A Therapeutic Vaccine for EBV-Associated Malignancies

EB 病毒相关恶性肿瘤的治疗疫苗

• 批准号: 7853397
• 负责人: PAUL M LIEBERMAN
• 金额: $ 49.58万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7853397
• 关键词: AIDS vaccine development; AIDS-Related Lymphoma; Acquired Immunodeficiency Syndrome; Address; Adenovirus Vector; Adult; Africa; Animal Model; Antigens; Attenuated; Binding; Biological Assay; Burkitt Lymphoma; CD8B1 gene; Cancer Patient; Cancer Vaccine Related Development; Cells; China; Chronic; Cytotoxic T-Lymphocytes; Defect; EBV-associated malignancy; Epstein-Barr Virus Infections; Frequencies; Glycoproteins; Goals; Herpesviridae; Herpesvirus 1; Homologous Gene; Human; Human Adenoviruses; Human Herpesvirus 4; Immune; Immune response; Immunization; Immunocompromised Host; Immunological Models; Immunology; Immunosuppression; Immunotherapy; Impairment; Inbred Mouse; Incidence; Individual; Infection; Laboratories; Lymphocryptovirus; Lymphoma; Lymphomagenesis; Macaca mulatta; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Memory; Methods; Modeling; Mus; Nasopharynx Carcinoma; Pan Genus; Pathway interactions; Patients; Pilot Projects; Population; Proteins; Relative (related person); Reporting; Research; Research Personnel; SIV; Saliva; Serologic tests; Serotyping; Signal Transduction; Simplexvirus; T-Lymphocyte; Testing; Therapeutic; Tissue Transplantation; Transplantation; Tumor Antigens; Upper arm; Vaccines; Viral; Viral Antigens; Viral Proteins; Virus; Virus Diseases; base; cytokine; defective adenoviral vector; immune function; immunogenicity; immunoregulation; in vivo; innovation; nonhuman primate; novel strategies; novel therapeutics; novel vaccines; persistent EBV infection; prevent; public health relevance; response; success; therapeutic vaccine; tumor; vaccine development; vaccine evaluation; vector; vector vaccine; viral carcinogenesis

DESCRIPTION (provided by applicant): This application is in response to Grand Opportunity (GO) RFA-OD-09-004 for Exploratory Research in the Development of Vaccines for AIDS-associated Malignancies. The goal of the application is to develop a novel therapeutic vaccine to Epstein-Barr virus (EBV) and its associated malignancies. EBV infection is responsible for the majority of AIDS-associated lymphomas. We propose to target the viral-encoded protein, EBNA1, which is the only viral protein consistently expressed in all EBV-associated malignancies. The vaccine will incorporate the fusion of the HSV gD protein to EBNA1 to overcome a negative regulatory arm of the adaptive immune response that has been implicated in tumor-associated immune escape. The vaccine vector will be derived from the E1-deleted adenoviral vectors based on the chimpanzee-serotype 68 (AdC68) to eliminate background immunogenicity to more common human serotypes. The vaccine will be tested in rhesus macaques, using the rhesus lymphocryptovirus (rhLCV) as the most appropriate animal model for EBV lymphomagenesis. To complete these goals, we have assembled a team of investigators with expertise in EBV, rhLCV, cancer-vaccine development and analysis, and immunology of non-human primates. For the studies proposed in this GO application, we will focus on a vaccine to rhEBNA1. Most rhesus macaques are naturally infected with rhLCV, and upon their infection with simian immunodeficiency virus (SIV), rhLCV becomes reactivated and can cause lymphomas, suggesting that this virus is an excellent model for proof-of- principle testing of a therapeutic vaccine to EBV. The EBNA1 vaccine will be tested first for the induction of T cell responses in inbred mice, comparing vaccines that express the rhLCV EBNA1 homologue (rhEBNA1) alone or within gD. Once the immunogenicity of the vaccines has been demonstrated in mice, they will be tested in a pilot study in rhesus macaques with pre-existing T cells to EBNA1 due to a natural infection. Immunization success will be measured by the following parameters: a) an increase in cell mediated responses following immunization; b) an increase in antigen specific memory responses to LCV rhEBNA1 in vivo post immunization; c) enhanced quality of the rhEBNA1 directed response based on the frequencies of polyfunctional (multi-cytokine) responses; d) a broader rhEBNA1 T cell repertoire; and e) an increase immune control in virus regression assays and decreased antigen shedding in saliva. These studies will serve as an important proof-of-principle analysis for an EBNA1-specific therapeutic vaccine for treatment of EBV- associated malignancies. PUBLIC HEALTH RELEVANCE: Epstein-Barr virus (EBV) infects over 95% of the adult population worldwide, and has been estimated to be a contributing agent in ~1% of all human cancer. Its carcinogenic potential is significantly elevated by immunosuppression, as is found in the context of HIV-AIDS and tissue transplantation. Evidence suggests that most EBV-associated malignancies arise through defects in the normal cellular mediated immune response. Methods that enhance the EBV-specific cytotoxic T-cell response, like adaptive immunotherapy, can be effective in the treatment of some EBV-associated cancers. Unfortunately, traditional vaccine-strategies have not been successful since these approaches do not overcome the defects in the T-cell response to viral infection. We propose to use a novel strategy to reverse the immunological defect in viral-specific T-cell response using new methods developed in our laboratories. This new vaccine strategy will be tested in mouse and rhesus macaques, which serve as the most relevant immunological models for human infection and viral- carcinogenesis. These pilot studies will provide important information on the mechanism of T-cell response and suppression in EBV-associated cancer, and potentially provide a new vaccine for therapeutic treatment of EBV-associated malignancies in cancer patients.

