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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 在这项研究中，我们希望产生多克隆EBV特异性细胞毒性T细胞，并将其过继转移到活动性鼻咽癌患者体内。用于产生多克隆CTL的淋巴母细胞样细胞系表达包括LMP-1和LMP-2在内的全部EBV衍生基因产物。 尽管LMP特异性CTL是少数，但即使是少量，它们也可能具有识别和杀死表达LMP-1的细胞（包括NPC肿瘤细胞）的能力。 本课题的具体目的是：1）确定从活动期鼻咽癌患者中产生EBV特异性细胞毒性T细胞系的可行性。2)目的探讨鼻咽癌患者静脉注射两种EB病毒特异性细胞毒性T淋巴细胞（CTL）的安全性。3)探讨EB病毒特异性细胞毒性T淋巴细胞系的存活率、免疫效力和抗肿瘤作用。 鼻咽癌是一种恶性疾病，其发病率范围取决于年龄、地理位置、种族和EB病毒（EBV）暴露。在美国，它的年发病率为每10万名<21岁的儿童中近1例。 对于大多数（75-91%）患者，联合治疗的长期预后良好。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。对于挽救化疗失败或第二次复发的其余患者，预后较差。在成人中，放射治疗后的总体5年生存率取决于分期，I期为70%至80%，IV期为20-40%。对于更晚期的疾病，在成人中使用综合疗法可使总生存率达到50%。 虽然儿童的总体生存率很高，但目前的治疗方案仍远未达到理想水平。鼻咽癌治疗后的晚期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型回顾性研究，纳入1，549例患者，以评估鼻咽癌患者放疗+/-化疗后继发性恶性肿瘤的风险。患者年龄范围为10- 80岁（中位数46.3岁），最长随访时间为16年。致死性肿瘤并发症包括与烷化剂化疗相关的继发性白血病和头颈癌（最可能是放射诱导的）以及胃癌。因此，需要开发新的疗法，其可以改善复发/难治性患者的无病生存期，并且其可以最终降低所有患者中长期治疗相关并发症的发生率。

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.