Multivirus-specific T Cells from Naive CB-derived T Cells

来自初始 CB 衍生 T 细胞的多病毒特异性 T 细胞

• 批准号: 8555382
• 负责人: Catherine M. Bollard
• 金额: $ 30.01万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-22 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8555382
• 关键词: Adenovirus Vector; Adenoviruses; Adoptive Transfer; Adult; Allogenic; Antibody Therapy; Antigen-Presenting Cells; Antigens; Antiviral Agents; Autologous; Cancer Patient; Cause of Death; Cell Death; Cell physiology; Cells; Cellular Structures; Clinical; Clinical Trials; Costs and Benefits; Cytomegalovirus; Cytomegalovirus Infections; Cytotoxic T-Lymphocytes; Dendritic Cells; Development; Disease; Donor Lymphocyte Infusion; Dose; Effectiveness; Engraftment; Epitopes; Hematopoietic Stem Cell Transplantation; Human Herpesvirus 4; Immune; Immunity; Immunotherapeutic agent; In Vitro; Incidence; Infection; Infusion procedures; Institutional Review Boards; Instruction; Life; Medical center; Modeling; Morbidity - disease rate; Outcome; Patient Monitoring; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase I Clinical Trials; Phenotype; Population; Procedures; Production; Proteins; Recovery; Research; Research Personnel; Research Project Grants; Resistance; Risk; Specificity; Staging; Stem cell transplant; Stem cells; T cell therapy; T memory cell; T-Cell Immunologic Specificity; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Texas; Therapeutic; Time; Toxic effect; Transplantation; Treatment Failure; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; Viral; Viral Antigens; Virion; Virus; Virus Diseases; cytokine; cytotoxic; design; effective therapy; ethnic minority population; experience; graft vs host disease; high risk; improved; in vitro activity; in vivo; interest; lymphoblastoid cell line; mortality; novel strategies; peripheral blood; prevent; reconstitution; vector; virus development

Viral infections remain a significant cause of treatment failure in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Recipients of cord blood (CB) or HSC from virus naive donors are at particular risk since their grafts contain no virus-specific memory T-cells. Antiviral drugs are effective only for some viruses, and most have significant toxicities. Adoptive transfer of virus-specific cytotoxic T lymphocytes (CTL) from the stem cell donor has proved safe and highly effective, but is available only for recipients of grafts from virus-experienced donors, thereby excluding those patients at highest risk. This lack of an effective strategy to activate and expand virus-specific T-cells from CB and naive donor T-cells has been a major obstacle to extending the approach to these high-risk recipients, whose continued prolonged morbidity and high mortality from viral diseases substantially reduces the cost:benefit ratio of the transplant procedure. We have developed a novel approach that effectively expands CTL specific for cytomegalovirus (CMV), Epstein-Barr virus (EBV) and adenoviruses (Ad) from naive CB T-cells. We expressed the CMVpp65 antigen from an Ad vector in dendritic cells and used them together with T-cell enhancing cytokines to activate T-cells specific for pp65 and Ad vector-derived virion proteins. Subsequent restimulation with CB-derived EBV-transformed lymphoblastoid cell lines transduced with the same vector also reactivated an EBV-specific T-cell component, so that the final T-cell product contained T-cells that were specific for all three viruses, and recognized multiple viral epitopes. We produced and validated the function of the virus-specific CTL from the 20% fraction of cryopreserved CB that will be available to us for our proposed phase I clinical trial of these cells. We now hypothesize that virus-specific CTL prepared from virus-naive CB (Aim 1) will restore antiviral immunity and reduce viral infection in CBT recipients (Aim 2). In these aims we will discover (i) if administration of CB-derived T-cells with multiple viral specificities can produce immune reconstitution to all three viruses, or if there is a consistent hierarchy of recovery, favoring one viral specificity over the others and (ii) whether viral infections will be prevented or controlled after adoptive transfer of CB-derived CTL. Aim 3 will determine whether the mechanisms by which cord blood T-cells respond to latent viral antigens are associated with their naivety or developmental stage. Our studies will show whether this approach can consistently produce effective CTL directed to three of the commonest pathogenic viruses after CBT and whether this approach has the potential to reduce morbidity and mortality after transplant. RELEVANCE (See instructions):

在接受同种异体造血干细胞移植（HSCT）的患者中，病毒感染仍然是治疗失败的重要原因。由于其移植物不含病毒特异性的记忆T细胞，因此病毒供体供应者的脐带血（CB）或HSC的接受者尤其处于危险之中。抗病毒药物仅对某些病毒有效，大多数具有明显的毒性。事实证明，从干细胞供体中的病毒特异性细胞毒性T淋巴细胞（CTL）转移已被证明是安全且高效的，但仅适用于病毒经验的供体的接收者，因此不包括那些处于最高风险的患者。缺乏一种有效的策略来激活和扩展来自CB和NAIVE供体T细胞的病毒特异性T细胞，这是扩展对这些高风险受体的方法的主要障碍，这些高危受体的方法继续延长了病毒疾病的长期发病率和高死亡率，从而大大降低了移植程序的好处。我们开发了一种新型的方法，该方法有效扩展了针对巨细胞病毒（CMV），Epstein-Barr病毒（EBV）和腺病毒（AD）（AD）（AD）的CTL。我们从树突细胞中的AD载体表达了CMVPP65抗原，并将它们与T细胞增强的细胞因子一起使用，以激活针对PP65和AD载体衍生的病毒粒子蛋白的T细胞。随后用CB衍生的EBV转化的淋巴细胞细胞系与同一载体转导的淋巴细胞细胞系也重新激活了EBV特异性T细胞成分，因此最终的T细胞产物包含对所有三种病毒特异的T细胞，并识别出多种病毒性表位。我们从冷冻保存的CB的20％比例中生产并验证了病毒特异性CTL的功能，这些功能将用于我们对这些细胞的I期临床试验可用。现在，我们假设从病毒-Noive CB制备的病毒特异性CTL（AIM 1）将恢复CBT受体中的抗病毒免疫并减少病毒感染（AIM 2）。在这些目标中，我们将发现（i）如果具有多种病毒特异性的CB来源的T细胞可以对所有三种病毒产生免疫重构，或者是否存在恢复的一致层次，有利于一种病毒特异性，并且（ii）是否会在CB衍生的CB CTL传递后预防或控制病毒感染。 AIM 3将确定脐带血T细胞对潜在病毒抗原反应的机制是否与它们的天真或发育阶段有关。我们的研究将表明，这种方法是否能够始终产生针对CBT后三种最常见的病原病毒的有效CTL，以及该方法是否有可能降低移植后发病率和死亡率。相关性（请参阅说明）：