Targeted Oncolytic Herpes Simplex Viruses for Aggressive Cancers
2012
Herpes simplex virus (HSV) is a well-known vector that is often used for gene therapy to treat cancers. The
most attractive feature of HSV is its ability to destroy tumors through a distinctive oncolytic mechanism where the virus
can destroy cancer cells via cell lysis, a killing function that no anti-cancer drugs can mimic. Importantly, HSV is a safe
and effective virus that can be easily manipulated to preferentially replicate in tumor cells. In the last 20 years of reengineering
efforts, a number of HSV designs, including the classical G207, have been focused on deleting viral genes in
order to render the virus tumor specific. Although such designs can successfully destroy tumor xenografts in animal models,
with minimal impact on normal tissues, a common trade-off is the marked attenuation of the virus. This problem is
most profound in many clinical tumors, where virus dissemination is often hindered by the difficult cellular and molecular
terrain of the human tumor mass. In order to harness all of HSV’s replication potential to destroy tumor cells, efforts in
our lab, as well as others, last several years have been focused on engineering an oncolytic HSV to target tumor cells
without deleting any viral genes, and have since generated highly tumor specific viruses including our transcriptional
translational dually regulated HSV (TTDR-HSV). In this review, we will discuss the improvements associated with the
newer TTDR-HSV design compared to the classical defective HSV designs such as G207 and tk- HSV. Lastly, we will
review additional cellular features of aggressive tumors, such as their immense cellular heterogeneity and volatility, which
may serve to hinder the dissemintation of TTDR-HSV. The challenge for future studies would be to explore how TTDRHSV
could be redesigned and/or employed with combinatorial approaches to better target and destroy the heterogeneous
and dynamic cell populations in the aggressive tumor mass.
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