Qian Chongsheng, Campidelli Arnaud, Wang Yingying, Cai Huili, Venard Véronique, Jeulin Hélène, Dalle Jean Hugues, Pochon Cécile, D'aveni Maud, Bruno Benedicte, Paillard Catherine, Vigouroux Stéphane, Jubert Charlotte, Ceballos Patrice, Marie-Cardine Aude, Galambrun Claire, Cholle Clément, Clerc Urmes Isabelle, Petitpain Nadine, De Carvalho Bittencourt Marcelo, Decot Véronique, Reppel Loïc, Salmon Alexandra, Clement Laurence, Bensoussan Danièle
Unité de Thérapie cellulaire et Tissus and FR 3209, CHRU de Nancy, Vandoeuvre-Lès-Nancy, F54511, France.
UMR 7365 and FR 3209 CNRS-UL-CHU, Université de Lorraine, Vandoeuvre-Lès-Nancy, F54511, France.
J Hematol Oncol. 2017 May 8;10(1):102. doi: 10.1186/s13045-017-0469-0.
Allogeneic hematopoietic stem cell transplantation (HSCT), the most widely used potentially curable cellular immunotherapeutic approach in the treatment of hematological malignancies, is limited by life-threatening complications: graft versus host disease (GVHD) and infections especially viral infections refractory to antiviral drugs. Adoptive transfer of virus-specific T cells is becoming an alternative treatment for infections following HSCT. We report here the results of a phase I/II multicenter study which includes a series of adenovirus-specific T cell (ADV-VST) infusion either from the HSCT donor or from a third party haploidentical donor for patients transplanted with umbilical cord blood (UCB).
Fourteen patients were eligible and 11 patients received infusions of ADV-VST generated by interferon (IFN)-γ-based immunomagnetic isolation from a leukapheresis from their original donor (42.9%) or a third party haploidentical donor (57.1%). One patient resolved ADV infection before infusion, and ADV-VST could not reach release or infusion criteria for two patients. Two patients received cellular immunotherapy alone without antiviral drugs as a pre-emptive treatment.
One patient with adenovirus infection and ten with adenovirus disease were infused with ADV-VST (mean 5.83 ± 8.23 × 10 CD3+IFN-γ+ cells/kg) up to 9 months after transplantation. The 11 patients showed in vivo expansion of specific T cells up to 60 days post-infusion, associated with adenovirus load clearance in ten of the patients (91%). Neither de novo GVHD nor side effects were observed during the first month post-infusion, but GVHD reactivations occurred in three patients, irrespective of the type of leukapheresis donor. For two of these patients, GVHD reactivation was controlled by immunosuppressive treatment. Four patients died during follow-up, one due to refractory ADV disease.
Adoptive transfer of rapidly isolated ADV-VST is an effective therapeutic option for achieving in vivo expansion of specific T cells and clearance of viral load, even as a pre-emptive treatment. Our study highlights that third party haploidentical donors are of great interest for ADV-VST generation in the context of UCB transplantation. (N° Clinical trial.gov: NCT02851576, retrospectively registered).
异基因造血干细胞移植（HSCT）是治疗血液系统恶性肿瘤最广泛使用的潜在可治愈的细胞免疫治疗方法，但受到危及生命的并发症限制：移植物抗宿主病（GVHD）和感染，尤其是对抗病毒药物难治的病毒感染。病毒特异性T细胞的过继转移正成为HSCT后感染的一种替代治疗方法。我们在此报告一项I/II期多中心研究的结果，该研究包括为接受脐带血（UCB）移植的患者从HSCT供体或第三方单倍体相同供体进行一系列腺病毒特异性T细胞（ADV-VST）输注。
14名患者符合条件，11名患者接受了通过基于干扰素（IFN）-γ的免疫磁珠分离从其原始供体（42.9%）或第三方单倍体相同供体（57.1%）的白细胞单采中产生的ADV-VST输注。1名患者在输注前解决了腺病毒感染，2名患者的ADV-VST未达到释放或输注标准。2名患者单独接受细胞免疫治疗，不使用抗病毒药物作为抢先治疗。
1名腺病毒感染患者和10名腺病毒疾病患者在移植后长达9个月接受了ADV-VST输注（平均5.83±8.23×10 CD3 + IFN-γ +细胞/kg）。11名患者在输注后60天内显示特异性T细胞在体内扩增，10名患者（91%）的腺病毒载量清除。输注后第一个月未观察到新发GVHD或副作用，但3名患者发生了GVHD再激活，与白细胞单采供体类型无关。其中2名患者的GVHD再激活通过免疫抑制治疗得到控制。4名患者在随访期间死亡，1名死于难治性腺病毒疾病。
快速分离的ADV-VST的过继转移是实现特异性T细胞体内扩增和病毒载量清除的有效治疗选择，即使作为抢先治疗。我们的研究强调，在UCB移植背景下，第三方单倍体相同供体对于产生ADV-VST非常有意义。（临床试验注册号：NCT02851576，回顾性注册）
