CD4+CD25+FoxP3+nTreg产品在肾移植后7天静脉注射0.5、1.0或2.5-3.0×106细胞/kg体重，随后逐步减少三重免疫抑制，直到48周为止。主要的临床和安全终点在60周时通过一个综合终点进行评估，并进行进一步的三年随访。评估包括活检证实的急性排斥反应的发生率，对注射nTreg相关不良反应的评估，以及过度免疫抑制的迹象。次级终点解决了同种异体移植的功能。随之而来的研究包括一个全面的探索性生物标志物组合。对于所有患者来说，在肾移植前两周从40-50毫升的外周血液中可以产生足够的产量、纯度和功能性的nTreg产品。三个nTreg剂量递增组都没有剂量限制性毒性。NTreg组和参照组的同种异体移植物三年存活率为100%，临床和安全性特征相似。在接受nTregs治疗的11名患者中，有8名(73%)获得了稳定的单一治疗免疫抑制，而对照组仍在接受标准的双重或三重药物免疫抑制(P=0.002)。从机制上讲，传统T细胞的活性降低，体内nTregs从多克隆T细胞受体转变为寡克隆T细胞受体。即使在肾移植和免疫抑制的患者中，应用自体nTregs也是安全和可行的。这些结果保证了对Treg疗效的进一步评估，并为在移植和任何免疫病理学中开发下一代nTreg方法奠定了基础。NCT02371434(ONEnTreg13)和EudraCT：2011-004301-24(ONErgt11)。
To assess whether reshaping of the immune balance by infusion of autologous natural regulatory T cells (nTregs) in patients after kidney transplantation is safe, feasible, and enables the tapering of lifelong high dose immunosuppression, with its limited efficacy, adverse effects, and high direct and indirect costs, along with addressing several key challenges of nTreg treatment, such as easy and robust manufacturing, danger of over immunosuppression, interaction with standard care drugs, and functional stability in an inflammatory environment in a useful proof-of-concept disease model. Investigator initiated, monocentre, nTreg dose escalation, phase I/IIa clinical trial (ONEnTreg13). Charité-University Hospital, Berlin, Germany, within the ONE study consortium (funded by the European Union). Recipients of living donor kidney transplant (ONEnTreg13, n=11) and corresponding reference group trial (ONErgt11-CHA, n=9). CD4+ CD25+ FoxP3+ nTreg products were given seven days after kidney transplantation as one intravenous dose of 0.5, 1.0, or 2.5-3.0×106 cells/kg body weight, with subsequent stepwise tapering of triple immunosuppression to low dose tacrolimus monotherapy until week 48. The primary clinical and safety endpoints were assessed by a composite endpoint at week 60 with further three year follow-up. The assessment included incidence of biopsy confirmed acute rejection, assessment of nTreg infusion related adverse effects, and signs of over immunosuppression. Secondary endpoints addressed allograft functions. Accompanying research included a comprehensive exploratory biomarker portfolio. For all patients, nTreg products with sufficient yield, purity, and functionality could be generated from 40-50 mL of peripheral blood taken two weeks before kidney transplantation. None of the three nTreg dose escalation groups had dose limiting toxicity. The nTreg and reference groups had 100% three year allograft survival and similar clinical and safety profiles. Stable monotherapy immunosuppression was achieved in eight of 11 (73%) patients receiving nTregs, while the reference group remained on standard dual or triple drug immunosuppression (P=0.002). Mechanistically, the activation of conventional T cells was reduced and nTregs shifted in vivo from a polyclonal to an oligoclonal T cell receptor repertoire. The application of autologous nTregs was safe and feasible even in patients who had a kidney transplant and were immunosuppressed. These results warrant further evaluation of Treg efficacy and serve as the basis for the development of next generation nTreg approaches in transplantation and any immunopathologies. NCT02371434 (ONEnTreg13) and EudraCT:2011-004301-24 (ONErgt11).
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DOI：
10.1016/j.omtm.2018.01.006
发表时间：
2018-03-16
期刊：
Molecular therapy. Methods & clinical development
影响因子：
--
作者：
Fraser H;Safinia N;Grageda N;Thirkell S;Lowe K;Fry LJ;Scottá C;Hope A;Fisher C;Hilton R;Game D;Harden P;Bushell A;Wood K;Lechler RI;Lombardi G
通讯作者：
Lombardi G
DOI：
10.1016/s1470-2045(19)30729-6
发表时间：
2020-02
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Elsallab M;Levine BL;Wayne AS;Abou-El-Enein M
通讯作者：
Abou-El-Enein M
影响因子：
8.8
作者：
Dziubianau, M.;Hecht, J.;Babel, N.
通讯作者：
Babel, N.
影响因子：
158.5
作者：
Ekberg, Henrik;Tedesco-Silva, Helio;Halloran, Philip F.
通讯作者：
Halloran, Philip F.
影响因子：
4.5
作者：
Abou-El-Enein, Mohamed;Roemhild, Andy;Reinke, Petra
通讯作者：
Reinke, Petra