ADMINISTRATION OF VIRUS-SPECIFIC CYTOTOXIC T-LYMPHOCYTES FOR THE PROPHYLAXIS

使用病毒特异性细胞毒性 T 淋巴细胞进行预防

• 批准号: 7605936
• 负责人: Catherine M. Bollard
• 金额: $ 1.32万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7605936
• 关键词: Acute; Adenovirus Infections; Adenoviruses; Adult; Allogenic; Animals; Antigen Targeting; Antigens; Antithymoglobulin; Antiviral Agents; Behavior; Biological Assay; Blood; Blood Screening; CMV protocol; Cells; Cidofovir; Clinical Research; Computer Retrieval of Information on Scientific Projects Database; Cytomegalovirus; Cytotoxic T-Lymphocytes; DNA Viruses; Disease; Dose; Feces; Frequencies; Funding; Goals; Grant; Hematopoietic stem cells; Human Herpesvirus 4; Immune response; Immunity; Immunocompromised Host; Individual; Infection; Infusion procedures; Institution; Jordan; Lymphocyte; Lytic; MabCampath; Maximum Tolerated Dose; Mediating; Methods; Monitor; Numbers; Pathogenicity; Patients; Polymerase Chain Reaction; Prevention; Prophylactic treatment; Proteins; Randomized Controlled Trials; Rate; Recovery; Reporting; Research; Research Personnel; Resources; Risk; Safety; Site; Source; Standards of Weights and Measures; Stem cell transplant; T-Lymphocyte; Time; Toxic effect; Transplant Recipients; Transplantation; United States National Institutes of Health; Urine; Viral Load result; Virus; Virus Diseases; Virus Replication; Week; abstracting; conditioning; cytotoxic; day; in vivo; intravenous injection; pathogen; patient safety; preclinical study; prospective; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ABSTRACT Adenoviruses (Ad) are non-enveloped, lytic, DNA viruses capable of infecting most animal species. The pathogenicity of Adenovirus varies according to group and type and, although acute infection is sometimes severe, it is rarely fatal in otherwise healthy adults. Thus, in normal individuals, the antiviral immune response of the host controls the extent of virus replication and spread. However, Ads are one of a group of opportunistic pathogens of immunosuppressed patients, where severe, prolonged and even fatal infections are common. The frequency of severe Ad disease is increasing in association with growing numbers of immunocompromised individuals, and fatality rates as high as 50% to 80% have been reported {Anderson & Jordan 1990 4252/id}{Carter, Karpen, et al. 2002 4259 /id}. While there are anecdotal reports of adenoviral disease responses to Cidofovir, {Carter, Karpen, et al. 2002 4259 /id} there are no approved antiviral agents with proven efficacy, nor are there currently any prospective randomized controlled trials of potentially useful anti-Ad therapies. Virus-specific CTL proven successful in the prevention and treatment of EBV and CMV-associated diseases in hematopoietic stem cell transplant (SCT) recipients. Since it is possible to transfer cell-mediated responses to EBV and CMV, we wish to evaluate this approach in patients with Ad infection by infusing donor-derived, Ad-specific CTL. In preclinical studies we can generate CTLs containing a CD4 and CD8-specific component using this method and have been successful in identifying the hexon protein as a dominant T cell target antigen. THe goal of our individuals, the antiviral immune response of our clinical study is to generate Ad-specific cytotoxic T-cells and adoptively transfer them as Adenoviral prophylaxis to patients at risk of Adenoviral infection after allogeneic stem cell