Herpes simplex virus (HSV) is among the most promising platforms for solid tumors because of its efficient entry and spread into a wide range of cell types and its ability to accommodate expression cassettes for multiple or very large foreign genes that can provide therapeutic functions.
Description
The most challenging, yet essential aspect of these strategies is the development of virus vectors that exclusively infect the cell population of interest. The University of Pittsburgh researchers utilized these to deliver oncolytic virotherapy to cancer cells. Identifying mutations to simplex virus allows us to target cancer cells while sparing healthy cells. The resultant triggering of NK (natural killer) immune response to a cancer cell induces cytolysis.
Advantages
Mutations can be tailored to the target cell to improve specificity and thereby reducing “off-target” infection. Identifying HSV mutations allows targeting cancer cells while sparing healthy cells. Previous strategies have involved infection of cancer cells with HSV and replication of the virus leading to cell death (oncolytic viruses). However, poor replication efficiency of oncolytic viruses, along with “off-target” infection and associated side effects limits the use of this strategy. Conditionally replicating HSV vectors, including mutants deleted for the neurovirulence factor ICP34.5 currently in clinical trials, have been designed to replicate uniquely in tumor cells, but not in normal cells; this group also includes vectors that use cell- or tumor-specific promoters to express essential replication functions. The University of Pittsburgh researchers demonstrated how to take mutated HSV vectors and design them to deliver therapeutic agents directly to cancer cells, including ligands to promote recognition by NK cells and induce cytolysis. Using engineered tumor-targeted glycoproteins on HSV that are mutagenized to prevent recognition of the normal viral receptors, it is possible to specifically infect cancer cells through designed virus recognition of cancer cell-related receptors and furthermore, the virus expressed NK activating ligands are limited to tumor cells since their expression is blocked in normal cells by selective inhibition by normal cell microRNAs that are not present in tumor cells. This combination of tumor targeting and NK activating products create a highly lytic and safe oHSV product.
Invention Readiness
In vivo work has demonstrated how mutated HSV vectors can infect cancer cells and induce NK mediated cytotoxicity.
IP Status
https://patents.google.com/patent/US10201575B2
