Randomized trial of viral specific T-cell infusion to prevent viral infection after hematopoietic stem cell transplant.

病毒特异性 T 细胞输注预防造血干细胞移植后病毒感染的随机试验。

• 批准号: 10436897
• 负责人: Stella Margaret Davies
• 金额: $ 75.34万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10436897
• 关键词: Acute Graft Versus Host Disease; Adenoviruses; Antigens; Antiviral Agents; BK Virus; Blood; Bone Marrow; Bone Marrow Transplantation; Cell Line; Cell Therapy; Cells; Characteristics; Child; Clinic; Clinical; Clinical Trials; Complication; Cytomegalovirus; Data; Disease; Double Stranded DNA Virus; Engineering; Enrollment; Exposure to; Failure; Frequencies; Future; Goals; Hematopoietic Stem Cell Transplantation; Hospitalization; Human Herpesvirus 4; Immune; Incidence; Infection; Infection prevention; Infusion procedures; Institution; Ligands; Morbidity - disease rate; Organ; Patients; Pediatric Hospitals; Peptide Mapping; Persons; Phase; Randomized; Reaction; Risk; Schedule; Stem cell transplant; T cell receptor repertoire sequencing; T cell response; T-Cell Depletion; T-Lymphocyte; Technology; Testing; Time; Toxic effect; Training; Transplant Recipients; Transplantation; Viral; Viral Antigens; Viremia; Virus; Virus Diseases; Virus Replication; arm; base; combat; donor stem cell; effective therapy; experimental arm; fighting; graft vs host disease; high risk; individual patient; infection risk; lymphocyte product; novel therapeutics; predicting response; prevent; programs; prophylactic; randomized trial; response; standard of care; stem cells; treatment arm; treatment response

ABSTRACT Hematopoietic stem cell transplantation (HSCT) is a highly effective treatment, but serious virus infections occur in 82% of children undergoing HSCT at our institution and others. Current anti- viral drugs have inadequate response rates, prolong hospitalizations, and are frequently associated with organ toxicity. An alternative cellular therapy approach uses engineered viral specific T-lymphocytes (VSTs) manufactured from blood donated by a patient’s stem cell donor. VST therapy is highly effective when cells are infused in response to viremia, with response rates of over 80%. We seek to make a critical advance in this technology by testing whether scheduled administration of bone marrow donor derived VSTs 21 days after HSCT will be safe and at least as effective as our current pre-emptive treatment approach of only administering VSTs once viral reactivation or infection has occurred. We propose two specific aims. Specific Aim 1: Randomized comparison of donor-derived scheduled vs treatment VSTs in HSCT recipients to prevent viral infections. Hypothesis: Recipients of scheduled VSTs given 21 days after stem cell infusion will have a significantly lower frequency of viremia and invasive viral infections 100 days after HSCT than patients randomized to treatment use of VST’s. Specific Aim 2: Identify product characteristics that predict response to therapy and compare responses in those with and without exposure to viral ligand. Hypothesis: Specific product characteristics can be established that will identify VST products likely to be clinically effective, and VSTs will persist in scheduled VST recipients without stimulation from viral ligand. Aim 2a: We will study the T cell response to adenovirus, EBV, CMV or BK virus, and product persistence by ELISpot testing, TCR clonogram and VST persistence using TCR sequencing to define more and less effective VST products, and to determine if VSTs expand and persist if they are infused on a schedule into a person with no active viral replication to provide ligand. Aim 2b: We will systematically assess HLA restriction of presentation of viral antigens, using peptide mapping and single antigen cell lines (SALs). These data are vital for future “third party” use of VSTs in persons without donor derived product. This clinical trial may change the paradigm of treatment for viral infections if we are able to show that prophylactic VST infusion prevents infections.

摘要 造血干细胞移植（HSCT）是一种高效的治疗方法，但严重的病毒 在我们机构和其他机构接受HSCT的儿童中，82%发生感染。电流反 病毒药物的反应率不足，延长住院时间， 与器官毒性有关。另一种细胞治疗方法使用工程化的病毒 特异性T淋巴细胞（VST）由患者的干细胞捐献者捐献的血液制成。 VST治疗是非常有效的，当细胞输注响应病毒血症，与反应率 超过80%。我们试图通过测试这项技术是否 HSCT后21天按计划给予骨髓供体来源的VST是安全的 至少和我们目前的先发制人的治疗方法一样有效， 一旦病毒再激活或感染发生VST。我们提出两个具体目标。 具体目标1：供体来源的计划VST与治疗VST的随机比较 HSCT接受者预防病毒感染。 假设：在干细胞输注后21天给予计划VST的接受者将有 HSCT后100天病毒血症和侵袭性病毒感染的频率显著低于 患者随机接受VST治疗。 具体目标2：确定预测治疗反应的产品特征， 比较有和没有接触病毒配体的人的反应。 假设：可以确定识别VST产品的特定产品特征 可能是临床有效的，VST将持续在预定的VST接受者， 来自病毒配体刺激。 目的2a：我们将研究T细胞对腺病毒、EBV、CMV或BK病毒的应答，并研究其产物 通过ELISpot测试、TCR克隆图和使用TCR测序的VST持久性来检测VST持久性， 定义更多和更少有效的VST产品，并确定VST是否扩展和持续，如果他们 按时间表输注到没有活跃病毒复制的人体内以提供配体。 目的2b：我们将系统地评估病毒抗原呈递的HLA限制， 肽作图和单抗原细胞系（SAL）。这些数据对未来的“第三方”至关重要 在无供体衍生产品的患者中使用VST。 如果我们能够证明， 预防性VST输注可预防感染。