Phase II Trial of Anti-PD1 Therapy for HPV-associated Recurrent Respiratory Papillomatosis (IND#128874)

项目摘要 复发性呼吸道乳头状瘤病(RPP)是一种孤儿疾病，在中国约有20,000例活跃病例 在美国，发病率约为4.3/10万儿童和1.8/100,000成年人。 RRP是由感染人类乳头瘤病毒(HPV)6型和11型引起的，以粘膜为特征 在呼吸道生长的肿瘤，影响呼吸、吞咽和说话。在3%-5%的患者中， 病变可发生恶变，并可导致癌症患者的预后 从他们的建议书来看是很差的。目前还没有有效的系统疗法治疗RRP，尽管它通常涉及 多个站点。因此，为RRP患者开发新的治疗方案是一个强烈的未得到满足的需求。我们和 其他研究表明，RPP是一种以对HPV无效的宿主免疫反应为特征的疾病，在 部分，通过上调PD1：PDL1轴。因此，我们假设对阻止的管理 PD-1单抗pembrolizumab可以重新激活宿主抗肿瘤反应，导致 现有RPP病变的消退，慢性HPV感染的清除，以及新疾病的预防 改善生活质量和实现可能的治愈的手段。为了验证这一假设，我们打开了一个 研究人员启动的第二阶段临床试验，对被诊断为晚期糖尿病的患者使用培溴利珠单抗 RPP评估免疫疗法作为一种新的治疗选择的有效性。在这项研究中，活组织检查和 在接受研究治疗的同时，每12周采集一次外周血样本，这提供了一种 独特的纵向组织采样，以了解肿瘤、肿瘤免疫微环境和 宿主的免疫反应可能会随着时间的推移而演变。我们寻求支持，以执行关键的相关分析的预案 和治疗中的人体样本，以产生基本数据，调查免疫疗法作为 RRP患者的新的有效的治疗选择。

PROJECT ABSTRACT Recurrent Respiratory Papillomatosis (RPP) is an orphan disease with approximately 20,000 active cases in the United States and with an incidence of approximately 4.3 per 100,000 children and 1.8 per 100,000 adults. RRP is caused by infection with human papillomavirus (HPV) types 6 and 11 and is characterized by mucosal tumors that grow in the respiratory tract, impacting breathing, swallowing, and speech. In 3-5% of patients, the lesions can undergo malignant transformation and the prognosis for patients who develop cancers derived from their RRP is poor. There is no effective systemic therapy for RRP, despite the fact that it typically involves multiple sites. Thus, there is a strong unmet need to develop novel treatment options for RRP patients. We and others have shown that RPP is a disease characterized by an ineffective host immune response to HPV, in part, through the upregulation of the PD1:PDL1 axis. Thus, we hypothesize that administration of a blocking PD-1 monoclonal antibody, pembrolizumab, can re-activate host anti-tumor responses, leading to the regression of existing RPP lesions, clearance of chronic HPV infection, and prevention of new disease as a means to improve the quality of life and achieve possible cure. To test this hypothesis, we have opened an investigator-initiated phase II clinical trial administering pembrolizumab to subjects diagnosed with advanced RPP to evaluate the effectiveness of immunotherapy as a novel treatment option. In this study, biopsies and peripheral blood samples are obtained every 12 weeks while receiving study treatment, which provides a unique longitudinal sampling of tissue to understand how the tumor, tumor immune microenvironment, and host immune responses may evolve over time. We seek support to perform key correlative analyses of the pre- and on-treatment human samples to generate essential data, investigating the role of immunotherapy as a novel and effective treatment option for RRP patients.