Therapeutic DNA vaccination and Immune Checkpoints in Recurrent Respiratory Papillomatosis

复发性呼吸道乳头状瘤病的治疗性 DNA 疫苗接种和免疫检查点

基本信息

批准号：
9982288
负责人：
SIMON R BEST
金额：
$ 19.59万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9982288
关键词：
Activities of Daily Living Address Adjuvant Adult Aerodigestive Tract Antigen-Presenting Cells Archives Award Biological Assay Biometry CD8-Positive T-Lymphocytes CD8B1 gene Cell physiology Cells Childhood Chronic Clinical Clinical Trials Clinical Trials Design Color Communication impairment Cytotoxic T-Lymphocytes DNA DNA Vaccines Data Differentiation Antigens Disease Environment Faculty Feedback Funding Future Generations Goals Growth Head and Neck Surgery Hoarseness Human Human Papillomavirus Human papilloma virus infection Human papillomavirus 6 Immune Immune Targeting Immune response Immune system Immunocompetent Immunohistochemistry Immunologic Factors Immunologic Markers Immunologics Immunology Immunotherapy Infection Inflammation Interdisciplinary Study Interferon Type II Interleukin-10 Intervention K-Series Research Career Programs Kinetics Knowledge Lead Lesion Ligands Malignant neoplasm of cervix uteri Measures Mediating Mentors Mentorship Modeling Mus Otolaryngology Papilloma Papillomavirus Papillomavirus Transforming Protein E6 Pathway interactions Patient-Focused Outcomes Patients Peripheral Blood Mononuclear Cell Play Population Pre-Clinical Model Production Quantitative Reverse Transcriptase PCR Recurrent respiratory papillomatosis Research Research Personnel Resources Reverse Transcriptase Polymerase Chain Reaction Risk Role Sampling Scientist Severity of illness Squamous Papilloma of the Larynx Stains Suppressor-Effector T-Lymphocytes Surgeon T-Lymphocyte Testing Therapeutic Translating Tumor Antigens Tumor-infiltrating immune cells Up-Regulation Vaccination Viral Viral Load result Virus Virus Diseases Voice Work anti-PD-1 cell type clinical practice cytokine cytotoxic CD8 T cells enzyme linked immunospot assay exhaust experience human tissue immune checkpoint immune function immunoregulation laser capture microdissection mRNA Expression medical schools member mouse model novel novel therapeutics programmed cell death ligand 1 programmed cell death protein 1 programs skills success therapeutic DNA therapeutic vaccine tumor-immune system interactions

项目摘要

Dr. Simon Best is a junior faculty member in the Department of Otolaryngology – Head and Neck Surgery at the Johns Hopkins School of Medicine where his clinical practice is dedicated to voice and airway disorders. With the support of this Mentored Career Development Award, Dr. Best seeks to better understand the immunologic environment that allows Human Papillomavirus types 6 and 11 to elude the immune system and cause Recurrent Respiratory Papillomatosis (RRP). Dr. Best will enhance his research knowledge and skills with coursework in immunology, biostatistics, and clinical trial design, and receive directed mentorship by an interdisciplinary team of experienced researchers. He will be immersed in the interdisciplinary research environment of the Cervical Cancer SPORE program at Johns Hopkins, which is a unique center of researchers dedicated to HPV-associated diseases. This award will provide Dr. Best with the resources that he needs to become an independent investigator and future leader in the treatment of papillomatosis. In Aim 1, Dr. Best will build on his prior research experience in papillomatosis to test the hypothesis that PD-1 and PD-L1 play a role in the immunologic microenvironment in a population of RRP patients and determine if expression of these markers is correlated with clinical disease severity. He will also seek to understand the mechanisms that drive PD-L1 expression in papilloma and the functional consequences of this pathway in RRP. In Aim 2, he will study a mouse model of papilloma to further understand how papilloma develops in immunocompetent mice, and test if DNA vaccines are able to treat this infection. He will further determine if blockade of the PD-1 pathway enhances the activity of DNA vaccination in this murine model of papilloma. Upon successful completion of this project, there will be promising data to suggest a role for immunologic therapies in RRP, and a better understanding of the immunologic factors that allow laryngeal papillomas to grow and evade immune-mediated clearance. Identifying these factors could lead directly to the testing of novel therapeutics in papillomatosis, as well as suggest generalized mechanisms for how the HPV virus escapes the immune system. At the conclusion of this award, Dr. Best will have obtained the preliminary data needed to successfully compete for independent funding and achieve long-term success as a surgeon-scientist dedicated to this debilitating disease.

Simon Best 博士是耳鼻喉科的初级教员 – 系主任和他在约翰·霍普金斯大学医学院的颈部外科专业从事临床实践在该指导职业发展奖的支持下， Best 博士寻求更好地了解使人类能够生存的免疫环境 6 型和 11 型乳头瘤病毒可逃避免疫系统并导致复发性呼吸道疾病 Best 博士将通过课程提高他的研究知识和技能。免疫学、生物统计学和临床试验设计方面的专业知识，并接受专家的直接指导他将沉浸在跨学科的经验丰富的研究人员团队中。约翰·霍普金斯大学宫颈癌 SPORE 项目的研究环境该奖项将授予致力于 HPV 相关疾病研究的独特研究中心。拥有成为独立调查员和未来领导者所需的最佳资源在乳头状瘤病的治疗中。在目标 1 中，Best 博士将根据他之前在乳头状瘤病方面的研究经验来测试 PD-1 和 PD-L1 在免疫微环境中发挥作用的假设 RRP 患者群体并确定这些标记物的表达是否与他还将寻求了解驱动 PD-L1 的机制。在乳头状瘤中的表达以及该通路在 RRP 中的功能后果，在目标 2 中，他。将研究乳头状瘤小鼠模型，以进一步了解乳头状瘤如何在他将进一步测试具有免疫能力的小鼠，并测试 DNA 疫苗是否能够治疗这种感染。确定阻断 PD-1 通路是否会增强 DNA 疫苗接种的活性该项目成功完成后，将有望产生乳头状瘤小鼠模型。数据表明免疫疗法在 RRP 中的作用，并更好地理解允许喉乳头状瘤生长并逃避免疫介导的免疫因素确定这些因素可以直接导致新疗法的测试。乳头状瘤病，以及 HPV 病毒如何逃逸的一般机制获得该奖项后，Best 博士将获得初步的免疫系统资格。成功竞争独立资助并取得长期成功所需的数据作为一名致力于研究这种使人衰弱的疾病的外科医生科学家。