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

Blitzer, Grace C.; Glazer, Tiffany A.; Burr, Adam R.; Gustafson, Sara; Ganz, O.; Meyers, Ross O.; McDowell, Kimberly A.; Nickel, Kwangok P.; Mattison, Ryan J.; Weiss, Marissa Steinberg; Chappell, Richard J.; Rogus-Pulia, Nicole; Galipeau, Jacques; Kimple, Randall J.

doi:10.1016/j.jcyt.2023.07.009

Cited by 10 publications

(7 citation statements)

References 33 publications

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“…In a systematic review of preclinical studies by Fenger Carlander et al [ 22 ], it was demonstrated that MSCs had a positive effect on salivary gland functioning with a significant increase in the salivary flow rate. A pilot study with IFNγ-stimulated MSCs in the submandibular gland of patients with radiation-induced xerostomia was well tolerated, and some patients experienced an increase in saliva production [ 23 ]. Due to the immunoregulatory properties of MSCs, chronic inflammation and fibrosis might be reduced.…”

Section: Discussionmentioning

confidence: 99%

Optimization of the Production Process of Clinical-Grade Human Salivary Gland Organoid-Derived Cell Therapy for the Treatment of Radiation-Induced Xerostomia in Head and Neck Cancer

Zanten,

Jorritsma-Smit,

Westra

et al. 2024

Pharmaceutics

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Head and neck cancer is a common cancer worldwide. Radiotherapy has an essential role in the treatment of head and neck cancers. After irradiation, early effects of reduced saliva flow and hampered water secretion are seen, along with cell loss and a decline in amylase production. Currently, there is no curative treatment for radiation-induced hyposalivation/xerostomia. This study aimed to develop and optimize a validated manufacturing process for salivary gland organoid cells containing stem/progenitor cells using salivary gland patient biopsies as a starting material. The manufacturing process should comply with GMP requirements to ensure clinical applicability. A laboratory-scale process was further developed into a good manufacturing practice (GMP) process. Clinical-grade batches complying with set acceptance and stability criteria were manufactured. The results showed that the manufactured salivary gland-derived cells were able to self-renew, differentiate, and show functionality. This study describes the optimization of an innovative and promising novel cell-based therapy.

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Section: Discussionmentioning

confidence: 99%

Optimization of the Production Process of Clinical-Grade Human Salivary Gland Organoid-Derived Cell Therapy for the Treatment of Radiation-Induced Xerostomia in Head and Neck Cancer

Zanten,

Jorritsma-Smit,

Westra

et al. 2024

Pharmaceutics

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“…However, in a pilot study, the same group has already used MSC prepared in this manner in six patients who received a single injection of 10x10 6 MSC into a single mandibular salivary gland and found that the therapy was well tolerated and showed a trend toward improvement in salivary volume and quality of life. 42 To our knowledge, there has been no research using allogeneic MSCs from umbilical cord tissue. We believe that this may have several advantages.…”

Section: Discussionmentioning

confidence: 99%

Post-radiation xerostomia therapy with allogeneic mesenchymal stromal stem cells in patients with head and neck cancer: study protocol for phase I clinical trial

Strojan,

Plavc,

Kokalj

et al. 2023

Radiology and Oncology

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Background Xerostomia is a common side effect of radiotherapy in patients with head and neck tumors that negatively affects quality of life. There is no known effective standard treatment for xerostomia. Here, we present the study protocol used to evaluate the safety and preliminary efficacy of allogeneic mesenchymal stromal stem cells (MSCs) derived from umbilical cord tissue. Patients and methods Ten oropharyngeal cancer patients with post-radiation xerostomia and no evidence of disease recurrence 2 or more years after (chemo)irradiation (intervention group) and 10 healthy volunteers (control group) will be enrolled in this nonrandomized, open-label, phase I exploratory study. MSCs from umbilical cord tissue will be inserted under ultrasound guidance into both parotid glands and both submandibular glands of the patients. Toxicity of the procedure will be assessed according to CTCAE v5.0 criteria at days 0, 1, 5, 28, and 120. Efficacy will be assessed by measuring salivary flow and analyzing its composition, scintigraphic evaluation of MSC grafting, retention, and migration, and questionnaires measuring subjective xerostomia and quality of life. In addition, the radiological, functional, and morphological characteristics of the salivary tissue will be assessed before, at 4 weeks, and at 4 months after the procedure. In the control group subjects, only salivary flow rate and salivary composition will be determined. Discussion The use of allogeneic MSCs from umbilical cord tissue represents an innovative approach for the treatment of xerostomia after radiation. Due to the noninvasive collection procedure, flexibility of cryobanking, and biological advantages, xerostomia therapy using allogeneic MSCs from umbilical cord tissue may have an advantage over other similar therapies.

