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

• 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
• 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

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博士是耳鼻喉科系的初级教员， 约翰霍普金斯医学院的颈部外科，他的临床实践致力于 声音和呼吸道疾病在这个指导职业发展奖的支持下， 博士最好的目的是更好地了解免疫环境，使人类 乳头瘤病毒6型和11型逃避免疫系统并引起反复呼吸道感染 乳头状瘤病（RRP）。贝斯特博士将通过课程提高他的研究知识和技能 在免疫学，生物统计学和临床试验设计，并接受指导导师 由经验丰富的研究人员组成的跨学科团队。他将沉浸在跨学科的 约翰霍普金斯的宫颈癌孢子项目的研究环境，这是一个 致力于HPV相关疾病的独特研究中心。该奖项将提供博士。 最好的资源，他需要成为一个独立的调查员和未来的领导者 乳头状瘤病的治疗 在目标1中，Best博士将根据他先前在乳头状瘤病方面的研究经验， 假设PD-1和PD-L1在免疫微环境中发挥作用， RRP患者群体，并确定这些标志物的表达是否与 临床疾病严重程度。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途径在RRP中的功能后果。在Aim 2中， 将研究乳头状瘤的小鼠模型，以进一步了解乳头状瘤是如何发展的， 免疫活性小鼠，并测试DNA疫苗是否能够治疗这种感染。他将进一步 确定PD-1通路的阻断是否增强了DNA疫苗接种的活性， 乳头状瘤的鼠模型。在成功完成该项目后，将有希望 数据表明免疫治疗在RRP中的作用，并更好地了解RRP的作用。 免疫因素使喉乳头状瘤生长并逃避免疫介导的免疫反应 间隙确定这些因素可以直接导致新疗法的测试， 乳头状瘤病，以及建议一般机制如何HPV病毒逃逸， 免疫系统在该奖项结束时，贝斯特博士将获得初步奖 成功竞争独立资金并取得长期成功所需的数据 作为一名外科医生兼科学家致力于这种使人衰弱的疾病。