Project 1, Combination Immunotherapy for HPV-Associated Cancer

项目1摘要 在美国，癌症是一个主要的健康差距，因为癌症的发病率和死亡率 非裔美国人与癌症相关的比例明显高于高加索人。此外, 华盛顿特区是美国癌症发病率最高的地区之一。至 在大华盛顿特区大都市区解决这些癌症健康差距， 必须结合领先的癌症中心和领先的少数群体服务的优势 机构。霍华德大学牙科学院(HUCD)是唯一一所面向少数族裔的牙科学校 巴尔的摩-华盛顿地区的一所学校，而约翰霍普金斯癌症中心是 在转化型癌症研究方面处于世界领先地位。这个项目的总体目标是 在霍华德大学之间建立合作研究、培训和职业发展 以及约翰·霍普金斯癌症中心。吴天正博士，一位经验丰富的临床研究人员， 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 作为导师和支持庞小武博士职业发展的基础科学 霍华德大学的一名研究员，在转化型癌症研究方面具有巨大的潜力。追寻 为了实现这一目标，庞晓武博士在资助期内将重点放在三个方面：1)制定 HPV相关癌症的固体翻译研究项目，2)加强研究 为霍华德大学的学生提供培训机会，以及3)创造 有足够的初步数据通过传统方式获得额外的外部支持 NIH/NCI的拨款申请。将通过联合研究积极实现这些目标 彭博士和吴博士的实验室之间专注于抗原特异性的项目 癌症的免疫疗法。由于人类乳头瘤病毒(HPV)病毒的持续表达 蛋白质E6和E7是转化和维持恶性表型所必需的， E6和E7抗原可能是HPV治疗性疫苗的理想靶点- 相关癌症。治疗性疫苗的效力可以通过以下方式进一步提高 结合肿瘤微环境的调节，自我复制的RNA载体 基于黄病毒的(称为RNA复制子)是近年来发展起来的，并显示出 作为疫苗载体的巨大潜力。复制子是非细胞病变的，诱导强烈的细胞 免疫应答，并可通过包装细胞并入病毒样颗粒(VLP) 台词。登革热病毒是一种由蚊子传播的黄病毒，在自然条件下会产生强烈的免疫反应。 感染。登革热病毒四种血清型间的免疫增强现象 可用于进一步提高登革热病媒的疗效。这项试点的具体目标是 项目是：1)表征接种疫苗后的抗原特异性免疫反应 一种使用登革病毒复制子载体的治疗性HPV相关癌症疫苗。2)至 人乳头瘤病毒E6/E7表达肿瘤模型的抗肿瘤作用 以登革热病毒载体为基础的治疗性疫苗接种。3)描述 治疗性疫苗与肿瘤微环境的联合免疫治疗 在小鼠肿瘤模型中的调制。这些具体目标将支持本组织更广泛的目标 通过与霍华德大学合作加强翻译研究的项目 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.