Increased oncolytic efficacy for high-grade gliomas by optimal integration of ionizing radiation into the replicative cycle of HSV-1

Abstract

Oncolytic viruses have been combined with standard cancer therapies to increase therapeutic efficacy. Given the sequential activation of herpes viral genes (herpes simplex virus-1, HSV-1) and the temporal cellular changes induced by ionizing radiation, we hypothesized an optimal temporal sequence existed in combining oncolytic HSV-1 with ionizing radiation. Murine U-87 glioma xenografts were injected with luciferase encoding HSV-1, and ionizing radiation (IR) was given at times before or after viral injection. HSV-1 replication and tumor-volume response were followed. Radiation given 6-9 h after HSV-1 injection resulted in maximal viral luciferase expression and infectious viral production in tumor xenografts. The greatest xenograft regression was also seen with radiation given 6 h after viral injection. We then tested if HSV-1 replication had a dose response to ionizing radiation. HSV-1 luciferase expression exhibited a dose response as xenografts were irradiated from 0 to 5 Gy. There was no difference in viral luciferase expression as IR dose increased from 5 Gy up to 20 Gy. These results suggest that the interaction of IR with the HSV-1 lytic cycle can be manipulated for therapeutic gain by delivering IR at a specific time within viral replicative cycle.

Association of genetic variants in the CART gene with glioma susceptibility in a Chinese population

“…Except that exposure to ionizing radiation has been established as a risk factor, most underlying cause for gliomas has not been identified [26][27][28][29][30]. Genetic factors, which have been explored for many decades, play an essential roles in the development of gliomas and are key component of preventive oncology, however, only a small proportion of the genetic effect has been yet established [1,14,[31][32][33][34].…”

Exploring the antitumor effect of virus in malignant glioma

“…For example, combining oHSV with current standard-of-care ionizing radiation (33), TMZ (34, 35), or anti-angiogenic inhibitors (36), or P13K/Akt pathway inhibitors (37) significantly enhanced anti-glioma efficacy in preclinical glioma models (31, 38). These provide the rationale for translating similar combinations to the clinic.…”

Oncolytic herpes simplex virus-based strategies: toward a breakthrough in glioblastoma therapy

“…When combined with IR, γ34.5 mutant oHSV resulted in increased viral replication and anti-tumor effects in murine glioma models (Advani et al, 1998). Advani et al used γ34.5-deleted HSV-1 carrying a late promoter driven luciferase in U87 glioma xenografts and administered IR before or after viral injection to determine optimal temporal sequencing (Advani et al, 2011). Delivering radiation 6–9 h after oHSV injection, i.e., coinciding with the onset of late viral gene expression, resulted in the greatest luciferase expression, infectious virus production, and tumor-xenograft regression (Advani et al, 2011).…”

“…Advani et al used γ34.5-deleted HSV-1 carrying a late promoter driven luciferase in U87 glioma xenografts and administered IR before or after viral injection to determine optimal temporal sequencing (Advani et al, 2011). Delivering radiation 6–9 h after oHSV injection, i.e., coinciding with the onset of late viral gene expression, resulted in the greatest luciferase expression, infectious virus production, and tumor-xenograft regression (Advani et al, 2011). Therefore, when combined with oHSV, IR administration at an optimal time during the HSV replicative cycle may maximize the combination effect.…”