Still thirsting for a fix
Editorial Commentary

Still thirsting for a fix

Grace C. Blitzer1,2, Jacques Galipeau2,3, Sara S. McCoy2,3, Randall J. Kimple1,2

1Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 2UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 3Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

Correspondence to: Randall J. Kimple, MD, PhD. Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 3107 WIMR, 1111 Highland Avenue, Madison, WI 53705, USA; UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. Email: rkimple@humonc.wisc.edu.

Comment on: Jakobsen KK, Carlander AF, Todsen T, et al. Mesenchymal Stem/Stromal Cell Therapy for Radiation-Induced Xerostomia in Previous Head and Neck Cancer Patients: A Phase II Randomized, Placebo-Controlled Trial. Clin Cancer Res 2024;30:2078-84.


Keywords: Radiation induced xerostomia; salivary dysfunction; cellular therapy


Submitted Jan 16, 2025. Accepted for publication Mar 20, 2025. Published online Apr 15, 2025.

doi: 10.21037/tcr-2025-150


Jakobsen and colleagues recently published the results of a Phase II randomized, placebo controlled trial investigating the use of adipose-derived mesenchymal stromal cells [MSC(A)] for treatment of radiation induced xerostomia (1). This work was a follow-up study based on promising initial studies previously reported by this group (2,3). Unfortunately, in this study, no statistically significant differences were found between patients who received MSC(A) and those who received a placebo injection.

Patients included those with head and neck cancer treated at least 2 years prior with radiation therapy (with or without concurrent chemotherapy) who suffered from symptomatic salivary dysfunction (i.e., xerostomia). Patients were randomized to receive an injection of either cryopreserved, allogeneic MSC(A) freshly thawed immediately prior to injection, or placebo control. Both quantitative (measured salivary production) and qualitative (quality of life) endpoints were used to assess efficacy over the 4-month study period. The primary outcome of this study was the difference in unstimulated whole salivary flow rate between baseline and 4-month follow-up between patients treated with MSC(A) and those who received placebo. Analysis of the primary endpoint demonstrated no significant difference between groups (P=0.11). Intriguingly, an improvement in unstimulated whole salivary flow rate was seen in patients treated with MSC(A) (P=0.0004) while no change was seen in the placebo treated group (P=0.1934). Unsurprisingly, no differences in stimulated salivary flow rate were seen. Finally, they used the European Organization for Research and Treatment of Cancer QoL Questionnaire, Head and Neck Module (EORTC QLQ-H&N35) and Xerostomia Questionnaire (XQ) questionnaires to assess patient-reported outcomes. No differences were seen between groups in these quality-of-life outcomes, although all patients appeared to have some improvement in dry mouth, sticky saliva, and swallowing.

While the results of this study were disappointing, some additional context may provide encouragement to those seeking treatments for patients with radiation induced xerostomia. Previous studies by this group and others demonstrated the safety of MSC therapy, adverse events were experienced in only 20% of patients and these side effects resolved within a few weeks. No serious adverse events related to the treatment were seen. MSCs have been shown to be safe and, with some careful attention to potential confounders and hurdles, may demonstrate efficacy for the treatment of radiation induced xerostomia.

The act of cryopreserving and thawing MSCs leads to altered MSC functionality including impaired immunomodulation (4,5). This altered functionality is reversed by interferon gamma (IFN-γ) priming (4,5), an approach we have taken in our studies of marrow derived MSCs [MSC(M)] in a similar subset of patients (6). The use of allogeneic MSCs has some logistical advantages over autologous MSCs, but use might be limited in situations where multiple injections are needed (32% of participants developed de novo donor specific antibodies). In fact, development of donor-specific antibodies appeared to result in less clinical benefit. A comparison of different sources of MSCs (e.g., marrow versus adipose versus salivary gland) could identify preferential sources for specific use cases. Additionally, the placebo used in this study differed from that utilized in their previous studies. Here, CryoStor10 containing 10% dimethyl sulfoxide (DMSO) was used as the placebo to match the cryopreservative used for cell banking. DMSO is a problematic control, as it is capable of anti-inflammatory effects including suppression of inflammatory cytokine production and T-cell function (7). Another potential study hurdle is the mean radiation dose received by the injected glands, which exceeded 50 Gy, and a higher mean radiation dose was accompanied with a smaller increase in salivary production. This suggests that MSC therapy may only be effective in glands that have received a “lower” dose of radiation, exactly what dose remains to be determined. Measurement of gland-specific production may help identify a dose of radiation predictive of potential benefit from MSC therapy. Finally, the quality-of-life surveys employed in the study were designed to measure the significant, acute changes in quality of life after radiation, rather than measure chronic quality of life after radiation, which may confound the surveys ability to detect small improvement in quality of life after MSC injection.

While this randomized, placebo controlled clinical trial did not demonstrate efficacy of MSC(A) to improve radiation induced xerostomia, multiple challenges in the clinical trial design may have impacted this result, with further study into treatments for radiation xerostomia needed.


Acknowledgments

None.


Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-150/prf

Funding: This work was supported by grants from the National Institutes of Health (grant Nos. UH3 DE030431 and R34 DE033042).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-150/coif). J.G., S.S.M., and R.J.K. report that this work was supported by grants from the National Institutes of Health (grant Nos. UH3 DE030431 and R34 DE033042). The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.


References

  1. Jakobsen KK, Carlander AF, Todsen T, et al. Mesenchymal Stem/Stromal Cell Therapy for Radiation-Induced Xerostomia in Previous Head and Neck Cancer Patients: A Phase II Randomized, Placebo-Controlled Trial. Clin Cancer Res 2024;30:2078-84. [Crossref] [PubMed]
  2. Grønhøj C, Jensen DH, Vester-Glowinski P, et al. Safety and Efficacy of Mesenchymal Stem Cells for Radiation-Induced Xerostomia: A Randomized, Placebo-Controlled Phase 1/2 Trial (MESRIX). Int J Radiat Oncol Biol Phys 2018;101:581-92. [Crossref] [PubMed]
  3. Lynggaard CD, Grønhøj C, Christensen R, et al. Intraglandular Off-the-Shelf Allogeneic Mesenchymal Stem Cell Treatment in Patients with Radiation-Induced Xerostomia: A Safety Study (MESRIX-II). Stem Cells Transl Med 2022;11:478-89. [Crossref] [PubMed]
  4. Chinnadurai R, Copland IB, Patel SR, et al. IDO-independent suppression of T cell effector function by IFN-γ-licensed human mesenchymal stromal cells. J Immunol 2014;192:1491-501. [Crossref] [PubMed]
  5. Chinnadurai R, Copland IB, Garcia MA, et al. Cryopreserved Mesenchymal Stromal Cells Are Susceptible to T-Cell Mediated Apoptosis Which Is Partly Rescued by IFNγ Licensing. Stem Cells 2016;34:2429-42. [Crossref] [PubMed]
  6. Blitzer GC, Glazer T, Burr A, et al. 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. Cytotherapy 2023;25:1139-44. [Crossref] [PubMed]
  7. Huang SH, Wu CH, Chen SJ, et al. Immunomodulatory effects and potential clinical applications of dimethyl sulfoxide. Immunobiology 2020;225:151906. [Crossref] [PubMed]
Cite this article as: Blitzer GC, Galipeau J, McCoy SS, Kimple RJ. Still thirsting for a fix. Transl Cancer Res 2025;14(4):2175-2177. doi: 10.21037/tcr-2025-150

Download Citation