Cellular effects of oncolytic viral therapy on the glioblastoma microenvironment

Abstract

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.

Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer

“…53 Some oncolytic herpes viruses reduce apoptosis; 45,46,54 whereas others enhance apoptosis. 43,44,47 The effect of oncolytic herpes viruses on apoptosis is strain specific and depends on the underlying genetic variation. Defects in the US3 arm or gamma 34.5 may induce apoptosis in infected cells; this may explain why gamma 34.5 deleted viruses such as G207 induce apoptosis.…”

“…[39][40][41][42] The effects of oncolytic herpes viruses on apoptosis are controversial: apoptosis is elevated upon viral treatment in some studies, 43,44 but reduced in others. 45,46 Some have argued that induction of premature apoptosis is not a desirable feature of oncolytic viral treatment; 47 instead, reducing or delaying apoptosis may enhance viral penetration of the tumor, another determinant of the potency of an oncolytic virus.…”

Preclinical Evaluation of a Genetically Engineered Herpes Simplex Virus Expressing Interleukin-12

“…The ␥ 1 34.5-deleted HSV G207, which also contains an inactivating insertion of lacZ within the U L 39 gene encoding ICP6 (ribonucleotide reductase heavy chain), has demonstrated efficacy in vivo against brain tumors in a number of syngeneic and xenogeneic models of GBM (1,2,15,16,34), neuroblastoma (52,53,55), and meningioma (59). The similar virus HSV1716 is also deleted for ␥ 1 34.5 but retains the U L 39 gene (26,32) and has demonstrated efficacy in two different brain tumor models (19,24).…”

Herpes Simplex Type 1 for Use in Cancer Gene Therapy: Looking Backward to Move Forward

“…This effect can be countered through the administration of thrombospondin-derived peptides. In models of glioblastoma, cases where oncolytic virus infection results in an anti-angiogenic response, adjacent virus-free areas have been shown to upregulate angiogenesis (Huszthy et al, 2010). Furthermore, increases in tumor angiogenesis can facilitate virus-induced inflammatory responses.…”