Oncolysis Using Herpes Simplex Virus Type 1 Engineered to Express Cytosine Deaminase and a Fusogenic Glycoprotein for Head and Neck Squamous Cell Carcinoma

Abstract

Background A replication-competent, attenuated, oncolytic herpes simplex virus-1, OncoVEXGALV/CD, has previously been engineered to express a fusogenic protein from the gibbon ape leukemia virus and cytosine deaminase/uracil phosphoribosyltransferase (CD/UPRT) which converts fluorocytosine (5-FC) to 5-fluorouracil (5-FU). OncoVEXGFP is an analogous vector that expresses enhanced green fluorescent protein. Methods We assessed the ability of OncoVEXGALV/CD and OncoVEXGFP to infect, replicate within, and lyse four head and neck squamous carcinoma (HNSCC) cell lines in vitro. The effects of adding 5-FC with OncoVEXGALV/CD were evaluated. Results HNSCC was permissive to GFP expression in100% of cells by OncoVEXGFP at a multiplicity of infection (MOI) of 1 after 48 hours, and supported logarithmic viral replication. Virus caused >60% cell death six days after exposure to virus at MOI 0.1 in three of the four cell lines. 5-FC failed to enhance cytotoxicity induced by OncoVEXGALV/CD at MOI 0.1. However, for the least sensitive SCC25 cell line, virus at MOI 0.01 was cytotoxic to only 4% of cells after six days, but was cytotoxic to 35% of cells with 5-FC. Conclusions OncoVEXGALV/CD efficiently infects, replicates within and lyses HNSCC at relatively low viral doses. Prodrug conversion by CD did not enhance therapy at viral doses which cause efficient cytotoxicity, but may have beneficial effects in less sensitive cell lines at low viral doses.

Combination of a fusogenic glycoprotein, pro-drug activation and oncolytic HSV as an intravesical therapy for superficial bladder cancer

“…In our study, we have shown that this viral-based triple therapy offers a novel approach to intravesical treatment of bladder cancer. Our choice of an oncolytic HSV, based on experience with Oncovex GALV/CD , has been found to be effective in treating various experimental cancers while maintaining an excellent safety profile ( Simpson et al , 2006 ; Price et al , 2010 ; Wong et al , 2010 ).…”

Advanced progress in the genetic modification of the oncolytic HSV-1 virus

“…GADD34 is homologous to γ134.5; like MyD116, it can substitute for γ134.5 to restore viral replication in glioblastoma and breast cancer cells, enhancing selective cytotoxicity ( 82 , 83 ). The Gibbon leukemia virus fusion glycoprotein (GALV-GP) increases the efficiency of viral vector entry while inducing cell fusion, significantly boosting tumor cell death in vitro and promoting tumor shrinkage in vivo ( 84 , 85 ). The Nestin promoter drives selective replication in glioma cells, enhancing glioma suppression when combined with cyclophosphamide ( 86 , 87 ).…”

Oncolytic HSV Vectors and Anti-Tumor Immunity

“…The large payload capacity of some oHSVs (Mazzacurati et al, 2015), approximately 25 kb, allows combinations of arming genes to be introduced into a single vector, but the most effective combinations have yet to be determined. Replimune, Inc., a company funded by the T-VEC developers, is leading the way with the progression in clinical trials of a first oHSV expressing the fusogenic protein GALV (Fu et al, 2003;Price et al, 2010;Thomas et al, 2019), in addition to GM-CSF, and a second oHSV candidate in addition expressing a CTLA-4 antagonist antibody.…”