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

摘要 造血干细胞移植(HSCT)是一种高效的治疗方法，但病毒感染严重 在我们机构和其他机构接受HSCT的儿童中，感染发生率为82%。当前的反- 病毒药物的应答率不足，延长了住院时间，而且经常 与器官毒性有关。另一种细胞治疗方法是使用工程病毒 从患者干细胞捐献者捐献的血液中制造的特异性T淋巴细胞(VSTs)。 VST疗法是非常有效的，当细胞被注入以响应病毒血症时，应答率 超过80%。我们寻求在这项技术上取得关键进展，通过测试 骨髓供者VSTs移植后21天定期给药将是安全的 而且至少和我们目前的预防性治疗方法一样有效 一旦病毒重新激活或感染，就会发生VST。我们提出了两个具体目标。 具体目标1：供者衍生计划VST与治疗VST的随机比较 HSCT接受者预防病毒感染。 假设：干细胞输注后21天接受常规VSTs的受者将有 HSCT后100天病毒血症和侵袭性病毒感染的发生率显著低于 患者随机接受VST的治疗。 具体目标2：确定可预测治疗反应的产品特性 比较接触病毒配体和不接触病毒配体的人的反应。 假设：可以建立特定的产品特征来识别VST产品 可能在临床上有效，VST将在计划的VST接受者中持续存在，而不是 来自病毒配体的刺激。 目的2a：研究腺病毒、EBV、CMV或BK病毒对T细胞的应答及其产物 通过ELISpot测试、TCR克隆图和使用TCR测序的VST持久性来实现持久性 定义更多和更不有效的VST产品，并确定VST是否会扩展并持续存在 按计划注射到没有活跃病毒复制的人体内以提供配体。 目的2b：我们将系统地评估人类白细胞抗原对病毒抗原呈递的限制，使用 多肽图谱和单抗原细胞系(SAL)。这些数据对未来的“第三方”至关重要 在没有供体衍生产品的人中使用VST。 如果我们能够证明，这项临床试验可能会改变病毒感染的治疗模式 预防性的VST输液可以防止感染。

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.