EBV Specific T-cells from 3rd party donors for treatment of EBV-associated malign

描述（由申请方提供）：EB病毒诱导的淋巴组织增生性疾病和EBV+淋巴瘤是异基因造血细胞（HSCT）和器官移植（SOT）接受者以及严重遗传性和获得性免疫缺陷患者发病和死亡的重要原因。EB病毒+霍奇金病（HD）、EB病毒+噬血细胞性淋巴组织细胞增生症、EB病毒+鼻咽癌和EB病毒+平滑肌肉瘤也构成了一组目前化疗通常无效的恶性肿瘤。 体外产生的供者来源的EBV特异性T细胞的连续性治疗在治疗和预防同种异体HSCT并发EBV淋巴瘤中是有效的。然而，由于缺乏T细胞生产所需的专门设施以及产生足够数量、EBV特异性和缺乏同种异体反应性的EBV特异性T细胞所需的时间（约65天），应用受到限制。EBV特异性T细胞的有效治疗也可能受到以下因素的阻碍或阻止：用于T细胞增殖的供体细胞的有限可用性、供体在体内对病毒缺乏预先致敏性、或供体的T细胞在肿瘤表达的HLA等位基因的情况下无法识别EBV。 基于我们的初步研究，我们假设从预先建立的T细胞系库中适当选择的第三方供体衍生的EBV特异性T细胞可以解决这些限制。因此，在目标1中，我们将：对来源于第三方供体的EBV特异性T细胞进行II期试验，所述第三方供体基于2种HLA等位基因匹配和适当的HLA限制而选择，用于治疗患有EBV淋巴瘤并发同种异体HSCT或器官移植或其他EBV相关恶性肿瘤（与免疫缺陷相关）的患者。在本试验中，我们将观察到的EBV DNA循环水平的临床反应和改变与过继转移后EBV特异性T细胞的体内生长、扩增和存活的定量评价相关联。在目标2中，我们将建立一个大型的、遗传多样性的EBV特异性T细胞系库，专门同意第三方使用。先前从知情同意的供体中生成的300个T细胞系中的每一个都是在GMP条件下生产的，并且是该库的候选细胞系，并对其HLA基因型、EBV特异性、缺乏同种异体反应性和必要的微生物无菌性进行了表征。我们计划鉴定每个细胞系中EBV特异性T细胞的HLA限制，以便允许为给定患者选择受患者肿瘤共有的HLA等位基因限制的EBV T细胞。我们还将鉴定含有LMP-1和/或LMP-2特异性T细胞的细胞系，其可用于治疗选择性表达这些抗原的EBV+恶性肿瘤。我们希望这项II期试验将提供启动III期研究所需的数据，将这种疗法与化疗和/或Rituxan进行比较。特征良好的EBV特异性T细胞库也应该为此类试验提供广泛适用和可获得的资源。

DESCRIPTION (provided by applicant): Epstein-Barr virus induced lymphoproliferative disease and EBV+ lymphomas are a significant cause of morbidity and mortality in recipients of allogenic hematopoietic cell (HSCT) and organ transplants (SOT) as well as patients with severe genetic and acquired immunodeficiencies. EBV+ Hodgkin's disease (HD), EBV+ hemophagocytic lymphohistiocytosis, EBV+ nasopharyngeal carcinoma and EBV+ leiomyosarcomas also constitute a group of malignancies for which current chemotherapy is often ineffective. Adoptive therapy with donor-derived EBV-specific T-cells generated in vitro has been effective in the treatment and prevention of EBV lymphomas complicating allogeneic HSCT. However, application has been limited by the lack of specialized facilities required for T-cell production and the time required (approximately 65 days) to generate EBV-specific T-cells that are adequate in number, EBV-specificity and lack of alloreactivity. Effective treatment with EBV-specific T-cells may also be hampered or prevented by limited availability of donor cells for T-cell propagation, lack of prior sensitization of the donor to the virus in vivo, or failure of the donor's T-cells to recognize EBV in the context of an HLA allele expressed by the tumor. Based on our preliminary studies, we hypothesize that EBV-specific T-cells derived from appropriately selected third party donors from a pre established bank of T-cell lines can address these limitations. Accordingly, in Aim 1 we will: conduct a Phase II trial of EBV-specific T-cells derived from third party donors selected on the basis of matching for 2 HLA alleles and appropriate HLA restriction, in the treatment of patients with EBV lymphomas complicating allogeneic HSCT or organ transplants or other EBV-associated malignancies associated with immune deficiencies. In this trial, we will correlate clinical responses and alterations in circulating levels of EBV DNA observed with quantitative evaluations of the in vivo growth, expansion and survival of the EBV-specific T-cells in vivo following adoptive transfer. In Aim 2, we will establish of a large, genetically diverse bank of EBV-specific T-cell lines specifically consented for third party use. Each of the 300 T-cell lines that has been previously generated from consenting donors, and is a candidate line for this bank has been manufactured under GMP conditions and characterized as to its HLA genotype, EBV specificity, lack of alloreactivity and requisite microbial sterility. We plan to identify the HLA restriction of the EBV-specific T-cells in each line, so as to permit selection of EBV T-cells for a given patient that are restricted by an HLA allele shared by the patient's tumor. We will also identify lines containing T-cells specific for LMP-1 and/or LMP-2, which could be used to treat EBV+ malignancies that selectively express these antigens. We expect this phase II trial will provide the data needed to initiate a phase III study comparing this therapy with chemotherapy and/or Rituxan. The bank of well characterized EBV-specific T-cells should also provide a broadly applicable and accessible resource for such trials.