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. Author manuscript; available in PMC: 2024 Nov 1.
Published in final edited form as: Cytotherapy. 2023 Aug 15;25(11):1139–1144. doi: 10.1016/j.jcyt.2023.07.009

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

Grace C Blitzer 1,2,*, Tiffany Glazer 3, Adam Burr 1, Sara Gustafson 4, Olga Ganz 2, Ross Meyers 2, Kimberly A McDowell 2, Kwangok P Nickel 1, Ryan J Mattison 2,4, Marissa Weiss 1, Richard Chappell 2,5, Nicole M Rogus-Pulia 2,4,6, Jacques Galipeau 2,4, Randall J Kimple 1,2,*
PMCID: PMC10615723  NIHMSID: NIHMS1925061  PMID: 37589639

Abstract

Background aims:

Xerostomia, or the feeling of dry mouth, is a significant side effect of radiation therapy for head and neck cancer (HNC). Preliminary data suggests 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 [MSC(M)] for the treatment of radiation-induced xerostomia (RIX). Here we present the primary safety and secondary efficacy endpoints.

Methods:

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 FDA IND using an IRB-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 one 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 (SD).

Results:

Six radiation-induced xerostomia patients who had completed radiation at least 2 years prior (average 7.8 years prior) were enrolled in the pilot study. The median age was 71 (61–74). 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 towards improvement.

Conclusions:

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 towards 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.

Keywords: mesenchymal stromal cells, xerostomia, radiation, head and neck cancer

Introduction

Xerostomia, or the subjective complaint of dry mouth, is a side effect of radiation to the head and neck that affects more than 40% of all patients with head and neck cancer (HNC) 1. Patients with radiation-induced xerostomia (RIX) are at increased risk for dental caries, impaired swallowing ability, difficulty speaking, and diminished taste. These complications can be severely detrimental to a patient’s overall quality of life (QoL). Current treatment options for RIX are supportive in nature: carrying a water bottle for frequent sips of water, consumption of specially prepared food, use of salivary substitutes, chewing gum, sugar-free mints, acupuncture, and pilocarpine 2–5. However, these supportive interventions do not reverse the causes of xerostomia and are palliative in nature highlighting the critical need for improved therapies.

Mesenchymal stromal/stem cells (MSCs) have been shown to promote tissue healing and regeneration in a variety of injurious settings 6. Several groups have demonstrated in preclinical systems that injecting MSCs into salivary glands results in a 32%−200% increase in salivary flow 7–12. There has been one trial to date examining autologous adipose-derived MSCs to treat RIX in humans: the MESRIX study demonstrated increased salivary flow rates at early time points and improved patient-reported salivary function in 30 patients randomized 1:1 to MSC injection or placebo13. However, the MESRIX trial utilized non-cryopreserved adipose-derived MSCs, requiring a procedure to harvest the MSCs each time an injection of MSCs is done, which may pose a challenge for many patients. The same group conducted MESRIX II, in which allogenic cryopreserved MSCs were utilized, and demonstrated an increase in salivary flow as well as QoL measures in 10 patients14. However, this approach’s effectiveness may be limited by alloimmunization to non-self MSCs, preventing future doses of MSCs 15.

Preliminary studies suggest that MSCs injected into salivary glands do not linger there; instead, their tissue healing effects may be due to their secretome. Thus, multiple injections of MSCs may be needed to effectively treat chronic RIX. One way to accomplish this is by expanding MSCs and cryopreserving them until clinically needed. The freeze-thaw cycle can result in cellular injury, less effective immunomodulation, or senescence 16–21. However, our group has shown that stimulating bone marrow-derived MSCs [MSC(M)] with interferon gamma (IFNγ) prior to cryopreservation can prevent this immune dysfunction and improve post-thaw recovery 17,18,22. To justify pursuit of a first-in-human phase I study, we first performed a pilot study involving six human subjects to assess the safety of an injection of our investigational medical product (IMP) into a single submandibular gland. Here we present the results of this study, a first-in-human pilot study of IFNγ-stimulated MSC(M) for the treatment of RIX.

