The first go-to approach would be to use engineered Oncotropic (or oncolytic) viruses (OVs) for tumour targeting.
Naturally, oncolytic viruses are selective for tumours. OVs like bovine Herpes simplex virus -1 (HSV-1), reovirus, parvovirus, and vesicular stomatitis virus (VSV) have an inherent capacity for oncotropism, i.e selective infection of cancerous cells. Both DNA and RNA viruses with oncolytic abilities have been identified, and the choice of which one to use completely depends on our end goal. If we want high genome stability and replication, oncolytic DNA viruses are suggested. However, if the goal is to induce a more immunogenic response, oncolytic RNA viruses are better candidates.
OVs engineering to specifically target cancer cells and not normal cells
a) The best way to use an engineered OV would be to engineer it to target tumor cells and tumor-associated stromal elements, while detargeting normal, non-tumor cells. Complex mosaic systems designed by modifying adenovirus vectors to contain hybrid fibers has been shown to target tumor cell population. In vivo, when the fiber modification was supplemented with pan-cancer ligand, specific targeting was attained in different cancer cells .
b) Another trick for selective targeting is to inhibit replication of the virus in normal cells by deleting genes that are functionally active in normal but defective in cancer cells (genes in tumor suppressor pathway). This makes it possible for the virus to replicate only in tumor cells. In fact, this is the mechanism used by T-VEC, the only approved OV based cancer treatment to date. T-VEC contains an HSV-1 backbone in which RL1, the gene encoding cell protein ICP34.5, is deleted. The protein ICP34.5 is a rescue mechanism for viral replication in normal cells where interferon responses inhibit viral replication. However, since tumor cells lack efficient interferon responses, the deletion of 34.5 gene effectively rescues the virus and it can easily replicate in the cancerous cells .
c) Substituting/inserting proteins from other viruses for tumour targeting. In one study, the researchers engineered a chimeric VSV that lacks its natural neurotoxicity yet retains the potent oncolytic activity. The envelope glycoprotein G of VSV was replaced with another glycoprotein of lumphocytic choriomeningitis virus (LCMV). This modified virus was found to effectively eliminate brain cancer while remaining benign in the normal brain, as seen in preclinical in vivo models .
Similarly, when thymidine kinase (TK) gene in HSV-1 was modified in HSV-1 and VACV, it allowed for selective replication in cancer cells .
Given we have correctly engineered the OV, how do we ensure it spreads efficiently?
For tumour-targeted viral infection, the spread of the virus needs to be efficient. Generally, extracellular matrix (ECM) that is composed of hyaluronic acid and collagen serves as a physical barrier that can prevent the engineered virus from penetrating and spreading within the tumor tissue. To overcome this stromal barrier, different strategies have been suggested. For instance, ECM-degrading protein like relaxin can be used. Oncolytic adenovirus with relaxin expression degraded fibrotic ECM in pancreatic cancer and enhanced tumor penentration .
Another protein that can be used to degrade ECM components is decorin, a proteoglycan. Decorin expressing adenovirus was found to enhance tissue penetration. Decorin acts via different mechanisms: by decreasing collagen fibril diameter, by inhibiting transforming growth factor-beta (TGF-B), and by promoting matrix metalloproteinase-1 activity. For solid tumours, the protein VCN-01 has shown improved targeting and efficacy.
mschiav3 Apr 11, 2022
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