Radiation-Induced Dry Mouth | Image Credit: 

Xerostomia, the subjective sensation of dry mouth, is one of the most consequential long-term adverse effects of head and neck radiation. Xerostomia results from hyposalivation (reduced volume of saliva production) and salivary dysfunction (a change in the composition of saliva). Patients with radiation-induced xerostomia (RIX) can develop dental caries, impaired swallowing, diminished taste, and difficulty speaking. These associated symptoms can have a significant negative impact on overall quality of life. Older, 3D conformal radiation therapy results in long-term xerostomia in up to 80% of patients. The use of more modern radiation techniques, such as intensity-modulated radiation, partially spares the salivary glands but still results in RIX in over 40% of patients.

Radiation damages the saliva-producing acinar cells of salivary glands and results in fibrosis and cellular dysfunction.

 Radiation also damages salivary gland adult stem cells, the ultimate source for replenishing salivary gland tissue. After radiation, patients are encouraged to increase water consumption, consume specially prepared food, utilize salivary substitutes, or attempt to stimulate salivary production through parasympathomimetic drugs, chewing gum, or sugar-free mints.

 These supportive interventions are minimally effective at best, illustrating a critical need for improved therapies for RIX.

Mesenchymal stromal cells (MSCs) are cellular products derived from bone marrow, adipose tissue, or minor salivary glands and propagated ex vivo using established methods.

 MSCs can promote tissue healing in a variety of injurious settings. This is likely due to the production of tissue-promoting morphogens through their secretome, which has broad immunomodulatory and trophic activity.

Autologous MSCs are a promising cell-based therapy that allows for rejuvenating adult stem cells, as demonstrated in the gut.

 Our laboratory and others have demonstrated that intraglandular infusion of MSCs results in a 30% to 50% increase in salivary flow rate in mouse models of radiation-induced salivary gland dysfunction (

 To further support the use of MSC for the treatment of RIX, autologous and allogeneic MSCs have shown encouraging effects in recovering salivary function in patients with radiation-induced xerostomia in a series of Danish studies.

 These data have informed a phase 1 pilot trial (NCT04489732) and phase 1 clinical trial (NCT05820711) at the University of Wisconsin examining the use of autologous bone marrow–derived MSCs for treatment of radiation- induced xerostomia in patients who are 2 or more years out from completing radiation.

. Radiation Decreases Saliva Production and Interferon-ƴ Prelicensed MSC Injection Abrogates Effect in Murine Model

Although the data are promising, this work has several clear limitations. First, the approach employed in the Danish clinical trials utilized MSCs maintained in culture from liposuction until implantation.

 To expand this approach to a multi-institutional setting, it is important to cryopreserve MSCs to be transported from a central cell therapy laboratory to a delivery site. We have previously demonstrated that cryopreservation and large-scale culture expansion—key features of deliverable, practical cellular therapy— lead to MSC senescence, which can impair MSC function.

 Additionally, although not tested in this or prior studies, it is possible that repeated injections of MSCs will be required to optimize salivary function. This will require patients to either undergo an MSC harvesting procedure before each injection or the ability to cryopreserve a patient’s MSCs for serial injection. Repeated allogeneic injections can lead to allogeneic reactivity and limit cell engraftment.

Our proposed approach of autologous interferon gamma, tumor necrosis factor-α (TNF-α) preactivation of cryopreserved MSCs overcomes both limitations. Bone marrow aspirates and liposuction as sources for bone marrow–derived and adipose-derived MSCs, respectively, are associated with undesirable procedure-related consequences.

 In contrast, the minor salivary gland biopsy is well tolerated, performed in office, and requires only local lidocaine before an incision of less than 1 cm in the inner lower lip. Minor salivary gland–derived MSCs, or MSC(SG), represent an attractive tissue source for patients who have not received radiation therapy due to the ease of harvesting procedure.

All prior studies have focused on treating chronic RIX rather than preventing it before fibrosis and other late radiation effects. Thus, we have designed a clinical trial to investigate whether transplantation of autologous minor salivary gland–derived, interferon gamma, TNF-α prelicensed, cryopreserved, and culture-rescued MSCs into salivary glands after radiation will provide an innovative remedy to prevent chronic xerostomia in patients with head and neck cancer.

The proposed clinical trial will enroll patients with newly diagnosed head and neck cancer recommended to undergo radiation as part of their curative treatment (

). Consenting patients will undergo minor salivary gland biopsy to obtain MSC(SG) and then proceed to standard-of-care radiation. The MSC(SG) will be expanded, prelicensed with interferon gamma and TNF-α, and cryopreserved. Three months after the completion of radiation, they will undergo history, physical examination, and posttreatment imaging. If they are found to have no evidence of residual cancer, then they will undergo injection of cryopreserved MSC(SG) into the major salivary glands. They will be followed for safety/tolerability, salivary production, and quality of life. Our study will be the first-in-human trial of interferon gamma, TNF-α prelicensed MSC(SG) for the prevention of chronic radiation-induced xerostomia.

Grace Blitzer, MD, is an assistant professor in the Department of Human Oncology at the University of Wisconsin Carbone Cancer Center.

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A phase 1 trial is examining the use of mesenchymal stromal cells for treatment of radiation-induced xerostomia in patients who have completed radiation.

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