PREVENTION AND ANTIVIRAL TREATMENT FOR EBV LYMPHOMAGENESIS

EBV 淋巴生成的预防和抗病毒治疗

• 批准号: 8502416
• 负责人: JOSEPH S PAGANO
• 金额: $ 17.86万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502416
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adult; Adverse effects; Affect; Alternative Therapies; Animal Model; Animals; Antiviral Agents; B-Cell Lymphomas; B-Lymphocytes; Blinded; Body Weight decreased; Cell Transplants; Cells; Clinical Trials Design; Controlled Study; Cytomegalovirus; Development; Disease; Dose; Epstein-Barr Virus Infections; Gene Rearrangement; Generations; Genomics; Hematopoietic stem cells; Human; Human Herpesvirus 4; Immune response; Immune system; Individual; Infection; Lymphoid; Lymphoid Cell; Lymphoma; Lymphomagenesis; Lymphoproliferative Disorders; Lytic; Lytic Phase; MS4A1 gene; Malignant Neoplasms; Modeling; Mus; Natural Killer Cells; Organ Transplantation; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Phenotype; Placebo Control; Placebos; Prevention; Signal Transduction; Stem cells; System; T-Lymphocyte; Testing; Therapeutic immunosuppression; Time; Tissue Donors; Transplant Recipients; Transplantation; Variant; Viral; Viral Load result; Virus; acquired immunodeficiency; antitumor agent; arm; base; cohort; control trial; design; dosage; effective therapy; experience; inborn immunodeficiency; infected B cell; latent infection; maribavir; mouse model; pilot trial; placebo controlled study; prevent; prospective; reconstitution; rituximab; standard of care; transmission process; tumor

DESCRIPTION (provided by applicant): Fifty years after discovery of Epstein - Barr virus there is still no effective treatment to interrpt pathogenesis of any EBV infections including those that result in fatal B-cell lymphomas in patients with acquired or inborn immunodeficiency. Rapid development of humanized mice models engrafted with transplanted human hematopoietic stem cells that generate human B, T, and NK cells and a reconstituted human immune system have now provided small animal models suitable for treatment of studies human EBV disease. Infection of humanized NOD/SCID ?C-/- (NSG) mice with EBV produces infection that proceeds from a subclinical phase during which virus is replicated to development of polyclonal EBV B-cell lymphoproliferative disease and ultimately lethal CD20+, EBV EBER-positive, large-cell monoclonal B-cell lymphomas. In a single Aim we will infect with EBV cohorts of NSG mice reconstituted with stem cells from single donors for controlled trials designed to test whether an anti-EBV drug, Maribavir (MBV) alone or together with Rituximab can abort or retard progression from the reversible polyclonal lymphoproliferative phase of disease, when there is cell-to-cell transmission of virus, to irreversible monoclonal lymphoma. Polyclonal and monoclonal phases will be distinguished both by IgH gene rearrangements and EBV genomic terminal probe analyses. Basis for comparisons between treatment and placebo groups will be survival of animals analyzed with Kaplan-Meier survival curves and for statistical significance. These studies will be conducted in blinded fashion and will provide the first prospective, placebo-controlled trials of whether an antiviral drug, either alone or together with the nontoxic anti-tumor agent Rituximab, can affect the course of an EBV malignancy. Results may provide the basis for a nontoxic alternative therapy for these ultimately lethal post-transplant lymphomas. Results may also be of use in patients with AIDS who have rising EBV viral loads that may herald genesis of B-cell lymphomas.

描述（由申请人提供）： 发现 Epstein-Barr 病毒 50 年后，仍然没有有效的治疗方法来中断任何 EBV 感染的发病机制，包括导致获得性或先天性免疫缺陷患者致命的 B 细胞淋巴瘤的感染。人源化小鼠模型的快速开发，移植了人类造血干细胞，产生人类 B、T 和 NK 细胞以及重建的人类免疫系统，现已提供适合研究人类 EBV 疾病治疗的小动物模型。 EBV 感染人源化 NOD/SCID ?C-/- (NSG) 小鼠会产生从亚临床阶段开始的感染，在此期间病毒复制发展为多克隆 EBV B 细胞淋巴增殖性疾病，并最终发展为致命的 CD20+、EBV EBER 阳性、大细胞单克隆 B 细胞淋巴瘤。在一个单一目标中，我们将感染用来自单一供体的干细胞重组的 EBV 小鼠群体，进行对照试验，旨在测试抗 EBV 药物 Maribavir (MBV) 单独或与利妥昔单抗联合使用是否可以中止或延缓疾病从可逆的多克隆淋巴增殖期（当病毒在细胞间传播时）发展为不可逆的单克隆 淋巴瘤。多克隆和单克隆阶段将通过 IgH 基因重排和 EBV 基因组末端探针分析来区分。治疗组和安慰剂组之间比较的基础是用 Kaplan-Meier 生存曲线分析动物的生存率和统计显着性。这些研究将以盲法进行，并将提供第一个前瞻性、安慰剂对照试验，以确定抗病毒药物（单独使用或与无毒抗肿瘤药物利妥昔单抗联合使用）是否可以影响 EBV 恶性肿瘤的病程。结果可能为这些最终致命的移植后淋巴瘤的无毒替代疗法提供基础。结果也可能对 EBV 病毒载量上升的艾滋病患者有用，这可能预示着 B 细胞淋巴瘤的发生。