EBV-Specific T-Cell Therapy for Nasopharynx Cancer: Immunomodulation and Response

鼻咽癌的 EBV 特异性 T 细胞疗法：免疫调节和反应

• 批准号: 7529780
• 负责人: MARSHALL R POSNER
• 金额: $ 38.87万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-26 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7529780
• 关键词: Adoptive Transfer; Autologous; Back; Blood; Cancer Etiology; Cancer Vaccines; Cells; China; Clinical; Clinical Trials; Confidence Intervals; Cytotoxic T-Lymphocytes; EBV-associated malignancy; Effectiveness; Epithelial; Epstein-Barr Virus Infections; Evaluation; Future; Hodgkin Disease; Human Herpesvirus 4; IL2RA gene; Immune; Immune system; Immunosuppression; Immunotherapy; In Vitro; Incidence; Infection Control; Laboratories; Laboratory Study; Lesion; Lymphocyte; Lymphoproliferative Disorders; Malignant Neoplasms; Malignant neoplasm of nasopharynx; Modification; Nasopharynx; Nasopharynx Carcinoma; North America; Numbers; Palliative Care; Patients; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Population; Prevalence; Process; Progression-Free Survivals; Proteins; Public Health; Rate; Recurrence; Refractory; Refractory Disease; Relapse; Role; Safety; T-Lymphocyte; Testing; Therapeutic; Therapeutic immunosuppression; Toxic effect; Translating; Transplantation; Tube; Tumor Antigens; Upper arm; Viral; Viral Proteins; Virus; Virus Diseases; Work; base; cancer immunotherapy; chemotherapy; clinical efficacy; immunoregulation; improved; in vivo; manufacturing process; neoplastic cell; prevent; response; success; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Nasopharyngeal carcinoma (NPC) is endemic in southern China and the incidence is increasing in North America. NPC is directly associated with Epstein-Barr Virus (EBV) where it exists in every tumor cell in a tightly controlled latent state. EBV-associated NPC is a promising target for cancer immunotherapy. EBV viral proteins can serve as unique foreign tumor antigens for cytotoxic T cells (CTLs). Immunotherapy with EBV-specific T cell populations expanded in vitro is effective in PTLD, however translating that success to other EBV-associated malignancies, such as NPC, is challenging. Despite the limited repertoire of potential CTL targets expressed in NPC, a recent phase I trial showed that adoptive transfer of ex vivo expanded autologous EBV-specific T cells was safe and provided evidence for activity in a small number of patients with relapsed or refractory disease. In order to develop improved immunotherapy, a firm estimation of clinical efficacy for EBV- specific immunotherapy in NPC is required. Further study is also necessary to more completely dissect the CTL response and identify the mechanisms underlying effective immunotherapy and mechanisms of enhancing the response in order to develop better therapeutic strategies. We propose a comprehensive clinical estimation and translational Phase II trial of ex vivo expanded EBV specific T cell therapy in patients with relapse NPC to (1) Estimate the overall response rate in patients with recurrent and/or metastatic EBV-associated NPC (2) Establish the repertoire and clinical correlates of response and (3) systematically study the contribution and potential impact of removing Tregs by CD25 depletion and/or inhibiting Treg activity. We will select a second treatment arm for a subsequent Phase IIb study based on the in vitro laboratory studies and in vivo clinical results from this translational estimation clinical trial. PUBLIC HEALTH RELEVANCE: Nasopharynx cancer is caused by a common virus that is present in all the tumor cells and causes the cancer. For some reason the patient can't eradicate the virus and the tumor cells, although most people do control the infection and don't get cancer. There is some evidence that artificially stimulating the patient's own immune cells with virus infected cells in a test tube can by-pass whatever is preventing the immune system from stopping the cancer. This creates a cellular anti-cancer vaccine that can be given back to the same patient and treat the cancer. We plan to study this process and see if we can improve the effectiveness of the therapy.

描述（由申请人提供）：鼻咽癌（NPC）在中国南方流行，在北美发病率呈上升趋势。 NPC 与 Epstein-Barr 病毒 (EBV) 直接相关，EB 病毒以严格控制的潜伏状态存在于每个肿瘤细胞中。 EBV 相关鼻咽癌是癌症免疫治疗的一个有前景的靶点。 EBV 病毒蛋白可以作为细胞毒性 T 细胞 (CTL) 的独特外源肿瘤抗原。使用体外扩增的 EBV 特异性 T 细胞群进行免疫治疗对 PTLD 有效，但将这种成功应用于其他 EBV 相关恶性肿瘤（例如鼻咽癌）具有挑战性。尽管在 NPC 中表达的潜在 CTL 靶标有限，但最近的一项 I 期试验表明，离体扩增的自体 EBV 特异性 T 细胞的过继转移是安全的，并为少数复发或难治性疾病患者的活性提供了证据。为了开发改进的免疫疗法，需要对鼻咽癌中 EBV 特异性免疫疗法的临床疗效进行可靠的评估。还需要进一步的研究来更全面地剖析 CTL 反应，并确定有效免疫治疗的机制和增强反应的机制，以便制定更好的治疗策略。我们建议对复发性鼻咽癌患者进行体外扩展 EBV 特异性 T 细胞治疗的全面临床评估和转化性 II 期试验，以 (1) 估计复发性和/或转移性 EBV 相关鼻咽癌患者的总体缓解率 (2) 建立(3) 系统地研究通过 CD25 耗竭和/或抑制 Treg 活性去除 Tregs 的贡献和潜在影响。我们将根据本次转化评估临床试验的体外实验室研究和体内临床结果，为后续的 IIb 期研究选择第二个治疗组。公共卫生相关性：鼻咽癌是由一种常见病毒引起的，这种病毒存在于所有肿瘤细胞中并导致癌症。由于某种原因，患者无法根除病毒和肿瘤细胞，尽管大多数人确实控制了感染并且没有患上癌症。有一些证据表明，在试管中用病毒感染的细胞人工刺激患者自身的免疫细胞可以绕过阻止免疫系统阻止癌症的任何因素。这创造了一种细胞抗癌疫苗，可以回输给同一患者并治疗癌症。我们计划研究这个过程，看看是否可以提高治疗的有效性。