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，在美国约有20，000例活动性病例。 在美国，发病率约为每100，000名儿童4.3人，每100，000名成人1.8人。 RRP是由人乳头瘤病毒（HPV）6型和11型感染引起的，其特征在于粘膜病变。 生长在呼吸道中的肿瘤，影响呼吸、吞咽和言语。在3-5%的患者中， 病变可能发生恶性转化， 他们的RRP很差。目前还没有有效的全身治疗RRP，尽管它通常涉及 多个站点。因此，存在开发用于RRP患者的新型治疗选择的强烈未满足的需求。我们和 其他人已经表明RPP是一种以对HPV无效的宿主免疫应答为特征的疾病， 部分，通过上调PD 1：PDL 1轴。因此，我们假设， PD-1单克隆抗体Pembrolizumab可以重新激活宿主抗肿瘤反应，导致肿瘤细胞凋亡。 现有的RPP病变的消退，慢性HPV感染的清除，以及预防新疾病， 意味着改善生活质量并实现可能的治愈。为了验证这个假设，我们打开了一个 帕博利珠单抗治疗诊断为晚期乳腺癌的受试者的药物启动的II期临床试验 RPP旨在评估免疫疗法作为一种新型治疗选择的有效性。在这项研究中， 在接受研究治疗的同时，每12周采集外周血样品，这提供了一个 独特的纵向组织取样，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，以执行前的关键相关分析， 和治疗中的人类样本，以产生必要的数据，研究免疫疗法作为一种治疗方法的作用。 为RRP患者提供一种新的有效治疗选择。

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.