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

唾液腺内自体骨髓间充质干细胞移植治疗放射引起的口干症

• 批准号: 10793666
• 负责人: RANDALL J KIMPLE
• 金额: $ 60.48万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10793666
• 关键词: Intra; salivary; gland; autotransplantation; marrow

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.

项目摘要 口干是头颈癌患者放射治疗的一个显着副作用。几个因素 导致口干。唾液分泌减少称为唾液分泌不足。质量和功能较差 唾液分泌过多称为唾液功能障碍。这些因素共同导致口干症，或者患者所经历的仅仅是 口干。口干症可导致蛀牙、感染、说话困难、吞咽障碍、发育不良 营养，并对生活质量产生显着的负面影响。医生建议患者用力吮吸 糖果、口香糖、使用唾液替代品和/或随身携带水瓶。这些都不是 特别有效。我们的长期目标是改善因辐射引起的干燥的患者的治疗结果 嘴。我们寻求通过提供令人信服的证据来实现这一目标，证明创新的细胞疗法可以 安全且显着地改善唾液腺功能和生活质量。调查小组正在解决这个问题 项目非常适合完成这项工作。成功将直接进入下一阶段的临床测试。 我们拥有护理头颈癌患者、开发骨髓间充质细胞的专业知识 基质细胞（MSC）作为细胞疗法，并研究唾液功能。该应用程序的总体目标 的目的是进行 1 期试验，以测试 IFN-g 预许可 MSC 治疗以下疾病的安全性和耐受性： 头颈癌患者辐射引起的口干症。 为了实现我们的目标，我们提出了贯穿本应用程序两个阶段的两个目标。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，以激活拟议的 临床试验（目标 1）并招募我们的第一位患者（UG3 阶段）。在目标 2 中，我们将执行第一阶段的安全和 IFN-g预许可自体间充质干细胞在辐射引起的口干症患者中的耐受性研究 确定推荐的 2 期剂量（UH3 期）。推荐的 2 期剂量的扩展队列 （n=12 名额外患者）将被纳入，以确认安全性、更好地描述毒性，以及 研究 MSC 注射治疗辐射引起的口干症的疗效。我们将使用以下方法评估疗效 既验证了患者报告的结果测量，又通过评估唾液产生和 作品。该试验预计将为设计下一个临床试验提供关键数据。第二阶段研究 将进一步测试间充质干细胞在头颈癌患者中的功效。这些研究还将提供 支持未来拨款申请的重要数据，旨在通过离体改善唾液反应 MSC 的工程。