Intra-salivary gland autotransplantation of marrow mesenchymal stromal cells for treatment of radiation induced xerostomia

项目摘要 口干是头颈部癌症患者放射治疗的一个重要副作用。几个因素 会导致口干。唾液分泌减少称为唾液分泌不足。质量和功能不佳 唾液被称为唾液功能障碍。这些因素加在一起，会导致口干症，或者说，患者的口干症 口干舌燥。口干症会导致龋齿、感染、说话困难、吞咽障碍、营养不良 营养不良，对生活质量有显著的负面影响。医生建议病人用力吮吸 糖果，嚼口香糖，使用唾液替代品，和/或随身携带水瓶。所有这些都不是 特别有效。我们的长期目标是改善患有放射性干燥症的患者的预后。 嘴。我们试图通过提供令人信服的证据来实现这一目标，即创新的细胞疗法可以 安全而显著地改善唾液腺功能和生活质量。正在处理这一问题的调查小组 项目是唯一适合完成这项工作的。成功将直接导致下一阶段的临床测试。 我们在护理头颈部癌症患者、开发骨髓间充质干细胞方面拥有专业知识。 基质细胞(MSCs)作为细胞疗法，并研究唾液功能。本应用程序的总体目标是 将进行一项第一阶段试验，以测试预先许可的干扰素-g骨髓间充质干细胞治疗慢性粒细胞白血病的安全性和耐受性 头颈部癌症患者的放射性口干症。 为了实现我们的目标，我们提出了两个目标，分布在此应用程序的两个阶段。在目标1中，我们将 与NIH、NIDCR和FDA密切合作，完成所有必要的里程碑，以激活提议的 临床试验(目标1)和招募我们的第一名患者(UG3期)。在目标2中，我们将执行阶段1安全和 干扰素-g诱导的自体骨髓间充质干细胞对放射性口干症患者的耐受性研究 以确定推荐的2期剂量(UH3期)。推荐的第二阶段剂量的扩展队列 (n=另外12名患者)将被纳入，以确认安全性，更好地描述毒性，以及 探讨骨髓间充质干细胞注射治疗放射性口干症的疗效。我们将使用以下方法评估疗效 既有经过验证的患者报告的结果衡量标准，也有通过评估唾液产量和 组成。这项试验预计将提供用于设计下一次临床试验的关键数据。第二阶段研究 将进一步测试MSCs在头颈部癌症患者中的疗效。这些研究还将提供 支持未来旨在通过体外改善唾液反应的赠款申请的重要数据 骨髓间充质干细胞工程。

Project Abstract Dry mouth is a significant side-effect of radiation therapy for head and neck cancer patients. Several factors contribute to dry mouth. Decreased production of saliva is called hyposalivation. Poor quality and function of saliva is called salivary dysfunction. Together, these cause xerostomia, or what a patient experiences as simply dry mouth. Xerostomia can lead to tooth decay, infections, difficulty speaking, impaired swallowing, poor nutrition, and has a significant negative effect on quality of life. Doctors recommend that patients suck on hard candy, chew gum, use saliva substitutes, and/or carry a water bottle with them at all times. None of these are particularly effective. Our long-term goal is to improve outcomes for patients suffering from radiation-induced dry mouth. We seek to achieve this goal by providing convincing evidence that innovative cellular therapies can safely and significantly improve salivary gland function and quality of life. The team of investigators tackling this project is uniquely suited to complete the work. Success would lead directly to the next phase of clinical testing. We have expertise in caring for head and neck cancer patients, developing bone marrow derived mesenchymal stromal cells (MSCs) as cellular therapies, and studying salivary function. The overall objective of this application is to perform a Phase 1 trial to test the safety and tolerability of IFN-g pre-licensed MSCs for treatment of radiation-induced xerostomia in head and neck cancer patients. To achieve our goals, we propose two aims spread across the two phases of this application. In Aim 1, we will work closely with the NIH, NIDCR, and FDA to complete all necessary milestones to activate the proposed clinical trial (Aim 1) and enroll our first patient (UG3 phase). In Aim 2, we will perform a Phase 1 safety and tolerability study of IFN-g pre-licensed autologous MSCs in patients with radiation-induced xerostomia in order to define the recommended phase 2 dose (UH3 phase). An expansion cohort at the recommended phase 2 dose (n=12 additional patients) will be included in order to confirm the safety profile, better describe the toxicity, and investigate the efficacy of MSC injection to treat radiation-induced xerostomia. We will assess the efficacy using both validated patient-reported outcome measures and through assessment of salivary production and composition. This trial is expected to provide key data used to design the next clinical trial. A phase 2 study would further test the efficacy of MSCs in head and neck cancer patients. These studies will also provide important data to support future grant applications aimed at improving the salivary response through ex vivo engineering of MSCs.