Methods and Materials

MSC(M) Isolation, Culture, IFNγ Stimulation, and Cryopreservation

This study was conducted under a UW Sponsor-Investigator FDA IND and with IRB approval (UW HSB IRB#20025, NCT04489732). After having given informed consent, MSC(M) were isolated from bone marrow aspirated from the iliac crest of patients with HNC and RIX, defined as qualitative salivary function <80% of baseline, who were a minimum of two years status post completion of definitive therapy. Good Manufacturing Practice compliance was observed and MSC(M) were expanded to a dose of at least 200 × 106 cells – see Appendix 1 in Supplementary Materials for a detailed manufacturing procedure including IFNγ stimulation and cryopreservation methods.

Injection of MSC(M)

Cryopreserved, banked IFNγ-stimulated MSC(M) were thawed and allowed to recover in culture for 16 hours prior to injection. Final formulation of the autologous IFNγ-stimulated MSC(M) product was prepared in 0.5% Human Serum Albumin in Plasmalyte© at a concentration of 10 × 106 cells/mL. MSC(M) product was tested for sterility, endotoxin, and mycoplasma. Cell viability of final product was 95–99% by Trypan blue exclusion method. Each manufactured MSC(M) product passed all quality control release specifications and met acceptance criteria.

The transcutaneous injection of the MSC(M) product was done by an experienced otolaryngology physician using sterile technique under ultrasound (US) guidance to ensure avoidance of intravascular injection. The skin over the right submandibular gland was cleansed and anesthetized with lidocaine. The center of the right submandibular gland was injected with 1 mL (10 × 106 cells) of autologous IFNγ-stimulated MSC(M) product via a 23-gauge, 1.5-inch needle.

Endpoints and Assessments

The primary endpoint for the pilot clinical trial was safety and tolerability of MSC(M) injection, measured by the proportion of participants experiencing dose-limiting toxicity (DLT), defined as pain >5 on a standard 10-point pain scale of 0 to 10 within 1 month after MSC(M) injection or any serious adverse event (SAE) within 1 month of MSC(M) injection (see Appendix 2 in Supplementary Materials). A maximum of 12 patients were to be enrolled, with up to six patients treated at the starting dose of 10×106cells and, if necessary, a de-escalation cohort of up to 6 patients at a dose of 5×106 cells. Subjects were asked to rate their pain at baseline (screening), 30 minutes after the MSC(M) IMP administration, three days after administration, one week after administration, and 30 days after MSC(M) administration. Subjects additionally kept a diary with daily entries recording the occurrence and severity of pain and occurrence and severity of other adverse events (AEs) for the first month after MSC injection, as well as a log of pain medications used.

Secondary endpoints of the pilot clinical trial included efficacy of autologous IFNγ-stimulated MSC(M) injection as defined by salivary quantity and xerostomia-related QoL surveys. Whole saliva production rates (sialometry) were measured under unstimulated and stimulated saliva collection conditions, as previously described 23,24 (see Appendix 3 in Supplementary Materials). Subjects completed the salivary flow rate assessments at the screening (baseline) visit and at 1- and 3-month follow-up visits. QoL was assessed using three validated tools: the University of Michigan Xerostomia Related Quality of Life (XeQOL) scale 25, the MD Anderson Dysphagia Index (MDADI) 26, and the visual analog scale (VAS) xerostomia questionnaire 27. Subjects completed the XeQoL, MDADI, and VAS at the screening (baseline) visit and at one- and three-month follow-up visits.

Statistical Analysis

Data are reported as mean +/− standard deviation, or median with range. Although the standard method to account for repeated measures over time to examine salivary trends would be a mixed-measures ANOVA, the small sample size renders such an analysis inappropriate. Instead, individual trends were estimated for each patient using a regression of outcomes vs. 0, 1, and 3 months. These were then used as meta-data in a two-sided one sample t-test to test the null hypothesis that mean trend is 0. Calculations were carried out using GraphPadPrism software (La Jolla, CA).

