ADOPTIVE TRANSFER OF CORD BLOOD T CELLS TO PREVENT AND TREAT CMV AND ADENOVIRUS

脐带血 T 细胞过继移植预防和治疗巨细胞病毒和腺病毒

• 批准号: 8356716
• 负责人: Catherine M. Bollard
• 金额: $ 0.59万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356716
• 关键词: Adenovirus Vector; Adenoviruses; Adoptive Transfer; Adult; Allogenic; Antigen-Presenting Cells; Antiviral Agents; B-Lymphocytes; Back; Blood Cells; Blood donor; Bone Marrow; Bone Marrow Transplantation; Cause of Death; Clinical Research; Complication; Cytomegalovirus; Cytotoxic T-Lymphocytes; Dendritic Cells; Disabled Persons; Disadvantaged; Disease; Donor person; Freezing; Funding; Genes; Grant; Hematologic Neoplasms; Histocompatibility Testing; Immune; Immunity; Incidence; Infection; Infusion procedures; Marrow; Maximum Tolerated Dose; Monitor; National Center for Research Resources; New Agents; Patients; Peripheral Blood Stem Cell; Principal Investigator; Recovery; Research; Research Infrastructure; Research Personnel; Resources; Risk; Safety; Source; Stem cell transplant; Stem cells; T memory cell; T-Lymphocyte; Testing; Toxic effect; Transplant Recipients; Transplantation; Umbilical Cord Blood; United States National Institutes of Health; Viral; Virus; Virus Diseases; allotransplant; cell killing; cost; ethnic minority population; graft vs host disease; high risk; intravenous injection; lymphocyte product; peripheral blood; prevent; reconstitution; vector

