CLINICAL TRIAL: EBV-SPECIFIC CYTOTOXIC T-LYMPHOCYTES FOR EBV-POSITIVE NASOPHARYN

临床试验：针对 EBV 阳性鼻咽的 EBV 特异性细胞毒性 T 淋巴细胞

• 批准号: 7950678
• 负责人: HELEN E HESLOP
• 金额: $ 0.39万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950678
• 关键词: Adult; Aftercare; Age; Alkylating Antineoplastic Agents; Antibodies; Antigen-Presenting Cells; Area; Asia; Autologous Epstein-Barr Virus-Specific Cytotoxic T Lymphocytes; B-Lymphocytes; Biopsy; Biopsy Specimen; CD8B1 gene; Cell Line; Cells; Cellular Immunity; Child; Clinical Research; Clinical Trials; Combined Modality Therapy; Computer Retrieval of Information on Scientific Projects Database; Cytotoxic T-Lymphocytes; Defense Mechanisms; Disease; Disease remission; Disease-Free Survival; EBV-Specific Cytotoxic T-Lymphocyte; Environmental Risk Factor; Epithelium; Funding; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Grant; Hand; Head and Neck Cancer; Human Herpesvirus 4; Human Papillomavirus; Hypothyroidism; Immunoglobulin A; Immunoglobulin G; Incidence; Infection; Institution; LMP1; Link; Malignant - descriptor; Membrane Proteins; Messenger RNA; Minority; Nasopharynx Carcinoma; Nuclear Antigens; Nuclear Pore Complex; Occupational; Oropharyngeal; Pathologic Processes; Patients; Peptide Fragments; Play; Process; Proteins; Pulmonary Fibrosis; Race; Radiation; Radiation therapy; Refractory; Relapse; Research; Research Personnel; Resources; Risk; Role; Route; Safety; Second Primary Cancers; Serological; Smoking; Source; Squamous Cell; Staging; Stimulus; Surface Antigens; Survival Rate; Taiwan; Time; Treatment Protocols; Undifferentiated; United States National Institutes of Health; Viral; Viral Antigens; Virus Diseases; advanced disease; alpha-Thalassemia; base; chemotherapy; cohort; follow-up; growth hormone deficiency; improved; infected B cell; intravenous injection; killings; lymphoblastoid cell line; malignant stomach neoplasm; medical complication; neoplastic; neoplastic cell; novel; outcome forecast; response; tumor; viral DNA

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. In this study we wish to generate polyclonal EBV specific cytotoxic T cells and adoptively transfer them to patients with active Nasopharyngeal Carcinoma. The lymphoblastoid cell lines, which are used to generate polyclonal CTLs, express the entire range of EBV derived gene products including LMP-1 and LMP-2. Although LMP-specific CTLs are in a minority, it is possible that even in small numbers they will have the ability to recognize and kill LMP-1 expressing cells including the NPC tumor cells. The Specific Aims of this project are: 1) To determine the feasibility of generating EBV specific cytotoxic T cell lines from patients with active Nasopharyngeal Carcinoma. 2) To determine the safety of two intravenous injections of autologous EBV specific cytotoxic T-lymphocytes (CTL) in patients with Nasopharyngeal Carcinoma. 3) To determine the survival, immunological efficacy and anti-tumor effects of EBV specific cytotoxic T-lymphocyte lines. Nasopharyngeal carcinoma, is a malignant disease with a variable range of incidence depending on age, geographical place, race and Epstein-Barr virus (EBV) exposure. It has an annual incidence of nearly 1 case per 100,000 children < 21yrs in the USA. For the majority (75-91%) of patients, the long-term prognosis is favorable with combined modality therapy. Of the 10-15% of patients who relapse after initial therapy, only 40% will enter a second remission. For the remainder who fail salvage chemotherapy or relapse for a second time, the prognosis is poor. In adults, the overall 5-year survival rates following radiotherapy are stage dependant and range from 70% to 80% for stage I, and 20-40% for stage IV. For more advanced disease, the use of combined modality therapy in adults results in an overall survival of 50%. Although overall survival rates are good in children, current treatment regimens are still far from ideal. Late medical complications after treatment for NPC include growth hormone deficiency, hypothyroidism and pulmonary fibrosis. A large restrospective study in Taiwan of a cohort of 1,549 patients was performed to assess the risk of secondary malignancies in NPC patients post radiotherapy +/- chemotherapy. The patients ranged in age from 10-80years (median 46.3years) with a maximum follow-up of 16 years. Fatal neoplastic complications included secondary leukemia related to alkylating agent chemotherapy and head and neck cancers (most likely radiation induced), and gastric cancer. It is therefore desirable to develop novel therapies that could improve disease free survival in relapsed/refractory patients and which might ultimately reduce the incidence of long term treatment related complications in all patients. The etiological factors of endemic NPC include EBV, environmental risk factors and genetic susceptibility. The etiological link between NPC and EBV was first based on serological evidence. Elevated IgG and IgA antibody titers are frequently seen. The association between EBV and NPC was subsequently confirmed by showing that EBV DNA was present in the NPC tumor cells and that EBV DNA in NPC biopsy samples is clonal, arising from a single EBV infected cell. EBV has been detected in virtually all cases of undifferentiated non-keratinizing NPC. On the other hand, squamous cell NPC appear to show a geographical variability with regard to their EBV association with higher EBV positive tumors seen in high incidence areas such as Asia. In addition, squamous cell NPC appears to represent a more heterogeneous group of tumors with other co-factors such as smoking and human papilloma virus (HPV) contributing to the pathogenic process. Nevertheless, the strong association of NPC with EBV remains. Thus NPC may represent a final common response to several pathological processes that include viral infections, occupational and environmental stimuli with, perhaps, a genetic contribution. In primary infection, the main route of entry for EBV is via the oropharyngeal epithelium. Viral replication in these cells subsequently allows infection of B lymphocytes thus resulting in a polyclonal expansion of transformed B cells. Both humoral and cell mediated immunity have important roles to play in the control of EBV. EBV-specific CD8+ CTLs are thought to be the most important defense mechanism against outgrowth of EBV-infected B cells. These cells recognize peptide fragments, derived from viral antigens, expressed on the surface of antigen presenting cells in association with MHC molecules. EBV positive NPC cells regularly express the nuclear antigen ENBA1 and a subset of tumors also appear to be latent membrane protein LMP1 positive. Transcriptional analysis has shown expression of LMP2 mRNA in the majority of tumor biopsies. In addition, transcription of the BARF0 gene has been detected in NPC cells.