Results

Demographics and MSC(M) Characterization

For this first-in-human pilot clinical trial, six patients with RIX who had completed radiation therapy for their HNC at least two years prior were enrolled. The median age was 71 (61–74), five (83%) patients were male, and five patients (83%) were treated with chemoradiation and one patient (17%) with radiation alone (Table 1). Radiation doses to the salivary glands are shown in Supplementary Table 1; the doses to the injected submandibular gland ranged from a mean of 37.7 Gy to 68.2 Gy.

Table 1.

Baseline characteristics of the 6 patients enrolled in our pilot clinical trial.

Subject Age Gender Race Screening KPS Tumor Site TNM Stage P16 Status Radiation Therapy End Date Interval Since RT Completion (years) RT Total Dose (Gy) Concurrent Chemotherapy
1 61 Male White 100 right base of tongue T3N2cM0 p16+ March 2014 7.9 70 Cisplatin
2 66 Male White 100 right base of tongue T3N2cM0 p16+ Feb 2014 8.2 70 Cetuximab
3 70 Male White 100 unknown primary TxN2aM0 Not Reported July 2011 10.9 64.8 None
4 73 Female White 100 right base of tongue T1N1M0 p16+ Dec 2014 7.6 70 Cisplatin
5 72 Male White 100 left base of tongue T4aN2aM0 p16+ Jan 2019 3.6 70 Cisplatin
6 74 Male White 100 right tonsil T2N2bM0 p16+ May 2014 8.4 70 Cetuximab
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Abbreviations: KPS: Karnofsky Performance Status; TNM: tumor, node, metastasis; RT: radiation therapy

Purity, identity, and potency of the autologous IFNγ-stimulated MSC(M) product were determined by flow cytometry (Supplementary Table 2). The average cell doubling time was 23 hours, and the MSC(M) product was manufactured within 14 to 17 days. Cell recovery from cryopreservation was on average 79% (range 69% - 90%).

No DLTs Occurred after MSC(M) Injection into Submandibular Gland

Three patients (50%) reported a pain score of 1 out of 10 (grade 1 adverse event) at the injection site after submandibular gland injection; all pain resolved within four days. No patients reported pain one month after injection, with no serious adverse events or other DLT reported one month after injection. Two patients (33%) had grade 1 lymphadenopathy that resolved within one month of injection. Two patients (33%) had a grade 1 decrease in lymphocyte count one month after injection. One patient had a grade 2 decrease in lymphocyte count – of note the patient’s baseline complete blood count demonstrated grade 1 lymphopenia. Additionally, one patient had grade 1 dizziness, neck pain, and lymphedema after injection – this patient was subsequently found to have a viral upper respiratory infection. All AEs are summarized in Table 2. Because no SAEs or DLTs were observed, the study was closed after accrual of six patients at the initial dose level.

Table 2.

Adverse events that occurred during the pilot clinical trial. No grade 3 or above events occurred.

Adverse Event Grade 1 Grade 2 Grade 3 Grade 4
Number of patients with event (percent)
Pain at MSC(M) injection site 3 (50%) 0 0 0
Lympadenopathy at MSC(M) injection site 2 (33%) 0 0 0
Lymphocyte decrease 2 (33%) 1 (17%)A 0 0
Pain at bone marrow aspiration site 2 (33%) 0 0 0
Neck pain 1 (17%) 0 0 0
Dizziness 1 (17%) 0 0 0
Lymphedema 1 (17%) 0 0 0
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MSC(M) Injection Results in Increased Salivary Production and Improved Salivary Quality of Life

MSC(M) Injection Results in Increased Salivary Production and Improved Salivary Quality of Life

The analysis of secondary endpoints demonstrated a trend of improvement in RIX. There was a trend towards increased salivary production. The mean unstimulated saliva was 0.13 mL/min (SD 0.17) at baseline and increased to 0.14 mL/min (SD 0.12) at 1 month after injection and 0.19 mL/min (SD 0.21) at 3 months, p=0.47 (Figure 1A). Three patients (50%) had an increase in unstimulated saliva at 1- and 3-months post-injection (Figure 1A). Patients 4 and 5 demonstrated large improvements in unstimulated salivary production; patient 5 demonstrated a 7-fold increase in unstimulated salivary production and patient 4 was able to produce unstimulated saliva at 1- and 3-months post-injection when none was produced at baseline. Additionally, stimulated saliva increased after MSC(M) injection. The mean stimulated saliva was 0.50 mL/min (SD 0.40) at baseline, 0.57 mL/min (SD 0.28) at 1 month after injection, and 0.58 mL/min (SD 0.43) at 3-months post-injection, p=0.65 (Figure 1B).

