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.

Bugs and Drugs: Oncolytic Virotherapy in Combination with Chemotherapy

“…In animal models, tumor growth was reduced significantly in groups treated with M012 and 5-FC when compared to groups treated with the parental (unarmed) virus and drug [191]. Another oncolytic HSV-1 armed with CD, OncoVEX(GALV/CD), showed enhanced cytotoxic effects in vitro when used in combination with 5-FC in head and neck squamous carcinoma cell lines that were less susceptible to the oncolytic effects of the virus [192]. An armed VSV expressing a CD/UPRT fusion gene combined with 5-FC also reported enhancement of cell killing and a considerable bystander effect in vitro .…”

“…Other armed viruses expressing other therapeutic genes such as second mitochondria derived activator of caspases (Smac) [196], manganese superoxide dismutase (MnSOD) [197] and even viral fusion proteins by themselves or along with the CD transgene [192, 198], have also been tested in combination with 5-FU chemotherapy and shown to be effective. Combination of two GEPT systems has also been reported.…”

Stem Cell Research for the Treatment of Malignant Glioma

“…A phase II clinical trial for patients with unresectable metastatic melanoma showed 26% response rate [60]. Moreover, a phase III clinical trial showed significant prolonged overall survival for unresectable metastatic melanoma [27,54].…”

Oncolytic activity of HF10 in head and neck squamous cell carcinomas

“…Before these clinical trials, mouse models were used to investigate oncolytic activity. Most previous preclinical studies used human HNSCC cell lines implanted into the flank of immunodeficient mice [13][14][15][16][17][18][19][20][21], or murine SCC-VII cells [22][23][24][25]; however, they did not investigate the immune response. Furthermore, no study to date has used primarycultured cells obtained from surgical specimens.…”