Olfactory Ensheathing Glia As A Cell-Based Therapy For Glioblastomas.

Abstract Introduction: Olfactory ensheathing glia (OEG) is a fully differentiated cell that promotes the continuous regeneration of odor receptors from the nasal mucosa to the olfactory bulb during adult lifespan. OEG secretes several factors making the environment more permissive to regeneration, and promotes differentitation of progenitor/neural stem cells. Recently, our group showed for the first time that OEG can target glioblastoma (GBM) cells and GBM stem-like cells (GSC) in the mice brain via intranasal delivery, the natural route of OEG to the brain. Here, we test the potential of OEG in inhibiting the proliferation and stemness of GSC, leading to their differentiation (similar to their neural stem cells counterpart), making them susceptible to conventional therapy. Methods: OEG derived from mice OB (1.5e+5 cells) were co-cultured with GSC at 1:1 ratio. We used a dual secreted luciferase reporter that can be multiplexed together to monitor both OEG and GSCs viability and proliferation in the same well. For in vivo analysis, mice-bearing patient-derived xenograft GSCs were treated with a single injection of 1e+5 OEG intranasally or control. One week later, each group was subdivided into two groups which either received ionizing radiation (IR, one dose of 4Gy) or control. Results: GSC or their corresponding differentiated glioma cells (cultured in serum for 10 days) displayed a decrease in cell viability when co-cultured with OEG compared to control. Analysis of mRNA levels and immunofluorescence images from these co-cultures (using a Transwell) showed a significant decrease in markers associated with stemness and aggressiveness, and an increase in both neuronal and astrocytic markers compared to control. When assessed tumor formation, GSC cultured with OEG conditioned media (OEGCM) failed to form tumors and became more susceptible to IR and Temozolomide. In mice bearing PDX, intranasal injection of non-modified OEG lead to inhibition of tumor growth prolonged mouse survival (48 days vs 34 days for control; P<0.0001). IR had a modest effect on this model (38 days; P<0.005 vs control). The combination of a single OEG injection and IR had the most therapeutic effect on tumor growth and animal survival (54 days; P<0.0001 vs control). Conclusion: Our findings show that OEG inhibits GBM stemness and malignancy, induces differentiation of GSCs, making them prone to conventional therapy. OEG have the advantage over other typical cell therapies since they are terminally differentiated and can be easily obtained from the olfactory mucosa, a simple procedure typically done for patients with spinal cord injury allowing autologous transplantation. Citation Format: Litia Carvalho, Renata Fleming, Gulsah Erel-Akbaba, Ghazal Lashgari, Daniel Ryan, Elie Tabet, Max Zinter, Jian Teng, Bakhos Tannous. Olfactory ensheathing glia as a cell-based therapy for glioblastomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3114.