Figure 1:

Figure 1:

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Secondary endpoints of salivary quantity and quality of life. A) Graph of all six patients’ mean unstimulated saliva produced at baseline, 1 month and 3 months after injection of autologous IFNγ-stimulated MSC(M) showing trend of increasing unstimulated salivary production, bars are standard deviation. Graph of individual patients’ unstimulated saliva demonstrating the large increase in saliva production seen in patient 5 and the ability of patient 4 to produce unstimulated saliva after injection of MSC(M). B) Graph of all six patients’ mean stimulated saliva produced at baseline, 1 month and 3 months after injection of autologous IFNγ-stimulated MSC(M) showing small trend of increasing stimulated salivary production, bars are standard deviation. Graph of individual patients’ stimulated saliva. C) Box and whisker plots overlayed on line graphs of individual patient’s QoL scores from all three surveys showing the trend for improvement in xerostomia-specific QoL. The box and whisker plots show the 5–95% range. Three validated, xerostomia-specific QoL surveys were used: the University of Michigan Xerostomia Related Quality of Life (XeQOL) scale, the visual analog scale (VAS) xerostomia questionnaire, and the MD Anderson Dysphagia Index (MDADI). For VAS and XeQoL lower scores represent better QoL and less severe xerostomia, for MDADI higher scores represent better QoL.

QoL surveys also showed a trend towards improvement (Figure 1C). At three months post-MSC(M) injection, five patients (83%) reported improvements on the XeQOL and MDADI surveys and three patients (50%) reported improvements on the VAS. Again, patients 4 and 5 demonstrated large improvements in xerostomia-specific QoL scores, correlating with the improvements seen in salivary output.

Discussion

In this first-in-human pilot clinical trial, we demonstrated that injection of autologous IFNγ-stimulated MSC(M) into the submandibular gland of patients with RIX is safe and well tolerated. There were no DLTs at the current dose of 10 × 106 cells injected into the submandibular gland. Three patients (50%) experienced pain at the injection site in the submandibular gland. This pain was rated as 1/10 for all three patients and resolved in less than one week. Additionally, two patients (33%) experienced transient lymphadenopathy proximal to the injection site. Interestingly, there was a decrease in blood lymphocytes seen at one month for three patients (50%) and at three months for two patients (33%). This could be due to the known immunoregulatory properties of MSC which may in turn improve RIX by reducing the chronic inflammatory state of the submandibular glands after radiation 28,29. However, a systemic decrease in lymphocytes is unlikely to be due to the localized MSC(M) injected into the submandibular glands and may instead be coincidental as many patients have decreased total lymphocyte counts after chemoradiation 30,31. Further research is needed to investigate the mechanisms by which MSC(M) may treat RIX.

A trend towards an improvement in secondary endpoints of salivary quantity and QoL was observed. In this small pilot trial, 50% of patients experienced an increase in unstimulated saliva with two of these patients experiencing meaningful improvements – one with a seven-fold increase in unstimulated saliva from baseline and one being able to produce unstimulated saliva when previously none was produced. The patient with the largest increase in unstimulated saliva had the shortest interval between radiation and study enrollment (3.6 years) as well as the lowest dose to the right submandibular gland (38 Gy as compared to all other patients receiving at least 60 Gy). Both of these patient factors may have a role in this patient’s significant response to autologous IFNγ-stimulated MSC(M).

We focused on the measurement of unstimulated saliva as the submandibular glands produce approximately two-thirds of unstimulated saliva. While measurement of salivary flow rates is a quantifiable endpoint, the variation of salivary flow rates between patients makes determining what constitutes a meaningful improvement in salivary flow challenging. As xerostomia is a subjective perception of dry mouth, patients can self-report xerostomia even when producing normal amounts of saliva, which may be due to alterations in salivary quality rather than quantity. Another complicating factor in measuring RIX is the chronicity – patients may produce the same amount of saliva over time, but as they grow accustomed to their lower salivary flow rates their quality of life may improve32.

