First-in-human study to investigate the safety and efficacy of effective-mononuclear cell therapy for radiogenic xerostomia.

Background: Salivary gland (SG) hypofunction is the most common complication following radiotherapy for head and neck cancer. Currently, there are no effective therapies for radiation-induced xerostomia. We recently developed a novel therapy for preclinical studies using effective-mononuclear cells (E-MNCs) induced from autologous peripheral blood mononuclear cells (PB-MNCs) via a new primary culture system for treatment of radiation-induced xerostomia. However, the safety and effectiveness of E-MNC therapy have not been assessed in humans. The objective of this first-in-human study was to evaluate the safety, tolerability, and in part the efficacy of E-MNC therapy for treating radiation-induced xerostomia. Methods: This first-in-human study was an open-label, single-center, two-step dose escalation study. A total of 5 patients who had no recurrence of head and neck cancer over a 5-year period following radiation therapy and suffered from radiation-induced xerostomia received a transplantation of E-MNCs to one-sided submandibular gland (SMG). The primary endpoint was the safety of the protocol. The secondary endpoint was effectiveness evaluated based on change from baseline in whole-saliva secretion, MRI/CT-evaluated volume of the SMG and subjective/objective symptoms after intervention. The duration of the intervention was 1 year. Results: During follow-up, no treatment-related adverse events were detected. The stimulated whole salivary flow rate increased from an average of 3.86 mL/10 min at baseline to 5.16 mL/10 min at 6 months post-investigational intervention. Additionally, subjective/objective symptoms improved in 4 of 5 treated patients. By contrast, imaging findings revealed no obvious changes in MRI/CT-evaluated volume of SMGs due to conspicuous progression of atrophy and fibrosis compared with baseline. Conclusion: This is the first clinical study to evaluate the safety and efficacy of E-MNC treatment in patients with severe radiation-induced xerostomia. The results of our study indicate that E-MNC treatment is safe and effective, and provide valuable information that will aid in designing subsequent clinical studies. Trial registration: This study was registered with the Japan Registry of Clinical Trials (http://jrct.niph.go.jp) as jRCTb070190057.