Project 1, Combination Immunotherapy for HPV-Associated Cancer

项目1 癌症是美国人健康状况的一个主要差异，其发病率和死亡率 非裔美国人与癌症相关的风险显著高于白人。此外，本发明还提供了一种方法， 华盛顿，华盛顿特区是美国癌症发病率最高的地区之一。到 解决这些癌症的健康差距在大华盛顿特区大都市区，它是 必须结合联合收割机的优势，领先的癌症中心和领先的少数民族服务 机构。霍华德大学牙科学院（HUCD）是唯一的少数民族为导向的牙科 学校在巴尔的摩-华盛顿地区，而约翰霍普金斯癌症中心是其中一个 世界转化癌症研究的领导者。该项目的总体目标是 在霍华德大学之间建立合作研究、培训和职业发展 和约翰霍普金斯癌症中心。T博士C. Wu是一位经验丰富的临床研究者， 约翰霍普金斯大学的一个活跃的翻译分子免疫学实验室，将为 作为导师，支持庞小武博士的职业发展，基础科学 他是霍华德大学的一名研究人员，在转化癌症研究方面具有巨大潜力。追求 这一目标，庞晓武博士将在资助期间重点关注三个方面：1）开发一个 在HPV相关癌症方面的坚实的转化研究项目，2）加强研究 和培训机会，为学生从霍华德大学，和3）产生 充分的初步数据，以获得额外的校外支持，通过传统的 NIH/NCI资助申请。将通过一项联合研究， Pang博士和Wu博士实验室之间的一个项目，专注于抗原特异性 癌症的免疫疗法。人乳头瘤病毒（HPV）是一种常见的病毒。 蛋白质E6和E7是恶性表型转化和维持所需的， E6和E7抗原可能是HPV治疗性疫苗的理想靶点。 相关癌症治疗性疫苗的功效可通过以下方式进一步增强： 与调节癌症微环境的组合，自复制RNA载体， 近年来，已经开发出基于黄病毒的RNA复制子（称为RNA复制子），并且显示 作为疫苗载体的巨大潜力。复制子是非致细胞病变的，诱导强烈的细胞毒性。 免疫应答，并可通过包装细胞掺入病毒样颗粒（VLP）中 线登革病毒是一种蚊媒黄病毒，在自然界中产生强烈的免疫反应， 感染四种血清型登革病毒的免疫增强现象 可用于进一步增加登革热载体的功效。该试点的具体目标是 项目是：1）表征接种后的抗原特异性免疫应答， 使用基于登革病毒复制子的载体的治疗性HPV相关癌症疫苗。2)到 表征对表达HPV E6/E7的肿瘤模型的抗肿瘤作用， 接种治疗性登革热病毒载体疫苗。3)表征 用治疗性疫苗和肿瘤微环境的联合免疫疗法 在小鼠肿瘤模型中的调节。这些具体目标将有助于实现更广泛的目标， 项目，以加强在霍华德大学的翻译研究，通过合作， 约翰霍普金斯癌症中心。

Project 1 Abstract Cancer represents a major health disparity in American, as both incidence of and mortality related to cancer are significantly higher in African Americans than in Caucasians. In addition, the Washington, D.C. area has one of the highest incidence rates of cancer in United States. To address these cancer health disparities in the greater Washington D.C. metropolitan area, it is essential to combine the strengths of a leading cancer center and a leading minority-serving institution. Howard University College of Dentistry (HUCD) is the only minority-oriented dental school in the Baltimore-Washington area, while Johns Hopkins Cancer Center is one of the world's leaders in translational cancer research. The overall objectives for this project are to establish collaborative research, training and career development between Howard University and the Johns Hopkins Cancer Center. Dr. T.-C. Wu, an experienced clinical investigator with an active translational molecular immunology laboratory at Johns Hopkins University, will serve as a mentor and support the career development of Dr. Xiaowu Pang, a basic science researcher at Howard University with great potential in translational cancer research. To pursue this goal, Dr. Xiaowu Pang will focus on three areas during the funding period: 1) to develop a solid translational research project in HPV-associated cancer, 2) to enhance research and training opportunities for students from Howard University, and 3) to generate sufficient preliminary data to acquire additional extramural support through traditional NIH/NCI grant applications. The objectives will be actively pursued through a joint research project between Dr. Pang's and Dr. Wu's laboratories focusing on antigen-specific immunotherapy for cancer. Since constant expression of Human papillomavirus (HPV) viral proteins E6 and E7 is required for transformation and maintenance of the malignant phenotype, E6 and E7 antigens may represent ideal targets for therapeutic vaccines against HPV- associated cancer. The efficacy of a therapeutic vaccine can be further enhanced by combination with modulation of the cancer microenvironment, Self-replicating RNA vectors (termed RNA replicons) based on flavivirus have been developed in recent years, and show great potential as vaccine vectors. The replicons are non-cytopathic, induce strong cellular immune responses, and can be incorporated into virus-like particles (VLP) by packaging cell lines. Dengue virus, a mosquito-borne flavivirus, produces strong immune reactions in natural infection. The phenomenon of immune enhancement among four serotypes of dengue viruses may be used to further increase the efficacy of dengue vectors. The specific aims of this pilot project are: 1) To characterize the antigen-specific immune responses following vaccination with a therapeutic HPV-associated cancer vaccine using dengue viral replicon-based vectors. 2) To characterize the antitumor effects against an HPV E6/E7-expressing tumor model following vaccination with the therapeutic dengue viral vector-based vaccine. 3) To characterize the combination immunotherapy with the therapeutic vaccine and tumor microenvironment modulation in a mouse tumor model. These specific aims will support the broader goals of this project to enhance translational research at Howard University through the collaboration with Johns Hopkins Cancer Center.