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代表。列出的机构是 对于中心，这不一定是调查员的机构。 在这项研究中，我们希望产生多克隆EBV特异性的细胞毒性T细胞，并将其传递给活跃的鼻咽癌患者。用于生成多克隆CTL的淋巴细胞细胞系表达了包括LMP-1和LMP-2在内的EBV衍生基因产物的整个范围。 尽管LMP特异性的CTL属于少数群体，但即使在少数情况下，他们也有能力识别和杀死包括NPC肿瘤细胞在内的LMP-1表达细胞。 该项目的具体目的是：1）确定来自活性鼻咽癌患者的EBV特异性细胞毒性T细胞系的可行性。 2）确定两种自体EBV特异性细胞毒性T淋巴细胞（CTL）对鼻咽癌患者的两次静脉注射的安全性。 3）确定EBV特异性细胞毒性T淋巴细胞系的生存，免疫学和抗肿瘤作用。 鼻咽癌是一种恶性疾病，其发病率范围可变，具体取决于年龄，地理位置，种族和爱泼斯坦 - 巴尔病毒（EBV）暴露。在美国，它的年发病率近100,000名儿童<21岁。 对于大多数（75-91％）的患者，长期预后具有联合态疗法。在初始治疗后复发的10-15％的患者中，只有40％将进入第二次缓解。对于第二次打捞化疗或复发失败的其余部分，预后很差。在成年人中，放疗后的总5年生存率取决于阶段，I期为I期为70％至80％，IV期为20-40％。对于更晚期疾病，在成年人中使用合并的方式疗法的总生存率为50％。 尽管总体生存率在儿童中良好，但目前的治疗方案仍然远非理想。 NPC治疗后的晚期医疗并发症包括生长激素缺乏症，甲状腺功能减退症和肺纤维化。在台湾进行了一项大量约束性研究，该研究对1,549例患者进行了一组，以评估放疗后NPC患者的继发性恶性肿瘤的风险+/-化学疗法。患者的年龄从10-80岁（中值46.3岁）年龄不等，最大随访为16岁。致命的肿瘤并发症包括与烷基化剂化疗有关的继发性白血病和头颈癌（最有可能诱发的辐射）和胃癌。因此，希望开发出可以改善复发/难治性患者无疾病生存的新型疗法，这最终可能会降低所有患者长期治疗并发症的发生率。 地方性NPC的病因因素包括EBV，环境风险因素和遗传敏感性。 NPC和EBV之间的病因联系首先基于血清学证据。经常看到升高的IgG和IgA抗体滴度。 EBV和NPC之间的关联随后证明了NPC肿瘤细胞中存在EBV DNA，并且NPC活检样品中的EBV DNA是克隆的，这是由单个EBV感染的细胞引起的。在几乎所有未分化的非核化NPC的情况下都检测到EBV。另一方面，鳞状细胞NPC似乎显示出其与在亚洲高发射率区域看到的EBV较高的EBV阳性肿瘤有关的地理变异性。此外，鳞状细胞NPC似乎代表了与其他共同因素（例如吸烟和人乳头状瘤病毒（HPV））的肿瘤组，这有助于致病过程。然而，NPC与EBV的牢固关联仍然存在。因此，NPC可能代表对包括病毒感染，职业和环境刺激在内的几个病理过程的最终共同反应，也许是遗传贡献。 在原发性感染中，EBV的主要进入途径是通过口咽上皮。这些细胞中的病毒复制随后允许感染B淋巴细胞，从而导致转化的B细胞的多克隆膨胀。体液和细胞介导的免疫都在控制EBV中起着重要作用。 EBV特异性的CD8+ CTL被认为是针对EBV感染的B细胞生长的最重要的防御机制。这些细胞识别源自病毒抗原的肽片段，这些肽片段在抗原表面与MHC分子搭配的细胞表面表达。 EBV阳性NPC细胞定期表达核抗原ENBA1，一部分肿瘤似乎也是潜在的膜蛋白LMP1阳性。转录分析显示了大多数肿瘤活检中LMP2 mRNA的表达。另外，在NPC细胞中已经检测到BARF0基因的转录。