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.
References:
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.
