Therapeutic DNA vaccination and Immune Checkpoints in Recurrent Respiratory Papillomatosis

西蒙·贝斯特博士是耳鼻咽喉科的初级教员。 约翰·霍普金斯医学院的颈部外科，他的临床实践就是在那里 到嗓音和呼吸道疾病。在本次导师职业发展奖的支持下， 贝斯特博士试图更好地了解免疫环境，使人类 6型和11型乳头状瘤病毒逃避免疫系统并导致呼吸道复发 乳头瘤病(RRP)。贝斯特博士将通过课程工作增强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方面，并接受由 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 约翰霍普金斯大学宫颈癌孢子项目的研究环境，这是一个 致力于人乳头瘤病毒相关疾病的独特研究中心。这一奖项将为Dr. 最好拥有他成为独立调查员和未来领导人所需的资源 治疗乳头状瘤病。 在目标1中，贝斯特博士将以他以前在乳头状瘤病方面的研究经验为基础，测试 假说PD-1和PD-L1在阿尔茨海默病免疫微环境中起作用 并确定这些标记物的表达是否与 临床疾病严重程度。他还将寻求了解驱动PD-L1的机制 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 将研究小鼠乳头状瘤模型，以进一步了解乳头状瘤是如何在 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 确定阻断PD-1通路是否增强了DNA疫苗在本病中的活性 小鼠乳头状瘤模型。在这个项目成功完成后，将会有希望 数据表明免疫疗法在RRP中的作用，并更好地理解 导致喉乳头状瘤生长和逃避免疫调节的免疫因素 通行证。确定这些因素可以直接导致对新疗法的测试 乳头状瘤病，以及为HPV病毒如何逃脱 免疫系统。在这个奖项结束时，贝斯特博士将获得初步的 成功竞争独立资金并取得长期成功所需的数据 作为一名致力于这种令人衰弱的疾病的外科医生兼科学家。

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.