Enhancing the bystander killing effect of an oncolytic HSV by arming it with a secretable apoptosis activator

• Published in: Gene therapy Vol. 22; no. 3; pp. 237 - 246
• Main Authors: Loya, S M W, Zhang, X
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2015; Nature Publishing Group
• Subjects: 42; 42/41; 631/154/51/201; Analysis; Animals; Antibodies; Antibodies - genetics; Antibodies - metabolism; Apoptosis; Biomedical and Life Sciences; Biomedicine; Breast cancer; Bystander Effect; Cancer; Care and treatment; Caspase; Cell Biology; Cell Line, Tumor; Cell viability; Cercopithecus aethiops; Clinical trials; Collagen; Epidermal growth factor; ErbB-2 protein; Fas Ligand Protein - genetics; Fas Ligand Protein - metabolism; FasL protein; Gene Expression; Gene Therapy; Genomes; Genomics; Health aspects; Herpes simplex; Herpes simplex virus; Herpes viruses; Herpesvirus 1, Human - genetics; Herpesvirus 1, Human - metabolism; Herpesvirus 2, Human - genetics; Herpesvirus 2, Human - metabolism; Herpesvirus infections; Heterografts; Human Genetics; Humans; Immunotherapy; Mammary gland; Medical schools; Methods; Mice; Nanotechnology; Oncolysis; Oncolytic viral therapy; Oncolytic Virotherapy - methods; Oncolytic Viruses - genetics; Oncolytic Viruses - metabolism; original-article; Receptor, ErbB-2 - immunology; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Therapeutics; Tumors; Viruses
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2014.113

Although oncolytic viruses have shown great promise as cancer therapeutics, results from a recent phase III clinical trial indicate that their potency may need further improvement for a clear clinical benefit. Here, we report a novel strategy to increase the bystander effect of virotherapy by arming an oncolytic virus with a secreted form of a Her2 single chain antibody linked to a self-multimerizing Fas ligand extracellular domain (Her2-COL-sFasL). The rationale is that, due to its much smaller size, this apoptosis activator can overcome obstacles such as the dense collagen in the tumor tissues to spread more freely than the viral particles. When measured in vitro , Her2-COL-sFasL was found to efficiently induce caspase cleavage, resulting in an 80% reduction in cell viability. Once incorporated into the genome of an oncolytic type 2 herpes simplex virus, FusOn-H3, Her2-COL-sFasL potentiates the therapeutic efficacy of the virus in an aggressive syngeneic mammary tumor model. Our data suggest that arming an oncolytic virus with a secretable and self-multimerizing apoptosis inducer is a feasible strategy to improve the potency of virotherapy.