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）： 在发现爱泼斯坦-巴尔病毒50年后，仍然没有有效的治疗方法来阻断任何EBV感染的发病机制，包括在具有获得性或先天性免疫缺陷的患者中导致致命性B细胞淋巴瘤的那些。移植有产生人B、T和NK细胞的移植的人造血干细胞和重建的人免疫系统的人源化小鼠模型的快速发展现在已经提供了适合于治疗研究人EBV疾病的小动物模型。人源化NOD/SCID感染？携带EBV的C-/-（NSG）小鼠产生从亚临床期开始的感染，在亚临床期期间病毒被复制，发展成多克隆EBV B细胞淋巴增生性疾病，并最终发展成致死性CD 20+、EBV EBER阳性、大细胞单克隆B细胞淋巴瘤。在单一目的中，我们将感染用来自单一供体的干细胞重建的NSG小鼠的EBV队列，进行对照试验，旨在检测抗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性多克隆淋巴增生期（当存在病毒的细胞间传播时）进展为不可逆性单克隆淋巴瘤。通过IgH基因重排和EBV基因组末端探针分析来区分多克隆和单克隆阶段。治疗组和安慰剂组之间比较的基础是采用Kaplan-Meier生存曲线分析的动物生存率和统计学显著性。这些研究将以盲法进行，并将提供第一个前瞻性的安慰剂对照试验，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一起使用是否会影响EBV恶性肿瘤的病程。这些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。结果也可能是用于艾滋病患者的EBV病毒载量上升，可能预示着B细胞淋巴瘤的发生。