描述（由申请人提供）：此申请是响应大机会（GO）RFA-OD-09-004，用于开发用于艾滋病相关的恶性肿瘤疫苗的探索性研究。该应用的目的是开发一种新型的治疗疫苗，向爱泼斯坦 - 巴尔病毒（EBV）及其相关的恶性肿瘤开发。 EBV感染负责大多数与艾滋病相关的淋巴瘤。我们建议靶向病毒编码的蛋白EBNA1，这是在所有与EBV相关的恶性肿瘤中始终表达的唯一病毒蛋白。该疫苗将融合HSV GD蛋白与EBNA1的融合，以克服与肿瘤相关的免疫逃生有关的适应性免疫反应的负调节臂。疫苗载体将基于Chimpanzee-Serotype 68（ADC68）源自E1删除的腺病毒载体，以消除对更常见的人类血清型的背景免疫原性。该疫苗将在恒河猕猴中进行测试，使用恒河猴淋巴结病毒（RHLCV）作为EBV淋巴细胞化的最合适的动物模型。为了完成这些目标，我们组建了一个在EBV，RHLCV，癌症疫苗发展和分析以及非人类灵长类动物的免疫学方面具有专业知识的研究人员。对于此GO应用中提出的研究，我们将重点介绍用于Rhebna1的疫苗。大多数猕猴自然地感染了RHLCV，在感染了猿猴免疫缺陷病毒（SIV）后，RHLCV会重新激活并可能引起淋巴瘤，这表明该病毒是对EBV治疗疫苗进行原理测试的绝佳模型。 EBNA1疫苗将首先进行测试，以便比较单独表达RHLCV EBNA1同源物（RheBNA1）或GD内表达RHLCV EBNA1同源物（RheBNA1）的疫苗。一旦在小鼠中证明了疫苗的免疫原性，就将在恒河猕猴的一项试点研究中对其进行测试，该研究由于自然感染而在恒河猕猴中，曾有T细胞已存在于EBNA1。免疫成功将通过以下参数来衡量：a）免疫后细胞介导的反应增加； b）免疫后体内对LCV RheBNA1的抗原特异性记忆反应增加； c）基于多功能（多功能）反应的频率，RheBNA1的指示反应提高了； d）更广泛的Rhebna1 T细胞库； e）病毒回归测定法的免疫控制增加并减少唾液中的抗原脱落。这些研究将作为EBNA1特异性治疗疫苗的重要原理分析，用于治疗EBV相关的恶性肿瘤。 公共卫生相关性：Epstein-Barr病毒（EBV）感染了全球95％以上的成人人群，据估计是所有人类癌症约1％的贡献者。在HIV-AID和组织移植的背景下发现，其致癌潜力通过免疫抑制显着提高。证据表明，大多数与EBV相关的恶性肿瘤是由于正常细胞介导的免疫反应中的缺陷而产生的。增强EBV特异性细胞毒性T细胞反应（如适应性免疫疗法）的方法可以有效地治疗某些EBV相关的癌症。不幸的是，传统的疫苗策略尚未成功，因为这些方法并未克服T细胞对病毒感染的反应中的缺陷。我们建议使用一种新型策略使用实验室中开发的新方法来扭转病毒特异性T细胞反应中的免疫缺陷。这种新的疫苗策略将在小鼠和恒河猕猴中进行测试，这是人类感染和病毒癌变的最相关的免疫学模型。这些初步研究将提供有关与EBV相关癌症中T细胞反应和抑制作用机制的重要信息，并有可能为癌症患者的EBV相关性恶性肿瘤提供新的疫苗。