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Marrow-Derived Autologous Stromal Cells for the Restoration of Salivary Hypofunction (MARSH): A pilot, first-in-human study of interferon gamma-stimulated marrow mesenchymal stromal cells for treatment of radiation-induced xerostomia.

Authors
  • Blitzer, Grace C1
  • Glazer, Tiffany2
  • Burr, Adam3
  • Gustafson, Sara4
  • Ganz, Olga5
  • Meyers, Ross5
  • McDowell, Kimberly A5
  • Nickel, Kwangok P3
  • Mattison, Ryan J6
  • Weiss, Marissa3
  • Chappell, Richard7
  • Rogus-Pulia, Nicole M8
  • Galipeau, Jacques6
  • Kimple, Randall J9
  • 1 Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA; UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA. Electronic address: [email protected].
  • 2 Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
  • 3 Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
  • 4 Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
  • 5 UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
  • 6 UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
  • 7 UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA; Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
  • 8 UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA; Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, USA.
  • 9 Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA; UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA. Electronic address: [email protected].
Type
Published Article
Journal
Cytotherapy
Publication Date
Nov 01, 2023
Volume
25
Issue
11
Pages
1139–1144
Identifiers
DOI: 10.1016/j.jcyt.2023.07.009
PMID: 37589639
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Xerostomia, or the feeling of dry mouth, is a significant side effect of radiation therapy for patients with head and neck cancer (HNC). Preliminary data suggest that mesenchymal stromal/stem cells (MSCs) can improve salivary function. We performed a first-in-human pilot study of interferon gamma (IFNγ)-stimulated autologous bone marrow-derived MSCs, or MSC(M), for the treatment of radiation-induced xerostomia (RIX). Here we present the primary safety and secondary efficacy endpoints. A single-center pilot clinical trial was conducted investigating the safety and tolerability of autologous IFNγ-stimulated MSC(M). The study was conducted under an approved Food and Drug Administration Investigational New Drug application using an institutional review board-approved protocol (NCT04489732). Patients underwent iliac crest bone marrow aspirate and MSC(M) were isolated, cultured, stimulated with IFNγ and cryopreserved for later use. Banked cells were thawed and allowed to recover in culture before patients received a single injection of 10 × 106 MSC(M) into the right submandibular gland under ultrasound guidance. The primary objective was determination of safety and tolerability by evaluating dose-limiting toxicity (DLT). A DLT was defined as submandibular pain >5 on a standard 10-point pain scale or any serious adverse event (SAE) within 1 month after injection. Secondary objectives included analysis of efficacy as measured by salivary quantification and using three validated quality of life instruments. Quantitative results are reported as mean and standard deviation. Six patients with radiation-induced xerostomia who had completed radiation at least 2 years previously (average 7.8 years previously) were enrolled in the pilot study. The median age was 71 (61-74) years. Five (83%) patients were male. Five patients (83%) were treated with chemoradiation and one patient (17%) with radiation alone. Grade 1 pain was seen in 50% of patients after submandibular gland injection; all pain resolved within 4 days. No patients reported pain 1 month after injection, with no SAE or other DLTs reported 1 month after injection. The analysis of secondary endpoints demonstrated a trend of increased salivary production. Three patients (50%) had an increase in unstimulated saliva at 1 and 3 months after MSC(M) injection. Quality of life surveys also showed a trend toward improvement. Injection of autologous IFNγ-stimulated MSC(M) into a singular submandibular gland of patients with RIX is safe and well tolerated in this pilot study. A trend toward an improvement in secondary endpoints of salivary quantity and quality of life was observed. This first-in-human study provides support for further investigation into IFNγ-stimulated MSC(M) injected in both submandibular glands as an innovative approach to treat RIX and improve quality of life for patients with HNC. Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.

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