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

Takashi I; Mayumi Iwatake; Takako Yoshida; Kazuhiro Nagai; Yuka Hotokezaka; Mika Nishihara; Ryo Honma; Hiroshi Harada; Munehiro Hayashida; Toshiki Nagano; Riho Kanai; Seigo Ohba; Atsutoshi Yoshimura; Haruchika Masuda; Takayuki Asahara; Yasushi Miyazaki; Atsushi Kawakami; Izumi Asahina; Makoto Seki; Yoshinori Sumita

doi:10.1016/j.reth.2025.101059

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

Regen Ther. 2026 Jan 10:31:101059. doi: 10.1016/j.reth.2025.101059. eCollection 2026 Mar.

Authors

Takashi I^{1

2}, Mayumi Iwatake^{1

3}, Takako Yoshida¹, Kazuhiro Nagai⁴, Yuka Hotokezaka⁵, Mika Nishihara⁶, Ryo Honma^{1

2}, Hiroshi Harada⁴, Munehiro Hayashida¹, Toshiki Nagano¹, Riho Kanai¹, Seigo Ohba^{2

7}, Atsutoshi Yoshimura⁸, Haruchika Masuda⁹, Takayuki Asahara⁹, Yasushi Miyazaki^{4

10}, Atsushi Kawakami¹¹, Izumi Asahina^{1

2

12}, Makoto Seki⁶, Yoshinori Sumita^{1

2}

Affiliations

¹ Department of Medical Research and Development for Oral Disease, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
² Department of Regenerative Oral Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
³ Research Institute for Quantum and Chemical Innovation, Institutes of Innovation for Future Society, Nagoya University, Nagoya, Japan.
⁴ Transfusion and Cell Therapy Unit, Nagasaki University Hospital, Nagasaki, Japan.
⁵ Department of Orthodontics and Dentofacial Orthopedics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
⁶ CellAxia Inc., Tokyo, Japan.
⁷ Department of Oral and Maxillofacial Surgery, Showa Medical University School of Dentistry, Tokyo, Japan.
⁸ Department of Periodontology and Endodontology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
⁹ Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, Kanagawa, Japan.
¹⁰ Department of Hematology, Atomic Bomb Disease Research Institute, Nagasaki University, Nagasaki, Japan.
¹¹ Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
¹² Department of oral surgery, Faculty of Medicine, Juntendo university, Tokyo, Japan.

Abstract

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.