Bioengineering of G47Δ HSV-1 Combined with Stem Cell Delivery as an Alternative Virotherapy against Colon Cancer

Abstract

Oncolytic virus (OV) therapy is a recently developed strategy in cancer treatment, especially towards patients who are unresponsive to conventional therapies. Numerous viruses have been identified efficiently lysing tumor cells both in vitro and in vivo and eliciting anti-tumor immunity, including but not limited to Herpes Simplex Virus (HSV), adenovirus, and Newcastle Disease Virus (NDV). However, there are some caveats with present OV therapies. The delivery of the virus to the human body and its replication before immune response are essential to the effectiveness of the therapy. Therefore, to maximize the efficacy of existing OV therapies, we propose a hypothetical herpes simplex virus (HSV)-based OV which combines several engineered traits to tackle colon cancer. The re-designed virus conceivably limits HSV neutralization by preexisting antibodies. It is also conceivable that the engineered oncolytic virus can secrete chimeric molecules that specifically bind to colon cancer cells. Also, we aim to activate neoantigen-specific T cell responses through the synergy of PD-L1 inhibition, GM-CSF activation, and viral immunogenic oncolysis. We hypothesize that a combination of OV therapies with the usage of mesenchymal stem cells (MSCs) as carriers could enhance the overall efficacy in tumor cell targeting and systemic immune response stimulation. MSC delivery is likely to aid in the migration of the engineered OV to tumor sites. In summary, the modifications of HSV enable more effective injection of oncolytic viruses and more accurate binding with tumors, improving therapeutic outcomes of existing HSV-based immunotherapies.