The majority of patients also reported improvement on xerostomia-specific QoL surveys at both one- and three-months post-injection of MSC(M). However, there was no clear correlation between QoL scores and amount of saliva produced, making the determination of efficacy endpoints challenging. In the QoL tool, XeQOL, it was found that the salivary flow rates were only weakly correlated with the QoL scores 25. Further complicating the determination of xerostomia efficacy, the three QoL tools used in this pilot clinical trial – VAS, XeQOL, and MDADI – were designed to measure the change in xerostomia-related QoL after radiation treatment and thus are imperfect at detecting changes over time and improvements in the years after radiation. Efforts are underway to validate new QoL tools that better measure changes in the years after radiation and correlate with quantifiable measures, such as salivary amounts.

These signals provide support for continued investigation into the use of autologous IFNγ-stimulated MSC(M) for the treatment of RIX. This is particularly true in the setting of only unilateral submandibular gland injection. The pilot clinical trial employed unilateral injection in order to determine the safety of autologous IFNγ-stimulated MSC(M) injection. However, future clinical trials will employ injection of bilateral submandibular glands, allowing for potential revitalization of both submandibular glands by MSC(M) and increased improvement in salivary production and QoL.

Our pilot clinical trial was limited by the small number of HNC patients enrolled. The six patients enrolled in the pilot clinical trial had 0 DLTs demonstrating the safety and tolerability of the dose of 10 × 106 autologous IFNγ-stimulated MSC(M). The secondary endpoints of salivary quantity and QoL were not statistically significant compared to baseline, as we expected from our small pilot study. However, the signal of improvements in salivary quantity and QoL, particularly in two of the patients, suggests that the MSC(M) product may prove to be a viable therapy for RIX. Additionally, as RIX is a chronic disease, we will follow these patients over the course of one year to investigate the longer-term impact of MSC(M) on RIX, collecting data on our secondary endpoints at 6 and 12 months. We will also examine salivary quality, including protein levels and viscoelasticity to determine the relationship between salivary quality, quantity, and patient perception of xerostomia both before and after MSC injection. All MSCs were cultured and phenotype-confirmed in a GMP facility, however no karyotyping nor other biosafety studies were conducted. Clinical studies have also shown the radiation and chemotherapy regimens given to patients with hematological malignancies can alter the genomics of the bone marrow and thus MSC(M)33–35. In our trial the chemotherapy regimen was either cisplatin or cetuximab, both of which are much less myelosuppressive than the regimens typically used for patients with hematological malignancies. Given this low risk for genetic alterations, we did not undertake biosafety studies.

This first-in-human pilot clinical trial provides support for further investigation into autologous IFNγ-stimulated MSC(M) as an innovative remedy to treat RIX and restore QoL. This pilot study has been used as the foundation for a phase I dose-escalation study injecting autologous IFNγ-stimulated MSC(M) into bilateral submandibular glands, which is accruing as of summer 2023.

Supplementary Material

1

Acknowledgements

The authors would like to acknowledge the contributions of Diana Trask, Belinda Buehl, and the entire DHO clinical trials coordinators. The authors thank James P. Zacny, PhD for manuscript preparation and formatting.

Funding

Funding for this study was provided by the University of Wisconsin Carbone Cancer Center Support Grant P30 CA014520, University of Wisconsin (UW) Head and Neck SPORE Grant P50 DE026787, NIDCR UG3 DE030431, Resident Research Grant from the Radiological Society of North America, American Society of Clinical Oncology Young Investigator Award, and the UW School of Medicine and Public Health and UW Health PACT fund.

Footnotes

Declaration of Competing Interests

The authors have no conflicts of interest.

Supplementary Material

Supplementary material associated with this article can be found in the online version: information to be completed after article acceptance.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Data Availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1
NIHMS1925061-supplement-1.docx (20.7KB, docx)

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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