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT Allogeneic stem cell transplantation is the treatment of choice for selected patients with high-risk hematologic malignancies. However a significant proportion of patients - especially non-Caucasians - lack a marrow or peripheral blood stem cell donor. Umbilical cord blood (CB) has therefore emerged as an important alternative source of stem cells for allotransplant patients. The major advantages of CB transplants (CBT) compared to unrelated marrow include more rapid procurement of the graft, the requirement for less stringent HLA matching (tissue typing), the higher likelihood of finding a match for ethnic minorities, and a decreased incidence of graft versus host disease (GVHD). However, one of the major disadvantages of CB is the delayed immune recovery due to the small numbers of T cells transferred and the absence of memory T cells within the donor grafts, Consequently, CB recipients are susceptible to an array of viral and other infections that are the leading cause of death in these patients. Cytomegalovirus and Adenovirus are two of the most common viruses that can cause problems after a cord blood transplant. Investigators have previously shown that it is possible to grow special T cells called virus-specific cytotoxic T lymphocytes (CTL) from the peripheral blood of adult transplant donors that will prevent and treat these viral infections when they are given back to the patient after bone marrow transplant. In this study, investigators will see if they can use a similar approach and make CTLs from cord blood to give to patients after cord blood transplant to prevent reactivation and infection with CMV and adenovirus. Virus specific CTL lines will be grown from normal umbilical cord blood units and frozen. To make the CTL they will first infect blood cells called dendritic cells with a specially produced adenovirus (a vector) that also carries part of the CMV gene. This is a disabled virus that cannot reproduce itself once infection has occurred so it cannot spread. These infected dendritic cells are irradiated and are then used to stimulate the T cells to respond to adenoviruses and CMV, and kill the cells infected with these viruses. The investigators will then give a second stimulation to the T cells, using irradiated B cells (also made from the same cord blood unit) which are also infected with EBV in addition to the same vector. Once we have made sufficient number of T cells they will test them to make sure they kill cells infected with these viruses and freeze them. The primary objective is to determine whether this strategy is feasible and safe. One risk is that because the T cell are donor-derived they may attack the subject and cause a condition called graft versus host disease (GVHD). We will closely monitor for this complication. Secondary objectives are to determine the effects of the T cell infusion on the virus infection and to see if the recipients can stay immune to these viruses. I. HYPOTHESIS In this trial, we will evaluate whether the administration of cord blood donor derived CTLs to recipients of cord blood transplants with or at risk for CMV and AdV will be able to clear or prevent reactivation or infection with these two viruses. The CTL product that we will use in this study is manufactured using antigen presenting cells transduced with an adenoviral vector encoding pp65 as we used in a previous study (RAC#0304-579). In this previous study the CTL were generated from donor peripheral blood and the infused donor-derived CTLs had antiviral activity after administration to bone marrow and peripheral blood stem cell transplant recipients. The study agent for this new study for patients after cord blood transplant will be assessed primarily for safety (stopping rules defined) and as secondary objectives antiviral activity and ability to reconstitute antiviral immunity. II. SPECIFIC AIMS The primary purpose or objective of the study is to determine the safety, toxicity and maximum tolerated dose (MTD) of one intravenous injection of donor-derived cytotoxic T lymphocytes (CTLs) specific for CMV and Adenovirus given to patients with or at risk for CMV and adenovirus disease after cord blood transplant. The secondary objectives will evaluate the impact of these CTLs on CMV/AdV-specific T-lymphocyte immune reconstitution and the efficacy of recovery of virus-specific immunity after CTL infusion and its correlation with protection from viral infection/disease. We will also evaluate the efficacy of recovery of virus-specific immunity after CTL infusion and its correlation with viral clearance and/or protection from viral infections/disease.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其他NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 摘要 异基因造血干细胞移植是高危血液系统恶性肿瘤患者的首选治疗方法。然而，很大一部分患者-特别是非高加索人-缺乏骨髓或外周血干细胞供体。 因此，脐带血（CB）已成为同种异体移植患者干细胞的重要替代来源。与无关骨髓相比，CB移植（CBT）的主要优点包括移植物的采购更快，对HLA配型（组织分型）的要求不那么严格，为少数民族找到匹配的可能性更高，以及移植物抗宿主病（GVHD）的发生率降低。然而，CB的主要缺点之一是由于转移的T细胞数量少和供体移植物内缺乏记忆T细胞而延迟的免疫恢复。因此，CB受体易受一系列病毒和其他感染的影响，这些感染是这些患者死亡的主要原因。巨细胞病毒和腺病毒是两种最常见的病毒，可以导致脐带血移植后的问题。 研究人员先前已经表明，有可能从成人移植供体的外周血中培养出称为病毒特异性细胞毒性T淋巴细胞（CTL）的特殊T细胞，当骨髓移植后将其送回患者时，这些细胞将预防和治疗这些病毒感染。 在这项研究中，研究人员将看看他们是否可以使用类似的方法，从脐带血中制备CTL，在脐带血移植后给予患者，以防止CMV和腺病毒的再激活和感染。病毒特异性CTL系将从正常脐带血单位生长并冷冻。 为了制造CTL，他们将首先用一种特殊产生的腺病毒（一种载体）感染称为树突细胞的血细胞，这种腺病毒也携带CMV基因的一部分。 这是一种禁用的病毒，一旦感染发生，它就无法复制自己，因此无法传播。 这些受感染的树突状细胞被照射，然后用于刺激T细胞对腺病毒和CMV做出反应，并杀死感染这些病毒的细胞。 然后，研究人员将对T细胞进行第二次刺激，使用辐照过的B细胞（也由相同的脐带血单位制成），除了相同的载体外，B细胞也感染了EBV。 一旦我们制造了足够数量的T细胞，他们将对其进行测试，以确保它们杀死感染这些病毒的细胞并将其冷冻。 主要目的是确定该策略是否可行和安全。 一个风险是，由于T细胞是供体来源的，它们可能会攻击受试者并引起称为移植物抗宿主病（GVHD）的疾病。 我们将密切监测这种并发症。 次要目的是确定T细胞输注对病毒感染的影响，并观察接受者是否可以对这些病毒保持免疫。 I. 假设 在本试验中，我们将评估对患有CMV和AdV或存在CMV和AdV风险的脐带血移植受者给予脐带血供体来源的CTL是否能够清除或预防这两种病毒的再激活或感染。 我们将在本研究中使用的CTL产物是使用用编码pp 65的腺病毒载体转导的抗原呈递细胞制备的，如我们在先前的研究（RAC#0304-579）中使用的。在先前的研究中，CTL从供体外周血产生，输注的供体来源的CTL在给予骨髓和外周血干细胞移植受体后具有抗病毒活性。 这项针对脐带血移植后患者的新研究的研究药物将主要评估安全性（定义的停药规则），并作为次要目标评估抗病毒活性和重建抗病毒免疫的能力。 二. 具体目标 本研究的主要目的或目标是确定脐带血移植后CMV和腺病毒疾病患者或存在CMV和腺病毒疾病风险的患者单次静脉注射CMV和腺病毒特异性供体来源的细胞毒性T淋巴细胞（CTL）的安全性、毒性和最大耐受剂量（MTD）。 次要目的将评价这些CTL对CMV/AdV特异性T淋巴细胞免疫重建的影响和CTL输注后恢复病毒特异性免疫的功效及其与病毒感染/疾病保护的相关性。我们还将评估CTL输注后恢复病毒特异性免疫的功效及其与病毒清除和/或保护免受病毒感染/疾病的相关性。