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• W4220802064 abstract "Purpose/Objective(s) Xerostomia, or dry mouth, is a common side effect of head neck radiation. Current treatment options for radiation-induced xerostomia are generally supportive in nature. Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are a viable cell-based therapy for xerostomia. Adult stem cells are the ultimate source for replenishment of salivary gland tissue and the secretome of BM-MSCs may allow for the regeneration of salivary gland stem cells after radiation. We have undertaken FDA IND enabling studies demonstrating the phenotype, functionality, and secretome of interferon gamma (IFNγ) stimulated BM-MSCs taken from patients with head and neck cancer who have undergone radiation. Previous clinical trials with MSCs often required injection of MSCs rapidly after expansion, without cryopreservation. However this is unrealistic for patient care where patients are traveling for therapy or may require multiple injections of MSCs. Cryopreservation allows for a more inclusive therapy but can result in cellular injury or immune dysfunction. Stimulating the BM-MSCs with IFNγ prior to cryopreservation has been shown to prevent this. Here we present the protocol of MARSH, a first-in-human clinical trial of bone marrow derived, interferon gamma activated BM-MSCs for the treatment of radiation-induced xerostomia. Materials/Methods This single-center phase I dose-escalation with expansion cohort, study will assess the safety and tolerability of BM-MSCs for treatment of radiation-induced xerostomia in patients who had head and neck cancer. This is a 2-part trial. The first is a phase I trial of unilateral injection of MSCs into the submandibular gland of 6 patients to demonstrate safety. The second part is a phase I dose escalation study with a 3+3 design with staggered enrollment. A total of 21-30 subjects (9-18 in phase I study, 12 in expansion cohort) will be enrolled. The primary endpoint is determining the recommended phase 2 dose (RP2D) of interferon gamma stimulated BM-MSCs in order to conduct further studies on the efficacy of BM-MSCs. Patients will have their bone marrow aspirated, BM-MSCs expanded and stimulated with IFNγ, and then injected into the submandibular gland. The RP2D will be determined by dose limiting toxicities occurring within one month of BM-MSC injection. Secondary outcomes of salivary amounts, composition, ultrasound of salivary glands, and quality of life surveys will be taken at 3, 6, 12, and 24 month visits. Results Recruiting will start January 3, 2022. Subject accrual will occur over 2.5 years with the total duration of the trial expected to be approximately 4.5 years. Conclusion Autotransplantation of IFNγ-stimulated BM-MSCs in salivary glands post-radiation may provide an innovative remedy to treat xerostomia and restore quality of life. Xerostomia, or dry mouth, is a common side effect of head neck radiation. Current treatment options for radiation-induced xerostomia are generally supportive in nature. Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are a viable cell-based therapy for xerostomia. Adult stem cells are the ultimate source for replenishment of salivary gland tissue and the secretome of BM-MSCs may allow for the regeneration of salivary gland stem cells after radiation. We have undertaken FDA IND enabling studies demonstrating the phenotype, functionality, and secretome of interferon gamma (IFNγ) stimulated BM-MSCs taken from patients with head and neck cancer who have undergone radiation. Previous clinical trials with MSCs often required injection of MSCs rapidly after expansion, without cryopreservation. However this is unrealistic for patient care where patients are traveling for therapy or may require multiple injections of MSCs. Cryopreservation allows for a more inclusive therapy but can result in cellular injury or immune dysfunction. Stimulating the BM-MSCs with IFNγ prior to cryopreservation has been shown to prevent this. Here we present the protocol of MARSH, a first-in-human clinical trial of bone marrow derived, interferon gamma activated BM-MSCs for the treatment of radiation-induced xerostomia. This single-center phase I dose-escalation with expansion cohort, study will assess the safety and tolerability of BM-MSCs for treatment of radiation-induced xerostomia in patients who had head and neck cancer. This is a 2-part trial. The first is a phase I trial of unilateral injection of MSCs into the submandibular gland of 6 patients to demonstrate safety. The second part is a phase I dose escalation study with a 3+3 design with staggered enrollment. A total of 21-30 subjects (9-18 in phase I study, 12 in expansion cohort) will be enrolled. The primary endpoint is determining the recommended phase 2 dose (RP2D) of interferon gamma stimulated BM-MSCs in order to conduct further studies on the efficacy of BM-MSCs. Patients will have their bone marrow aspirated, BM-MSCs expanded and stimulated with IFNγ, and then injected into the submandibular gland. The RP2D will be determined by dose limiting toxicities occurring within one month of BM-MSC injection. Secondary outcomes of salivary amounts, composition, ultrasound of salivary glands, and quality of life surveys will be taken at 3, 6, 12, and 24 month visits. Recruiting will start January 3, 2022. Subject accrual will occur over 2.5 years with the total duration of the trial expected to be approximately 4.5 years. Autotransplantation of IFNγ-stimulated BM-MSCs in salivary glands post-radiation may provide an innovative remedy to treat xerostomia and restore quality of life." @default.
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• W4220802064 date "2022-04-01" @default.
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• W4220802064 title "Marrow Derived Autologous Stromal Cells for the Restoration of Salivary Hypofunction (MARSH): Study Protocol for a Phase I Dose Escalation Trial of Patients with Xerostomia after Radiation Therapy for Head and Neck Cancer" @default.
• W4220802064 doi "https://doi.org/10.1016/j.ijrobp.2021.12.146" @default.
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