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

来自第三方捐赠者的 EBV 特异性 T 细胞，用于治疗 EBV 相关恶性肿瘤

• 批准号: 8189121
• 负责人: Richard John O'REILLY
• 金额: $ 37.57万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-19 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8189121
• 关键词: Address; Adoptive Immunotherapy; Adoptive Transfer; Alleles; Allogenic; Antigens; Atypical lymphocyte; Cell Line; Cells; Clinical; Complication; Consent; DNA; Data; Disease; Donor person; Dose; EBV-associated malignancy; Engraftment; Failure; Genetic; Genotype; Grant; Growth; Hematopoietic; Hemophagocytic Lymphohistiocytoses; Hodgkin Disease; Human Herpesvirus 4; Immune; Immunocompromised Host; In Vitro; Incidence; Infusion procedures; Kinetics; Life; Lymphoma; Lymphoproliferative Disorders; Malignant Neoplasms; Morbidity - disease rate; Nasopharynx Carcinoma; Organ Transplantation; Patients; Phase; Phase II Clinical Trials; Prevention; Production; Proteins; Quantitative Evaluations; Resources; Roche brand of rituximab; Solid; Source; Specificity; Sterility; T-Lymphocyte; Therapy Clinical Trials; Third-Party Consent; Time; Toxic effect; Transplant Recipients; United Kingdom; Virus; acquired immunodeficiency; base; chemotherapy; effective therapy; in vivo; leiomyosarcoma; microbial; mortality; phase 3 study; prevent; response; selective expression; tumor

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. PUBLIC HEALTH RELEVANCE: EBV-associated PTLDs and lymphomas are a major and life-threatening complication for patients receiving hematopoietic cell and solid organ transplants and patients with severe genetic and acquired immunodeficiencies. Current treatment with chemotherapy and/or Rituxan is durably effective in no more than 50% of cases and may induce significant toxicity. Adoptive transfer of donor-derived EBV specific T-cells has been found to be effective for prevention and treatment of these disorders. Studies in the United Kingdom and at our center may also be effective. This grant proposes a Phase II trial of third-party derived EBV-specific T-cells selected on the basis of partial HLA matching and tumor-directed HLA restriction to assess this approach. It also proposes the establishment of a fully characterized specifically consented bank of GMP-grade EBV-specific T-cells so as to provide a broadly applicable and immediately accessible resource for adoptive therapy of these diseases.

描述（由申请人提供）：Epstein-Barr 病毒诱导的淋巴增殖性疾病和 EBV+ 淋巴瘤是同种异体造血细胞 (HSCT) 和器官移植 (SOT) 受者以及患有严重遗传性和获得性免疫缺陷的患者发病和死亡的重要原因。 EBV+霍奇金病(HD)、EBV+噬血细胞性淋巴组织细胞增多症、EBV+鼻咽癌和EBV+平滑肌肉瘤也构成一组目前化疗通常无效的恶性肿瘤。 使用体外产生的供体来源的 EBV 特异性 T 细胞进行过继治疗可有效治疗和预防并发同种异体 HSCT 的 EBV 淋巴瘤。然而，由于缺乏 T 细胞生产所需的专门设施以及生成数量充足、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），该技术的应用受到限制。 EBV特异性T细胞的有效治疗也可能因用于T细胞增殖的供体细胞的可用性有限、供体事先缺乏体内病毒致敏、或供体的T细胞无法在肿瘤表达的HLA等位基因的情况下识别EBV而受到阻碍或阻碍。 根据我们的初步研究，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：对源自根据 2 个 HLA 等位基因匹配和适当的 HLA 限制而选择的第三方供体的 EBV 特异性 T 细胞进行 II 期试验，用于治疗并发同种异体 HSCT 或器官移植或其他与免疫缺陷相关的 EBV 相关恶性肿瘤的患者。在这项试验中，我们将观察到的临床反应和 EBV DNA 循环水平的变化与过继转移后体内 EBV 特异性 T 细胞的体内生长、扩增和存活的定量评估相关联。在目标 2 中，我们将建立一个大型的、遗传多样化的 EBV 特异性 T 细胞系库，专门同意第三方使用。之前从同意的捐赠者中产生的 300 个 T 细胞系中的每一个都是在 GMP 条件下生产的，并具有 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。我们计划确定每个细胞系中 EBV 特异性 T 细胞的 HLA 限制，以便为特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，这些细胞系可用于治疗选择性表达这些抗原的 EBV+ 恶性肿瘤。我们预计这项 II 期试验将提供启动 III 期研究所需的数据，将该疗法与化疗和/或 Rituxan 进行比较。充分表征的 EBV 特异性 T 细胞库还应该为此类试验提供广泛适用且可访问的资源。 公共卫生相关性：对于接受造血细胞和实体器官移植的患者以及患有严重遗传性和获得性免疫缺陷的患者来说，EBV 相关的 PTLD 和淋巴瘤是一种严重且危及生命的并发症。目前使用化疗和/或 Rituxan 的治疗在不超过 50% 的病例中具有持久有效，并且可能会引起显着的毒性。已发现供体来源的 EBV 特异性 T 细胞的过继转移可有效预防和治疗这些疾病。在英国和我们中心的研究也可能有效。该拨款提议对基于部分 HLA 匹配和针对肿瘤的 HLA 限制选择的第三方衍生 EBV 特异性 T 细胞进行 II 期试验，以评估该方法。它还建议建立一个完全特征化、特别同意的 GMP 级 EBV 特异性 T 细胞库，以便为这些疾病的过继治疗提供广泛适用且可立即获取的资源。