Combined CTL /CD45 antibody for nasopharyngeal carcinoma

描述（由申请人提供）：鼻咽癌的标准治疗方式无法治愈大量患者的局部区域巨大病变，并伴有严重的长期副作用。由于几乎所有未分化的NPC都与Epstein巴尔病毒（EBV）相关，因此这种类型的肿瘤是针对肿瘤相关EBV抗原的免疫治疗的有吸引力的候选者。最近，我们已经证明了为EBV + NPC患者产生自体EBV特异性细胞毒性T淋巴细胞（CTL）的可行性。这些CTL的连续转移已被证明是安全的，并在所有4例接受治疗的难治性/复发性疾病患者中诱导临床应答。尽管这些结果很有希望，但并非所有患有巨大疾病的患者都完全有反应。由于T细胞区室的大小通过许多有效的稳态机制维持在稳定状态，我们认为这种失败部分是由于输注的T淋巴细胞在体内无法进行充分的扩增。由于这些稳态机制在淋巴细胞减少症期间驱动淋巴细胞增殖，我们现在建议在CTL输注之前耗尽患者的淋巴隔室。为此，我们将使用短寿命的CD45单克隆抗体（MAbs），我们已经证明，它可以深刻地消耗外周血和淋巴器官中的淋巴细胞，同时保留造血祖细胞。EBV特异性CTL的后续过继转移应导致输注细胞的扩增以恢复T细胞区室。在这里提出的I期研究中，递增剂量的自体EBV特异性CTL将被施用给复发高风险或患有难治性或复发性疾病的NPC患者。每名患者将首先接受一剂单独的CTL，然后8周后接受固定剂量的CD45 MAb，随后接受相同剂量的CTL。本研究设计使我们能够评估CTL和CD45单克隆抗体组合在NPC患者中的安全性和获得的T细胞耗竭的程度和范围（目的1），以及抗CD45对EBV特异性CTL的扩增和体内功能的影响的患者内比较（目的2）。实施本临床研究所需的所有技术和操作规程均已在申请人的实验室中实施。本项目完成后，CD45 MAb治疗后给予EBV特异性CTL的最大安全剂量以及CD45 MAb介导的T细胞耗竭对过继转移CTL的扩增、持久性和功能的影响都将明确。 2003年12月8日（见审查说明）

DESCRIPTION (provided by applicant): Standard treatment modalities for nasopharyngeal carcinoma fail to cure local-regional bulky disease in a significant number of patients and are accompanied by severe long-term side effects. Since virtually all undifferentiated NPC are associated with Epstein Barr virus (EBV), this type of tumor is an attractive candidate for immunotherapy targeted against tumor-associated EBV antigens. Recently we have demonstrated the feasibility of generating autologous EBV-specific cytotoxic T lymphocytes (CTL) for patients with EBV+ NPC. Adoptive transfer of these CTL has proven safe and induced clinical responses in all 4 patients with refractory/relapsed disease treated. Although these results are promising, not all patients with bulky disease responded completely. Since the size of the T cell compartment is maintained at a steady state by a number of potent homeostatic mechanisms, we believe this failure was due in part to failure of infused T lymphocytes to undergo adequate expansion in vivo. Since these homeostatic mechanisms drive lymphoproliferation during lymphopenia, we now propose to deplete the patient's lymphoid compartment prior to CTL infusion. For this purpose, we will use short-lived CD45 monoclonal antibodies (MAbs), which we have shown can profoundly deplete lymphocytes in peripheral blood and lymphoid organs, whilst sparing hematopoietic progenitor cells. Subsequent adoptive transfer of EBV-specific CTL should result in expansion of the infused cells to restore the T cell compartment. In the phase I study proposed here, escalating doses of autologous EBV-specific CTL will be administered to NPC patients either at high risk for relapse or with refractory or relapsed disease. Each patient will first receive one dose of CTL alone and then 8 weeks later a fixed dose of CD45 MAbs followed by the same dose of CTL. This study design allows us to evaluate the safety of the combination of CTL and CD45 MAbs in NPC patients and the degree and extent of T cell depletion obtained (Aim 1) as well as an intra-patient comparison of the effect of anti-CD45 on the expansion and in vivo function of EBV-specific CTL (Aim 2). All of the technologies and operating procedures needed to implement this clinical study are in place in the applicant's laboratory. Upon completion of this project, both the maximum safe dose of EBV-specific CTL when given after CD45 MAb treatment as well as the effect of CD45 MAb-mediated T cell depletion on the expansion, persistence and function of adoptively transferred CTL should be clear. December 08, 2003 (See review notes)