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）：爱泼斯坦 - 巴尔病毒诱导的淋巴结增生性疾病和EBV+淋巴瘤是同种异体造血细胞（HSCT）和有机器官移植（SOT）的发病率和死亡率的重要原因，以及患有严重遗传和获得的免疫缺陷的患者。 EBV+ Hodgkin病（HD），EBV+型淋巴淋巴细胞增多症，EBV+鼻咽癌和EBV+ elimomyosarcomas也构成了当前化学疗法的一组恶性肿瘤。 在体外产生的供体衍生的EBV特异性T细胞的产卵疗法在治疗和预防EBV淋巴瘤中有效，使同种异体HSCT复杂化。但是，由于缺乏T细胞生产所需的专门设施以及生成EBV特异性T细胞所需的时间（约65天）所需的时间（大约65天），因此应用的限制是限制。用EBV特异性T细胞进行有效治疗也可能会受到供体细胞的可用性有限的T细胞传播，缺乏对体内病毒病毒的事先致敏的供体细胞的限制或供体T细胞在肿瘤表达的HLA等位基因中识别EBV的失败。 基于我们的初步研究，我们假设从适当选择的第三方捐助者中获得的EBV特异性T细胞从预先建立的T细胞系列的银行中可以解决这些限制。因此，在目标1中，我们将：对EBV特异性T细胞进行II期试验，该试验是根据与2个HLA等位基因匹配和适当HLA限制的第三方捐助者进行的，以治疗EBV淋巴瘤患者复杂的同种异体HSCT HSCT或有机体移植或其他EBV相关的不友善的不受欢迎的ebviencies Immignancies。在这项试验中，我们将与观察到的EBV DNA循环水平的临床反应和变化相关联，并对在产前转移后体内EBV特异性T特异性T细胞的体内生长，扩张和存活的定量评估。在AIM 2中，我们将建立一个专门同意第三方使用的大型，多样化的EBV特异性T细胞线。先前已从同意捐助者产生的300个T细胞线中的每一条，并且是该银行的候选产品线，是在GMP条件下制造的，并在其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的情况下进行了特征。我们计划确定每条线中EBV特异性T细胞的HLA限制，以便为给定患者选择EBV T细胞，这些患者受患者肿瘤共享的HLA等位基因限制。我们还将确定包含针对LMP-1和/或LMP-2的T细胞的线，这些线可用于治疗有选择地表达这些抗原的EBV+恶性肿瘤。我们预计这项II期试验将提供需要进行III期研究所需的数据，该研究将这种疗法与化学疗法和/或rituxan进行比较。具有良好特征的EBV特异性T细胞也应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：与接受造血细胞和固体器官移植的患者以及患有严重遗传和获得性免疫缺陷的患者，与EBV相关的PTLD和淋巴瘤是一种重大且威胁生命的并发症。当前用化学疗法和/或rituxan治疗在不超过50％的病例中持久有效，并且可能引起明显的毒性。发现供体衍生的EBV特定T细胞的收养转移对预防和治疗这些疾病是有效的。在英国和我们中心的研究也可能有效。该赠款提出了第三方派生的EBV特异性T细胞的II期试验，该试验是根据部分HLA匹配和肿瘤指导的HLA限制来评估这种方法的。它还提出了建立一个完全特征的GMP级EBV特定T细胞的特定特征，以提供广泛适用且可立即获得的资源，用于对这些疾病的产物治疗。