Background

Opportunistic infections including cytomegalovirus (CMV) are a major cause of morbidity and mortality in solid organ transplant (SOT) recipients. The recurrent and protracted use of antiviral drugs with eventual emergence of drug resistance represents a significant constraint to therapy. Although adoptive T-cell therapy has been successfully used in hematopoietic stem cell transplant recipients, its extension to the SOT setting poses a considerable challenge because of the inhibitory effects of immunosuppressive drugs on the virus-specific T-cell response in vivo and the perceived risk of graft rejection.

Methods

In this prospective study, 22 SOT recipients (13 renal and 8 lung and 1 heart transplants) with recurrent or ganciclovir-resistant CMV infection were recruited, and 13 of them were treated with in vitro–expanded autologous CMV-specific T cells. These patients were monitored for safety, clinical symptoms, and immune reconstitution.

Results

Autologous CMV-specific T-cell manufacture was attempted for 21 patients, and was successful in 20. The use of this adoptive immunotherapy was associated with no therapy-related serious adverse events. Eleven (84%) of the 13 treated patients showed improvement in symptoms, including complete resolution or reduction in DNAemia and CMV-associated end-organ disease and/or the cessation or reduced use of antiviral drugs. Furthermore, four of these patients showed coincident increased frequency of CMV-specific T cells in peripheral blood after completion of T-cell therapy.

Conclusions

The data presented here demonstrate for the first time the clinical safety of CMV-specific adoptive T-cell therapy and its potential therapeutic benefit for SOT recipients with recurrent and/or drug-resistant CMV infection or disease.

Clinical Trials Registration

ACTRN12613000981729.

中文翻译：

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自发性过继性T细胞疗法用于固体器官移植接受者中复发或耐药的巨细胞病毒并发症：单臂开放标签的I期临床试验

背景

包括巨细胞病毒（CMV）在内的机会性感染是固体器官移植（SOT）受者发病和死亡的主要原因。反复和长期使用抗病毒药物以及最终出现耐药性代表了对治疗的重大限制。尽管过继性T细胞疗法已成功用于造血干细胞移植受者中，但由于免疫抑制药物对体内病毒特异性T细胞反应的抑制作用和可察觉的风险，其扩展至SOT设置提出了相当大的挑战。移植排斥反应。

方法

在这项前瞻性研究中，招募了22例复发或更昔洛韦耐药性CMV感染的SOT受体（13例肾脏，8例肺和1例心脏移植），其中13例接受了体外扩增的自体CMV特异性T细胞治疗。监测这些患者的安全性，临床症状和免疫重建。

结果

尝试制造21例患者的自体CMV特异性T细胞，并在20例中获得成功。使用这种过继免疫疗法不会导致与治疗相关的严重不良事件。在13名接受治疗的患者中，有11名（84％）的症状有所改善，包括完全解决或降低了DNAemia和CMV相关的终末器官疾病和/或停止或减少了抗病毒药物的使用。此外，这些患者中有四名在完成T细胞治疗后，外周血中CMV特异性T细胞的频率同时增加。

结论

此处提供的数据首次证明了CMV特异的过继性T细胞疗法的临床安全性及其对于SOT复发和/或耐药CMV感染或疾病的SOT接受者的潜在治疗益处。

临床试验注册

ACTRN12613000981729。