Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene
Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene
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DOI：
10.1182/blood-2014-01-551671
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发表时间：
2014-06-19
期刊：
影响因子：
20.3
通讯作者：
Dotti, Gianpietro
中科院分区：
文献类型：
--
作者：
Zhou, Xiaoou;Di Stasi, Antonio;Dotti, Gianpietro
表达安全开关的供体来源的 T 淋巴细胞的过继转移可能会促进接受单倍体相合造血干细胞移植 (haplo-HSCT) 的患者的免疫重建，而不会出现不受控制的移植物抗宿主病 (GvHD) 的风险。因此，在输注表达诱导型人半胱天冬酶 9 (iC9) 的同种异体去除供体来源的 T 细胞后发生 GvHD 的患者，通过单次施用小分子药物 (AP1903) 可有效控制其疾病，该药物可二聚化并激活 iC9 转基因。我们现在报告了 10 名接受这种安全开关修饰 T 细胞输注的患者的长期随访。我们发现，在没有出现寡克隆性和强大的免疫学益处的情况下，iC9 修饰（iC9-T）T 细胞在体内长期持续存在，最初由输注的细胞本身介导，随后由内源性幼稚 T 淋巴细胞明显加速重建介导。因此，这些患者在没有急性或慢性 GvHD 的情况下，能够立即、持续地免受主要病原体的侵害，包括巨细胞病毒、腺病毒、BK 病毒和 Epstein-Barr 病毒，这支持了这种方法对单倍体造血干细胞移植后免疫重建的有益作用。这项研究在 www.clinicaltrials.gov 上注册为#NCT00710892。
Adoptive transfer of donor-derived T lymphocytes expressing a safety switch may promote immune reconstitution in patients undergoing haploidentical hematopoietic stem cell transplant (haplo-HSCT) without the risk for uncontrolled graft versus host disease (GvHD). Thus, patients who develop GvHD after infusion of allodepleted donor-derived T cells expressing an inducible human caspase 9 (iC9) had their disease effectively controlled by a single administration of a small-molecule drug (AP1903) that dimerizes and activates the iC9 transgene. We now report the long-term-follow-up of 10 patients infused with such safety switch-modified T cells. We find long-term persistence of iC9-modified (iC9-T) T cells in vivo in the absence of emerging oligoclonality and a robust immunologic benefit, mediated initially by the infused cells themselves and subsequently by an apparently accelerated reconstitution of endogenous naive T lymphocytes. As a consequence, these patients have immediate and sustained protection from major pathogens, including cytomegalovirus, adenovirus, BK virus, and Epstein-Barr virus in the absence of acute or chronic GvHD, supporting the beneficial effects of this approach to immune reconstitution after haplo-HSCT. This study was registered at www.clinicaltrials.gov as #NCT00710892.