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利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在这项研究中，我们希望产生多克隆的EBV特异性细胞毒性T细胞，并过继地将它们转移给活动性鼻咽癌患者。用于产生多克隆CTL的淋巴母细胞系表达包括LMP-1和LMP-2在内的所有EBV衍生基因产物。尽管LMP特异性CTL为数不多，但即使在少数情况下，它们也有可能识别和杀伤表达LMP-1的细胞，包括鼻咽癌肿瘤细胞。 本项目的具体目标是：1)确定从活动性鼻咽癌患者中产生EBV特异性细胞毒T细胞株的可行性。2)探讨鼻咽癌患者静脉注射两种自体EBV特异性细胞毒性T淋巴细胞(CTL)的安全性。3)检测EBV特异性细胞毒T淋巴细胞株的存活率、免疫效力和抗肿瘤作用。 鼻咽癌是一种恶性疾病，其发病率随年龄、地理位置、种族和EB病毒(EBV)的暴露而变化。在美国，它的年发病率接近每100,000名儿童中就有1例。对于大多数患者(75-91%)来说，综合治疗的远期预后良好。在最初治疗后复发的10%-15%的患者中，只有40%的患者会进入第二次缓解。对于其余未能挽救化疗或第二次复发的患者，预后很差。在成人中，放射治疗后的总5年存活率与分期有关，I期为70%至80%，IV期为20%至40%。对于更晚期的疾病，成人综合治疗的总存活率为50%。 尽管儿童的总体存活率很好，但目前的治疗方案仍然很不理想。鼻咽癌治疗后的晚期医学并发症包括生长激素缺乏、甲状腺功能减退和肺纤维化。在台湾对1,549名患者进行了一项大规模的回顾研究，以评估鼻咽癌患者放疗+化疗后继发恶性肿瘤的风险。患者年龄10-80岁，中位年龄46.3岁，最长随访16年。致命的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(最有可能是辐射引起的)，以及胃癌。因此，开发新的治疗方法是可取的，它可以提高复发/难治性患者的无病存活率，并最终可能减少所有患者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.