Abstract 3152: IFN-gamma stimulated cryopreserved mesenchymal stromal cells for treatment of radiation induced xerostomia

Abstract

Abstract Purpose/Objectives: There is a critical need for a treatment that will safely and effectively alleviate radiation-induced xerostomia (RIX). Head and neck radiation results in hyposalivation and altered sialochemistry which patients experience as xerostomia. We performed a preclinical and a pilot clinical study to determine if IFN-ɣ stimulated marrow-derived mesenchymal stromal cells (MSC(M)) from HNC patients could function as a source of autologous cells for the treatment of RIX and as a tool in preclinical murine studies of RIX. Materials/Methods: Bone marrow aspirates from HNC patients previously treated with chemoradiation were obtained (IRB #2019-0497, NCT 04007081). MSC(M)s were isolated from bone marrow. MSC(M) were expanded in culture, surface marker expression was confirmed via flow cytometry, stimulated with IFN-ɣ, and cryopreserved. Thawed MSC(M)s were profiled to evaluate their functionality after cryorecovery. Cells were tested for their ability to stimulate salivary production in a murine model of RIX by injecting 1x106 cells into the submandibular gland (SMG) one week after a single 15 Gy fraction of radiation. Efficacy was evaluated by saliva production and histology. Results: MSC(M)s from six patients were expanded to >20x106 cells (median 15.5, range of 8-20 days). Post-thaw cultures demonstrated robust growth, with a median doubling time of 3.1 days. Cultured cells showed an MSC(M) phenotype, positive for CD73, CD90, and CD105 and negative for CD14, CD20, CD34, or CD45. IFN-ɣ stimulated MSC(M)s had immunomodulatory potential based on increased expression of IDO, ICAM-1, PD-L1, MHC I and MHC II expression compared with non-stimulated MSC(M)s (391%, 263%, 114%, 70% and 196% percent increase respectively). In a murine model of RIX, radiation resulted in structural changes to the gland as evidenced by increased fibrosis, decreased acinar size, and immune cell infiltration. Injection of MSC(M)s to the SMG following radiation resulted in improved saliva production, a reduction in fibrosis, and an increase in the size and density of acini within the tissue compared to control. Conclusions: These data strongly support the feasibility of a first-in-human clinical trial of autologous IFN-ɣ stimulated MSC(M)s to treat RIX and the potential of using human-derived MSC(M)s in future murine studies of RIX. Citation Format: Cristina Paz, Grace Blitzer, Annemarie Glassey, Kwangok P. Nickel, Jayeeta Giri, Andrea Pennati, Daniel Robbins, Tadeas Lunga, Susan Thibeault, Jacques Galipeau, Randall Kimple. IFN-gamma stimulated cryopreserved mesenchymal stromal cells for treatment of radiation induced xerostomia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3152.