A Pilot, First in Human Study of Autologous IFN-Gamma Stimulated Mesenchymal Stromal Cells for Treatment of Radiation-Induced Xerostomia.

PURPOSE/OBJECTIVE(S): There are no existing effective treatments for radiation-induced xerostomia (RIX), a common side effect of head and neck radiation. Mesenchymal stromal cells (MSCs) exhibit regenerative effects in multiple tissues and may represent an effective cell therapy for the treatment of RIX. Here we present the primary safety and secondary efficacy endpoints of a first-in-human pilot study of IFNγ-stimulated autologous bone marrow- derived MSCs [MSC(M)] for the treatment of RIX.

MATERIALS/METHODS: We conducted a single-center clinical trial investigating the safety and tolerability of autologous IFNγ-stimulated MSC(M). The study was conducted under an FDA-IND and approved by the local IRB. Patients underwent bone marrow aspiration, MSC(M) were then culture-expanded, stimulated with IFNγ, and cryopreserved. Banked IFNγ-stimulated MSC(M) were thawed, allowed to recover, and then 10 × 106 MSC(M) were injected transcutaneously via ultrasound guidance into one submandibular gland. The primary objective was safety and tolerability determined by dose-limiting toxicity (DLT) defined as submandibular pain > 5 on a standard 10-point pain scale or any serious adverse event (SAE) within one month after injection. Secondary objectives included analysis of efficacy as measured by salivary quantification and using 3 validated quality of life instruments. Quantitative results are reported as mean and standard deviation (SD).

RESULTS: Six radiation-induced xerostomia patients with head and neck cancer who had completed radiation at least 2 years earlier were enrolled. The median age was 71 (61-74) and 5 (83%) patients were male. Five patients (83%) were treated with chemoradiation and one patient (17%) with radiation alone. The average dose of radiation to the injected submandibular gland was 59.9 Gy. Three patients (50%) reported a pain score of 1 after submandibular gland injection, all pain resolved within 4 days. No patients reported pain 1 month after injection, with no SAEs or other DLTs reported 1 month after injection. The analysis of secondary endpoints demonstrated a trend of increased salivary production. The mean unstimulated saliva was 0.13 mL/min (SD 0.17) at baseline and increased to 0.14 mL/min (SD 0.12) at 1 month after injection and 0.19 mL/min (SD 0.21) at 3-months. Quality of life surveys also showed a trend towards improvement.

CONCLUSION: Injection of autologous IFNγ-stimulated MSC(M) into the submandibular gland of patients with RIX is safe and well tolerated. A trend towards an improvement in secondary endpoints of salivary quantity and quality of life was observed. This first-in-human pilot study provides support for further investigation into IFNγ-stimulated MSC(M) as an innovative, potentially curative, remedy to treat RIX. A phase I dose-escalation study injecting into bilateral submandibular glands is scheduled to begin accrual in the spring of 2023.