Oncolytic Herpes Simplex Virus type 1 armed with CXCL12-antagonist “P2G” to impair glioblastoma stem-like cells self-renewal and migration

Glioblastoma is an aggressive high-grade astrocytoma. Current standard treatments consist of maximal surgical resection followed by chemo-/radio- therapy. Unfortunately, this treatment protocol is impaired by incomplete resections and systematic relapses often leading to poor prognoses. Migration of CXCR4+ glioblastoma stem-like cells (GSCs) from the tumor mass to the sub-ventricular zone (SVZ), following a CXCL12 gradient, participates to the disease progression. When hidden in the SVZ niche, GSCs evade resection and become resistant to radio-/chemo- therapy. High expression of CXCR4 positively correlates with tumor progression, recurrence, and low patient survival. Thus, GSCs and CXCL12/CXCR4 pathway appear as interesting targets for new therapies against glioblastoma growth, invasion of brain tissues and recurrence.
In this context, we have developed an attenuated oncolytic HSV-1 (oHSV) expressing a specific CXCL12/CXCR4 pathway inhibitor (oHSV-P2G) that leads to a continuous production of the inhibitor at the tumor site. oHSV-P2G is expected to cause tumor cell lysis and to disrupt CXCL12/CXCR4 pathway, thereby interfering with GSCs self-renewal ability and preventing their migration towards the SVZ. This could facilitate maximal resection, reduce tumor size and probability of relapse, and increase overall survival.
Our results showed that in vitro, neural stem markers expression, self-renewal and migration abilities of both murine and human GSCs are impaired upon treatment. Moreover, in an in vivo orthotopic immunodeficient mice model, tumor cells migration towards the SVZ was shown to be reduced. Future experiments will focus on combined treatments in which oHSV-P2G will be administered with chemo-/radio- therapy to show potential sensitization of radioresistant GSCs.