白血病患者接受单倍体相合造血干细胞移植后输注自杀基因工程供体淋巴细胞（TK007试验）：一项非随机的I-II期研究
Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I-II study.
作者信息
Ciceri Fabio, Bonini Chiara, Stanghellini Maria Teresa Lupo, Bondanza Attilio, Traversari Catia, Salomoni Monica, Turchetto Lucia, Colombi Scialini, Bernardi Massimo, Peccatori Jacopo, Pescarollo Alessandra, Servida Paolo, Magnani Zulma, Perna Serena K, Valtolina Veronica, Crippa Fulvio, Callegaro Luciano, Spoldi Elena, Crocchiolo Roberto, Fleischhauer Katharina, Ponzoni Maurilio, Vago Luca, Rossini Silvano, Santoro Armando, Todisco Elisabetta, Apperley Jane, Olavarria Eduardo, Slavin Shimon, Weissinger Eva M, Ganser Arnold, Stadler Michael, Yannaki Evangelia, Fassas Athanasios, Anagnostopoulos Achilles, Bregni Marco, Stampino Corrado Gallo, Bruzzi Paolo, Bordignon Claudio
机构信息
Haematology and BMT Unit, San Raffaele Scientific Institute, Milan, Italy.
出版信息
Lancet Oncol. 2009 May;10(5):489-500. doi: 10.1016/S1470-2045(09)70074-9. Epub 2009 Apr 1.
BACKGROUND
Procedures to prevent severe graft-versus-host disease (GVHD) delay immune reconstitution secondary to transplants of haploidentical haemopoietic stem cells for the treatment of leukaemia, leading to high rates of late infectious mortality. We aimed to systematically add back genetically engineered donor lymphocytes to facilitate immune reconstitution and prevent late mortality.
METHODS
In a phase I-II, multicentre, non-randomised trial of haploidentical stem-cell transplantation, we infused donor lymphocytes expressing herpes-simplex thymidine kinase suicide gene (TK-cells) after transplantation. The primary study endpoint was immune reconstitution defined as circulating CD3+ count of 100 cells per muL or more for two consecutive observations. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00423124.
FINDINGS
From Aug 13, 2002, to March 26, 2008, 50 patients (median age 51 years, range 17-66) received haploidentical stem-cell transplants for high-risk leukaemia. Immune reconstitution was not recorded before infusion of TK-cells. 28 patients received TK-cells starting 28 days after transplantation; 22 patients obtained immune reconstitution at median 75 days (range 34-127) from transplantation and 23 days (13-42) from infusion. Ten patients developed acute GVHD (grade I-IV) and one developed chronic GVHD, which were controlled by induction of the suicide gene. Overall survival at 3 years was 49% (95% CI 25-73) for 19 patients who were in remission from primary leukaemia at the time of stem-cell transplantation. After TK-cell infusion, the last death due to infection was at 166 days, this was the only infectious death at more than 100 days. No acute or chronic adverse events were related to the gene-transfer procedure.
INTERPRETATION
Infusion of TK-cells might be effective in accelerating immune reconstitution, while controlling GVHD and protecting patients from late mortality in those who are candidates for haploidentical stem-cell transplantation.
FUNDING
MolMed SpA, Italian Association for Cancer Research.
背景
预防严重移植物抗宿主病（GVHD）的程序会延迟单倍体造血干细胞移植治疗白血病后的免疫重建，导致晚期感染死亡率很高。我们旨在系统性地回输基因工程改造的供体淋巴细胞，以促进免疫重建并预防晚期死亡。
方法
在一项单倍体干细胞移植的I-II期多中心非随机试验中，我们在移植后输注表达单纯疱疹胸苷激酶自杀基因的供体淋巴细胞（TK细胞）。主要研究终点是免疫重建，定义为连续两次观察到循环CD3 +细胞计数每微升100个细胞或更多。分析采用意向性分析。该试验已在ClinicalTrials.gov注册，编号为NCT00423124。
结果
从2002年8月13日至2008年3月26日，50例患者（中位年龄51岁，范围17 - 66岁）接受了单倍体干细胞移植治疗高危白血病。在输注TK细胞之前未记录到免疫重建情况。28例患者在移植后28天开始接受TK细胞；22例患者在移植后中位75天（范围34 - 127天）和输注后23天（13 - 42天）实现了免疫重建。10例患者发生了急性GVHD（I-IV级），1例发生了慢性GVHD，通过诱导自杀基因得到了控制。对于19例在干细胞移植时原发性白血病处于缓解期的患者，3年总生存率为49%（95%CI 25 - 73）。输注TK细胞后，最后一例因感染死亡发生在166天，这是唯一一例发生在100天以上的感染死亡。没有急性或慢性不良事件与基因转移程序相关。
解读
输注TK细胞可能有效地加速免疫重建，同时控制GVHD并保护单倍体干细胞移植候选患者免于晚期死亡。
资助
MolMed SpA，意大利癌症研究协会。
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