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

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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.