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An oncolytic HSV-1 vector induces a therapeutic adaptive immune response against glioblastoma.

Authors :
Reale, Alberto
Gatta, Andrea
Shaik, Amruth Kaleem Basha
Shallak, Mariam
Chiaravalli, Anna Maria
Cerati, Michele
Zaccaria, Martina
La Rosa, Stefano
Calistri, Arianna
Accolla, Roberto Sergio
Forlani, Greta
Source :
Journal of Translational Medicine. 9/27/2024, Vol. 22 Issue 1, p1-13. 13p.
Publication Year :
2024

Abstract

Background: Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults with the lowest survival rates five years post-diagnosis. Oncolytic viruses (OVs) selectively target and damage cancer cells, and for this reason they are being investigated as new therapeutic tools also against GBM. Methods: An oncolytic herpes simplex virus type 1 (oHSV-1) with deletions in the γ34.5 neurovirulence gene and the US12 gene, expressing enhanced green fluorescent protein (EGFP-oHSV-1) as reporter gene was generated and tested for its capacity to infect and kill the murine GL261 glioblastoma (GBM) cell line. Syngeneic mice were orthotopically injected with GL261cells. Seven days post-implantation, EGFP-oHSV-1 was administered intratumorally. Twenty-one days after parental tumor challenge in the opposite brain hemisphere, mice were sacrified and their brains were analysed by immunohistochemistry to assess tumor presence and cell infiltrate. Results: oHSV-1 replicates and induces cell death of GL261 cells in vitro. A single intracranial injection of EGFP-oHSV-1 in established GL261 tumors significantly prolongs survival in all treated mice compared to placebo treatment. Notably, 45% of treated mice became long-term survivors, and rejected GL261 cells upon rechallenge in the contralateral brain hemisphere, indicating an anamnestic antitumoral immune response. Post-mortem analysis revealed a profound modification of the tumor microenvironment with increased infiltration of CD4 + and CD8 + T lymphocytes, intertumoral vascular collapse and activation and redistribution of macrophage, microglia, and astroglia in the tumor area, with the formation of intense fibrotic tissue suggestive of complete rejection in long-term survivor mice. Conclusions: EGFP-oHSV1 demonstrates potent antitumoral activity in an immunocompetent GBM model as a monotherapy, resulting from direct cell killing combined with the stimulation of a protective adaptive immune response. These results open the way to possible application of our strategy in clinical setting. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
14795876
Volume :
22
Issue :
1
Database :
Academic Search Index
Journal :
Journal of Translational Medicine
Publication Type :
Academic Journal
Accession number :
179969318
Full Text :
https://doi.org/10.1186/s12967-024-05650-5