Can regulatory T cells improve outcomes of sensitised patients after HLA-Ab incompatible renal transplantation: study protocol for the Phase IIa GAMECHANgER-1 trial.
Can regulatory T cells improve outcomes of sensitised patients after HLA-Ab incompatible renal transplantation: study protocol for the Phase IIa GAMECHANgER-1 trial.
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DOI：
10.1186/s12882-023-03157-7
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发表时间：
2023-04-28
期刊：
影响因子：
2.3
通讯作者：
Dorling, A.
中科院分区：
文献类型：
--
作者：
Dudreuilh, C.;Jarvis, P.;Beadle, N.;Pilecka, I;Shaw, O.;Gardner, L.;Scotta, C.;Mamode, N.;Game, D. S.;Sanchez-Fueyo, A.;Lombardi, G.;Learoyd, A.;Douiri, A.;Dorling, A.
关键词：
肾移植是治疗肾衰竭患者的金标准。然而，三分之一等待肾移植的患者对人类白细胞抗原（HLA）高度敏感，导致与非高度敏感患者相比，等待合适肾脏的时间增加，急性和慢性排斥反应增加，移植物存活时间缩短。目前的标准免疫抑制方案不能充分抑制记忆反应，因此需要替代策略。自体多克隆扩增的调节性T细胞（TCRs）已被证明在移植环境中是安全的，并可能成为调节记忆性免疫同种异体反应的潜在替代方案。本试验的目的是确定将自体T细胞过继转移到HLA致敏患者体内是否可以抑制记忆性T和B细胞对特异性HLA抗原的应答。这是一项由两部分组成的多中心前瞻性临床试验，包括观察期（第1部分），旨在确定对HLA（纯HLA蛋白质）具有不受调节的细胞记忆应答的患者，随后是干预期（第2部分）。第1部分中确定为合格的前9例患者将接受2个月的基线免疫监测，以告知主要终点的统计分析。第2部分是一项基于Simon两阶段设计的适应性、开放标签试验，21例患者接受了5 - 10 × 106个细胞/kg体重剂量的药品生产质量管理规范（GMP）级多克隆扩增Tclase。主要EP是输注后2个月的体外记忆反应抑制。12例患者将在第2部分的第1阶段接受治疗，如果≥ 50%的患者在第1阶段通过主要EP，则9例患者将在第2部分的第2阶段接受治疗。这是一项前瞻性研究，旨在识别对纯HLA蛋白质具有不受调节的细胞记忆应答的患者，并确定这些应答模式的基线变异。第2部分将是一项适应性IIa期临床试验，21例患者分两个阶段接受GMP级多克隆扩增Tclase单次输注。它仍然有待证明，调节记忆alloresponses临床使用Treg治疗是可以实现的。EudraCT编号：2021 - 001，664 - 23。REC编号：21/SC/0253。试验注册号ISRCTN14582152。在线版本包含补充材料，可通过10.1186/s12882 - 023 - 03157 - 7获得。
Kidney transplantation is the gold-standard treatment for patients with kidney failure. However, one-third of patients awaiting a kidney transplant are highly sensitized to human leukocyte antigens (HLA), resulting in an increased waiting time for a suitable kidney, more acute and chronic rejection, and a shorter graft survival compared to non-highly sensitised patients. Current standard immunosuppression protocols do not adequately suppress memory responses, and so alternative strategies are needed. Autologous polyclonally expanded regulatory T cells (Tregs) have been demonstrated to be safe in transplant settings and could be a potential alternative to modulate memory immune alloresponses. The aim of this trial is to determine whether adoptive transfer of autologous Tregs into HLA sensitised patients can suppress memory T and B cell responses against specific HLA antigens. This is a two-part, multi-centre, prospective clinical trial, comprising an observational phase (Part 1) aiming to identify patients with unregulated cellular memory responses to HLA (Pure HLA Proteins) followed by an interventional phase (Part 2). The first 9 patients identified as being eligible in Part 1 will undergo baseline immune monitoring for 2 months to inform statistical analysis of the primary endpoint. Part 2 is an adaptive, open labelled trial based on Simon’s two-stage design, with 21 patients receiving Good Manufacturing Practice (GMP)-grade polyclonally expanded Tregs to a dose of 5–10 × 106 cells/kg body weight. The primary EP is suppression of in vitro memory responses for 2 months post-infusion. 12 patients will receive treatment in stage 1 of Part 2, and 9 patients will receive treatment in stage 2 of Part 2 if ≥ 50% patients pass the primary EP in stage 1. This is a prospective study aiming to identify patients with unregulated cellular memory responses to Pure HLA Proteins and determine baseline variation in these patterns of response. Part 2 will be an adaptive phase IIa clinical trial with 21 patients receiving a single infusion of GMP-grade polyclonally expanded Tregs in two stages. It remains to be demonstrated that modulating memory alloresponses clinically using Treg therapy is achievable. EudraCT Number: 2021–001,664-23. REC Number: 21/SC/0253. Trial registration number ISRCTN14582152. The online version contains supplementary material available at 10.1186/s12882-023-03157-7.
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影响因子：
8.8
作者：
Sanchez-Fueyo, Alberto;Whitehouse, Gavin;Lombardi, Giovanna
通讯作者：
Lombardi, Giovanna
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：
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作者：
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通讯作者：
Lombardi G
影响因子：
8.8
作者：
Gao, W.;Lu, Y.;Strom, T. B.
通讯作者：
Strom, T. B.
DOI：
10.1016/s0140-6736(20)30167-7
发表时间：
2020-05-23
期刊：
Lancet (London, England)
影响因子：
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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
通讯作者：
Geissler EK
影响因子：
19.6
作者：
Shiu, Kin Y.;McLaughlin, Laura;Dorling, Anthony
通讯作者：
Dorling, Anthony