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“…However, it should be clearly emphasized that the remainder of the works, of varying methodologies, focus on the use of MSCs of various origins for treating irradiation-induced salivary dysfunction, such as hyposalivation and xerostomia/dry mouth in patients with head and neck cancers (for instance PROSPERO CRD42021227336, NCT04489732, NCT047765392, NCT03874572, MESRIX-SAFE, MESRIX, MESRIX-II and MESRIX-III studies). The above-mentioned works will be discussed in the next section [202][203][204][205][206][207][208][209][210][211][212][213][214].…”

Section: The Pharmacological Strategies Of Msc-based Treatment For Hu...mentioning

confidence: 99%

“…These properties make the cells a very promising direction of research for use in anti-cancer therapy and as a source of cells that can promote the regeneration of the salivary gland parenchyma and restore radiation-induced damage. Unfortunately, despite progress in various preclinical in vivo models and human studies, only a few publications have examined the use of MSC transplantation as a potentially curative treatment option in HNC [202][203][204][205][206][207][208][209][210][211][212][213][214].…”

Section: The Pharmacological Strategies Of Msc-based Treatment For Hncmentioning

confidence: 99%

“…It should be noted that all existing prospective, randomized and controlled preclinical in vitro and animal models and clinical in vivo or human tissue studies, evaluate the use of MSCs derived from various origins for treating irradiation-induced salivary dysfunction (MARSH) and xerostomia (RIX) in specific head and neck cancers [202][203][204][205][206][207][208][209][210][211][212][213][214]. Many of these are reviewed in the present paper, particularly those concerning radiotherapy-induced xerostomia, e.g., the PROSPERO study (www.crd.ac.uk/prospero), registration number CRD42021227336, and I/II phase clinical studies such as NCT04489732, NCT047765392, NCT03874572 [202][203][204][205][206][207][208][209][210][211][212][213][214]. However, as an analysis of all available publications exceeds the scope of this study, only the most interesting and promising articles were included, based on data obtained from ClinicalTrials.gov., U.S. National Library of Medicine (available on April 30, 2024) and PubMed/Medline/EMBASE Library database and Cochrane Database of Systematic Reviews.…”

Section: The Pharmacological Strategies Of Msc-based Treatment For Hncmentioning

confidence: 99%

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The Role of Mesenchymal Stem/Stromal Cells in Head and Neck Cancer – Regulatory Mechanisms of Tumorigenic and Immune Activity, Chemotherapy Resistance, and Therapeutic Benefits of the Use of Stromal Cell-Based Pharmacological Strategies

Starska-Kowarska

2024

Preprint

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The most common type of head and neck cancer (HNC) is head and neck squamous cell carcinoma (HNSCC). It describes a heterogenous neoplastic disease that arises from the mucosal epithelium of the of the upper respiratory system and the gastrointestinal tract. It is characterized by high morbidity and mortality, being is the eighth most common cancer worldwide, with 931,931 newly diagnosed cases and 467,125 deaths according to the latest Global Cancer Statistics (GLOBOCAN) data. Despite the use of modern low-invasive surgical techniques and application of promising new chemoradiotherapies or combination treatment, the frequency of recurrences and the five-year survival of these patients remains unsatisfactory. The microenvironment of head and neck cancer comprises various cells that regulate neoplastic expansion. It is believed that the mesenchymal stromal cells (MSCs) present in the tumour milieu play a key role in the modulation of tumour initiation, development and progression, in the regulation of cancer treatment response, survival rates, patient outcomes and long-term prognosis; they also influence the resistance to cisplatin-based chemotherapy, the gold standard for advanced HNSCC. MSCs, are multipotent, heterogeneous, mobile cells, which meet specific stemness criteria defined by the International Society for Cellular Therapy (ISCT). Although no MSC-specific markers exist, they can be recognized based on several others, such as CD73, CD90 and CD105, while lacking the presence of CD45, CD34, CD14 or CD11b, CD79α, or CD19 and HLA-DR antigens; they share phenotypic similarity with stromal cells and their capacity to differentiate into other cell types. In the tumour niche, MSC populations are characterized by cell quiescence, self-renewal capacity, low reactive oxygen species production and the acquisition of epithelial-to-mesenchymal transition properties, they may play a key role in the process of acquiring drug resistance, and thus treatment failure. MSCs must also demonstrate plastic adherence in vitro and be able to differentiate into specific mesodermal cell types after stimulation i.e., adipocytes, chondrocytes, and osteoblasts when cultured under well-defined conditions. The present narrative review examines the links between mesenchymal stromal/stem cells and HNC, as well as the different mechanisms involved in the development of resistance to current chemo- and radiotherapies in HNSCC. It provides an overview of the current literature, including key opinion-forming systematic reviews, as well as cross-sectional, longitudinal, prospective and interventional studies based on cell culture models in vitro, animal or in vivo models of HNSCC; it also examines the possibilities of pharmacological targeting of stemness-related chemoresistance in HNSCC. It describes promising new strategies to optimize chemoradiotherapy with the potential to personalize patient treatment approaches, and highlights future therapeutic perspectives in HNC. The data concerning tumour-associated MSCs is arranged according to increasing clinical credibility.

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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

Cited by 10 publications

References 33 publications

Optimization of the Production Process of Clinical-Grade Human Salivary Gland Organoid-Derived Cell Therapy for the Treatment of Radiation-Induced Xerostomia in Head and Neck Cancer

Optimization of the Production Process of Clinical-Grade Human Salivary Gland Organoid-Derived Cell Therapy for the Treatment of Radiation-Induced Xerostomia in Head and Neck Cancer

Post-radiation xerostomia therapy with allogeneic mesenchymal stromal stem cells in patients with head and neck cancer: study protocol for phase I clinical trial

The Role of Mesenchymal Stem/Stromal Cells in Head and Neck Cancer – Regulatory Mechanisms of Tumorigenic and Immune Activity, Chemotherapy Resistance, and Therapeutic Benefits of the Use of Stromal Cell-Based Pharmacological Strategies

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