Tuesday, May 13, 2014

VSV Variants as the "Perfect" Oncolytic Virus?

This post is going to be a continuation from my previous post. I received some very insightful comments challenging me to look further into the use of virus particles and variants as means of ridding the body of cancerous cells. The idea that researchers have been injecting live virus variants into animals, in this case mice, and these variants have been successful at killing off tumor cells is encouraging to the world of cancer research (Ref. 4). However there are a few caveats that even the paper’s authors recognize and explore.
To begin, I shall explain the basics of using oncolytic viruses to treat cancer. Oncolytic viruses are described as “tumor-selective, multi-mechanistic antitumor agents who kill infected cancer and associated endothelial cells via direct oncolysis…” (Ref. 1) Another definition further describes the oncolytic virus’ role in activating the immune system’s response: “As the infected cancer cells are destroyed by lysis, they release new infectious virus particles to help destroy the remaining tumor. Oncolytic viruses are thought not only to cause direct destruction of the tumor cells, but also to stimulate host anti-tumor immune responses” (Ref. 3) Through various tests, it has been shown that virus variants, and I will explain the difference between wild type and variant viruses in the following paragraph, have shown major success in ridding mice of various tumor types.
The virus that was used in this paper and in all the experiments reported by the paper was vesicular stomatitis virus (VSV) which is a “potent oncolytic virus”. There are two naturally occurring variants of VSV which are AV1 and AV2. They created by one (M51R) and two (V221F and S226R) amino acid substitutions, respectively. A third variant was synthesized by researchers that is very similar to AV1 except that instead of this amino acid substitution methionine 51 was deleted entirely (Ref. 4). This was for the purpose of making it extremely unlikely for the variant to revert back to its wild type state. The benefit to using VSV, according to researchers is that growth of the virus is strongly inhibited by IFN (Ref. 4).
Injecting prophylactic IFN into mice before using VSV to attempt to treat their tumors has been shown to fully recover even immunocompromised mice from cancer. This being said, there are always dangers associated with live virus use, even with the deletion of methionine as a way to prevent reverting to the dangerous wild type. Another problem presents itself in the form of absence of an IFN receptor. Results show that without an IFN receptor, to activate the necessary immune response by the body to these virus variants, the AV1 and AV2 variants can be as toxic to the body as the wild type virus (Ref. 4). In this situation, no amount of prophylactic IFN will prevent a live virus from ravaging an already immunocompromised body, because there will be no receptors to bind the interferon. The risk one is assuming with treatment by virus variants could be devastatingly huge, however how to the benefits compare?

Figure 1. Results from in vivo experiments showing toxicity of AV1 and AV2 in mouse cells as mediated by interferon.

            As illustrated in the results of these tests on IFN responsiveness from the body, the variant AV3 induced IFN-α quicker and to a greater extent than wild type VSV, as measured in serum taken from mice at the indicated time points (Figure 1d). This shows that the variant created from VSV would be a more effective immune response alert, increasing a patients chance of their immune system detecting the cancer, and virus, and initiating lysis of the cancer cells. The next set of results look at morbidity and mortality results. Morbidity simply meaning the relative incidence of a disease. The interesting thing about these results is that it shows that AV2 actually increases protection of the body from WT VSV. This variant boosts the immune system’s natural defense system against WT VSV (Ref. 4). Results show zero instances of morbidity or mortality when infected with AV2 but 100% results of morbidity and mortality in mice infected with WT VSV. The amount of virus injected is displayed in plaque forming units (PFUs). When AV2 is co-infected alongside WT VSV, the results continue to show no morbidity or mortality, in all varying amounts injected (Figure 1f.).
Based on these results, it seems to be a clear cut solution however one consideration would be how would the body react should a virulent strain arise while treating a tumor? The response   “cytokine cloud” produced by infection with the IFN-inducing viruses would protect the normal tissues of the host from the more virulent WT strain (should there be a WT virus among the VSV variants) (Ref. 4). Cytokines themselves can be slightly problematic to a person already undergoing therapies for cancer treatment. There are certain symptoms, as Steve mentioned in response to my previous post, such as lethargy, depression, fever, cognitive impairment, and changes in blood pressure that need to be taken under consideration when deciding if this method would ever be appropriate to use on a patient with cancer (Ref. 2).
To conclude, I find the potential to use live virus variants to treat cancer fascinating. Many more studies, and more complex studies of the effects of viruses on human cells, need to be completed however this method does seem to have promise. As the authors of the paper put it, these attenuated viruses “provide the best of both worlds; they grow rapidly in a broad spectrum of tumor cells but, because of their ability to trigger antiviral responses in normal cells, may be exceptionally safe to the treated animal” (Ref. 4). Are VSV variants as "ideal" as results from mice experiments make them out to be? The human body is much more complex as is the immune system and responses.They have a long way to go but considering the results of the preliminary experiments that have been done and the attention that has been paid to these virus variants, I believe that we will soon have enough data and information to determine if the benefits outweigh the risk. Perhaps we will have a new therapy for treating tumor cells in human patients.

1         1.  Bartlett, David L, Zuqiang Liu, and Magesh Sathaiah. "Oncolytic Viruses as Therapeutic           Cancer Vaccines." Molecular Cancer 12.103 (2013) Print.
           2.  Myers, Jamie S. "Proinflammatory Cytokines and Sickness Behavior: Implications for Depression and Cancer-Related Symptoms." Oncology Nursing Forum 35.5 (2008): 802-807. Print.
3         3.  "Oncolytic virus." Wikipedia. Wikimedia Foundation, 5 Nov. 2014. Web. 13 May 2014. <http://en.wikipedia.org/wiki/Oncolytic_virus>.
           4.   Stojdl, David F, John Hiscott, Anthony T Power, et al. "VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents." Cancer Cell 4.4 (2003): 263-275. Print.