Cellular effects of oncolytic viral therapy on the glioblastoma microenvironment

• Published in: Gene therapy Vol. 17; no. 2; pp. 202 - 216
• Main Authors: Huszthy, P C, Immervoll, H, Wang, J, Goplen, D, Miletic, H, Eide, G E, Bjerkvig, R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-02-2010; Nature Publishing Group
• Subjects: Ageing, cell death; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Apoptosis; Applied cell therapy and gene therapy; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Biotechnology; Blood vessels; Brain cancer; Brain Neoplasms - blood supply; Brain Neoplasms - therapy; Care and treatment; Cell Biology; Cell Death; Cell Line, Tumor; Cell physiology; Cell proliferation; Cells; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene Therapy; Genetic aspects; Genetic Vectors; Glioblastoma; Glioblastoma - blood supply; Glioblastoma - therapy; Glioblastoma multiforme; Health aspects; Health. Pharmaceutical industry; Herpes simplex; Herpes simplex virus 1; Herpesvirus 1, Human - genetics; Human Genetics; Humans; Industrial applications and implications. Economical aspects; Inflammation; Lesions; Magnetic resonance imaging; Medical sciences; Metastases; Mice; Mice, Nude; Molecular and cellular biology; Nanotechnology; Neoplasm Transplantation; Oncolysis; Oncolytic Virotherapy - methods; original-article; Plaques; Replication; Therapy; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Tumor microenvironment; Tumors; Viral infections; Virus Replication; Xenografts; Norway; microvessel density; oncolytic herpes viral vector; G207; apoptotic index; proliferation index; glioblastoma xenograft; Cell proliferation; Nervous system diseases; Recombinant virus; Glioblastoma; Herpes; Index; Malignant tumor; Heterograft; Density; Infection; Malignant glioma; Microcirculation; Viral disease; Central nervous system disease; Gene therapy; Cancer; Apoptosis
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2009.130

The objective of the present study was to evaluate the cellular effects of the oncolytic HSV-1 based vector, G207, on the tumor microenvironment. We established progressively growing intracerebral xenografts in athymic nude rats generated from three different human GBM surgical specimens. The lesions were identified by MRI and subsequently injected with a concentrated vector stock. The animals were killed 10 or 30 days after G207 injection and the tumors were quantitatively evaluated for virus-induced changes in proliferation, apoptosis and vascularity. Moreover, we assessed vector spread as well as the infiltration pattern of CD68-positive inflammatory cells. In all G207-injected lesions, immunostaining identified widespread regions of viral infection and replication (plaques). Proliferation indices were significantly lower, whereas apoptotic counts were significantly elevated in plaques as compared with that in non-infected areas of the same lesions, as well as in corresponding control xenografts. Furthermore, there was a significant decline in the number of blood vessels in the plaques and the vascular area fractions were reduced. CD68-positive inflammatory cells accumulated in the plaques. The present study highlights the favorable cellular responses to G207 treatment seen from a clinical viewpoint, such as reduced tumor cell proliferation, more frequent events of tumor cell death and a strongly attenuated tumor vascular compartment. However, our results suggest that transduction of a significant volume of tumor tissue is essential, as these beneficial changes were only observed in areas of active viral replication, leaving non-transduced tumor tissues unaffected.