transplant. These are patients who receive either a T cell depleted transplanted from a mismatched related donor or an unrelated donor (MUD) or an anti T cell antiboy such as Campath or ATG in conditioning. One dose of Ad-specific CTL will be given from 30 days after transplant and toxicity will be assessed by standard NIH criteria. Antiviral prophylaxis will not be used, but patients will be monitored for Ad reactivation by screening blood, stool, and urine by adenoviral PCR assay. Unlike CMV and EBV which are persistent viral infections, adenoviruses produce only transient infection. This may have a substantial impact on the survival and expansion of the infused cells. Hence one of the aims of this study is to assess the effects of adenovirus infection on CTL survival and expansion in vivo. While patients will receive a single dose of adenovirus specific CTL regardless of their adenoviral status, a second dose of CTL will be administered to patients who become adenovirus infected 4 weeks or more after the initial dose of CTL. Adenovirus infection will be defined as the presence of adenoviral positivity as detected by PCR or culture from ONE site such as stool or blood or urine. The functionality of this seconddose compared to the behavior of the first will provide important information about the correct timing of AdCTL administration after stem cell transplant. Since no effective alternate treatment for adenoviral infection exists (in contrast to CMV) this protocol should not compromise patient safety. SPECIFIC AIMS To determine the safety, toxicity and maximum tolerated dose (MTD) of one intravenous injection of donor-derived adenovirus-specific cytotoxic T lymphocytes (CTLs) given as adenovirus prophylaxis to patients at risk of developing adenorius infection after allogeneic stem cell transplant. To evlauate the recovery of virus-specific immunity after CTL infusion and assess its correlation with protection from viral load and disease. To obtain preliminary information regarding whether the presence of antigen is required for Ad-specific CTL persistence in vivo.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此，可以在其他清晰的条目中表示。列出的机构是 对于中心，这不一定是调查员的机构。 抽象的 腺病毒（AD）是不发育的，裂解的DNA病毒，能够感染大多数动物物种。 腺病毒的致病性因组和类型而异，尽管急性感染有时很严重，但在其他健康的成年人中很少致命。 因此，在正常个体中，宿主的抗病毒免疫反应控制病毒复制和扩散程度。 但是，AD是一组免疫抑制患者的机会病原体之一，在严重，长时间甚至致命的感染很常见。 与越来越多的免疫功能低下的个体相关的严重AD疾病的频率正在增加，据报道，死亡率高达50％至80％{Anderson＆Jordan 1990 4252/ID} {Carter，Carter，Karpen等。 2002 4259 /id}。 虽然有有关腺病毒疾病对Cidofovir的反应的轶事报道，但{Carter，Karpen等。 2002 4259 /id}没有批准的抗病毒剂具有可靠的疗效，目前也没有任何潜在有用的抗AD疗法的前瞻性随机对照试验。 病毒特异性CTL被证明在造血干细胞移植（SCT）受体中预防和治疗与EBV和CMV相关疾病的预防和治疗方面成功。 由于可以将细胞介导的对EBV和CMV的反应转移，因此我们希望通过注入供体衍生的AD特异性CTL来评估AD感染患者的这种方法。 在临床前研究中，我们可以使用此方法生成含有CD4和CD8特异性组件的CTL，并已成功地识别己酮蛋白作为主要的T细胞靶抗原。 我们个体的目的是，我们临床研究的抗病毒免疫反应是产生AD特异性的细胞毒性T细胞，并通过同种异体干细胞移植后具有腺病毒感染风险的患者将其作为腺病毒预防。 这些患者接受了从不匹配的相关供体或无关供体（MUD）或抗T细胞抗抗体（例如CAMPATH或ATG）中接受的T细胞耗尽的T细胞。 从移植后30天开始给出一剂AD特异性CTL，并通过标准NIH标准评估毒性。 不会使用抗病毒预防，但通过腺病毒PCR测定法筛选血液，粪便和尿液，将监测患者的AD重新激活。 与持续性病毒感染的CMV和EBV不同，腺病毒仅会产生瞬态感染。 这可能会对注入细胞的存活和扩展产生重大影响。 因此，这项研究的目的之一是评估腺病毒感染对体内CTL存活和扩张的影响。 尽管患者将接受一剂腺病毒特异性CTL的腺病毒状态，但在初始剂量CTL后4周或更长时间被感染的腺病毒感染的患者将进行第二剂CTL。 腺病毒感染将定义为PCR或从一个部位（例如粪便，血液或尿液）中检测到的腺病毒阳性的存在。 与第一次的行为相比，该二剂的功能将提供有关干细胞移植后ADCTL给药正确时机的重要信息。 由于没有有效的腺病毒感染替代治疗（与CMV相比），该方案不应损害患者的安全性。 具体目标 确定一种供体衍生的腺病毒特异性腺病毒特异性细胞毒性T型淋巴细胞（CTL）的静脉注射的安全性，毒性和最大耐受剂量（MTD），以预防腺病毒预防症患者，以对同种异性茎细胞过植物后出现adenorius感染的风险。 为了消除CTL输注后病毒特异性免疫的恢复，并评估其与病毒负荷和疾病的保护相关性。 要获得有关在体内是否需要抗原的存在的初步信息。