A pilot, first in human study of autologous ifn-gamma stimulated, refreshed autologous bone marrow mesenchymal stromal cells for treatment of radiation-induced xerostomia – 1 year results

Background & Aim There are no effective treatments for radiation-induced xerostomia (RIX), a common side effect of head and neck radiation. Mesenchymal stromal cells (MSCs) exhibit regenerative effects and may represent an effective cell therapy for the treatment of RIX. Here we present the updated primary safety and secondary efficacy endpoints of a first-in-human pilot study of IFNγ-stimulated refreshed autologous bone marrow- derived MSCs [MSC(M)] for the treatment of RIX. Methods, Results & Conclusion Methods: We conducted a single-center clinical trial (NCT04489732) investigating the safety and tolerability of autologous IFNγ-stimulated MSC(M) under an FDA-IND. Patients underwent bone marrow aspiration, MSC(M) were then cultured, stimulated with IFNγ, and cryopreserved. Banked IFNγ-stimulated MSC(M) were thawed, allowed to recover, and then 10 × 106 MSC(M) were injected into the right 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 validated quality of life instruments. Results Six patients with RIX who had completed radiation at least 2 years earlier were enrolled. The median age was 71 (61-74), 5 (83%) patients were male. Three patients (50%) reported a pain score of 1 after submandibular gland injection, all pain resolved within 4 days. No DLTs occurred and no SAEs were reported up to 12 months after injection. The analysis of secondary endpoints demonstrated a trend of increased salivary production, with the 2 responders having persistent increased saliva production at 1 year. The mean unstimulated saliva was 0.13 mL/min (SEM 0.07) at baseline and increased to 0.18 mL/min (SEM 0.08) at 12 months after injection. There was additionally a trend in improved quality of life. Conclusions 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 a potentially curative remedy to treat RIX. A phase I dose-escalation study injecting into bilateral submandibular glands is currently accruing at our institution (NCT05820711).