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Longitudinal analysis of glioblastoma response to oncolytic HSV1 guides PLX3397 combination for enhanced viral permissiveness

Ito, H.; Shono, N.; Zagami, C.; Kim, M. J.; Quazim, A. A.; McLaughlin, E.; Goins, W. F.; Fernandez, S.; Chiocca, E. A.; Nakashima, H.

2024-09-21 bioengineering
10.1101/2024.09.17.613527 bioRxiv
Show abstract

Clinical trial data underscores the need to improve oncolytic virus (OV) distribution within tumors, a challenge compounded by the lack of predictive biomarkers and limited opportunities for post-treatment analysis. To decipher the factors influencing treatment outcomes, we employed multimodal bioluminescence imaging (MM-BLI) in conjunction with magnetic resonance imaging (MRI) to monitor OV infection, replication, and tumor viability in orthotopic brain glioma mouse models. This approach revealed two distinct therapeutic responses: "Responders" with tumor regression and "Non-Responders" with tumor progression. In-depth analysis of individual brains from both groups uncovered dynamic interactions between the OV and the tumor microenvironment, highlighting the involvement of Iba-1+ microglia and tumor necrosis in hindering OV distribution within the tumor. To address this, we incorporated a CSF-1 receptor inhibitor (PLX3397), which improved tumor control by enhancing OVs direct cytopathic effects and reducing microglial interference. Our findings highlight microglia as a significant barrier to effective OV therapy, suggesting that targeting brain-resident immune cells could enhance the therapeutic efficacy of OVs in resistant brain tumors.

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