Although this topic is unrelated to my cancer project, I came across the article and was too excited about the abstract to not read it. The article, originally published in the Blood Cancer Journal on July 12th, 2013, details a potential anticancer therapy for multiple tumor types, particularly leukemia (Ref. 2). The method in question is the use of non-replicating rhabdovirus-derived particles or NRRPs, as they are called. I will explain in detail how these particles have the potential to destroy cancer cells in the human body, but first, I will give some background information.
Rhabdoviruses are RNA viruses that are considered noninfectious because their negatively charged genomes cannot be translated once they have entered a host cell. There are two viruses that infect humans: the rabies virus and the stomatitis virus (Ref. 3). I think we have all heard of the rabies virus, infecting animals and then potentially being transmitted to humans either by a bite or a scratch. It is very perplexing to think that this virus, with a nearly 100% fatality rate in humans, could be the answer to eradicating leukemia cancer cells from our bodies (Ref. 3). Currently, in order for Rhabdoviruses (RVs) to be successful in spreading among and inducing apoptosis of the leukemic cells, the RVs must be administered in high doses, which exceed the “maximum tolerable dose” of the virus (Ref. 2). Such high amounts of a live virus inside a human patient also present the danger of uncontrollable spreading of the virus, leading to more stress on an already fragile immune system. Clearly there must be a safer way.
So what is the solution? Live viruses that are unable to replicate themselves and are therefore controlled in terms of number. This helps to diminish the possibility of uncontrolled growth of the viral colony and allows physicians to control the virus when utilizing them for care. Acute lymphocytic leukemia is the overproduction of abnormal white blood cells. These cells are called lymphocytes or lymphoblasts and they overtake the healthy white blood cells in our body, causing your immune defenses to be lowered (Ref. 1). Non-replicating Rhabdovirus-derived particles (NRRPs) are fatal to leukocytes because of their ability to lyse the cells but are resisted by normal cells because of the immuno defense system releasing interferon (IFN) proteins in response to the virus (Ref. 2). These IFNs increase recognition of the virus and increase the ability of the normal, non-cancerous cell to resist infection by the virus (Ref. 4).
What specifically are being used by doctors are these particles derived from the Rhabdovirus. RVs disrupt the normal metabolic activities of the tumor cells and impair the antiviral programs so that resistance to the virus is futile. However, as stated above, there are problems associated with using live, replicating viruses. What scientists have then attempted to do is to treat the virus with UV irradiation to create a bioparticle that can serve as an alternative to a live RV. They write, “We posited that if one could devise a method to generate non-replicating particles, which maintain both oncolytic and immunogenic properties, many of the above barriers in the treatment of hematopoietic malignancies may be overcome” (Ref. 2).
The results of the experiments done, with the methods and procedures found here, can be summarized nicely in Figure 2a and 2c (below). Another figure shows in detail how the NRRPs act on the cancer cells and the response functionality of the IFN with introduction of the particles, therefore I have included a link to it for your interest however I will only focus on Figure 2 to explain the results simply.
Figure 2a (above) shows human dermal fibroblasts in response to PBS (the control) and NRRPs (Ref. 2). It is clear that the leukocytes are being broken open and digested while the normal cells remain intact. This is a nice visual that shows the physical destruction of the cancer cells. Figure 2c is more qualitative in its measurements of viability in the leukemic and normal cells used in this experiment. The cell lines were again treated with PBS (the control) and NRRPs and their viability per cent was evaluated. Normal cells continued to flourish, notably the HDF cells, which reached a high viability level than the control cells when in the presence of NRRPs. The leukemic cells remained <50% viable after 72 hours of treatment when exposed to “the NRRP-mediated cytotoxicity” (Ref. 2).
This method of treating ALL brings a new therapy option to patients whose cancers are unresponsive to more traditional methods of treatment. A few discussed were allogenic hematopoietic stem cell transplantation (HSCT), myeloblative conditioning, and targeted tyrosine kinase inhibitor therapy (Ref. 2). These treatments are both associated with unpleasant side effects, possibly negative outcomes, and even mortality. The benefit to using NRRPs is that it is effective even when the disease progresses to the “acute blast crisis” stage which none of the preceding are capable of should the cancerous cells develop multidrug resistance and the rapid rate of growth of the leukemia (Ref. 2). One of the potential problems I have with this method of treatment is the possibility of normal cells being unable to activate sufficient IFN proteins in response to the viruses being injected into the body to fight the tumor cells. In an already weakened immune system, there is always a possibility of our cells failing to fight off viruses, and it certainly does not help to be purposefully injecting particles which have retained the cell-lysing properties of the viruses they were derived from. I would need to research more on the abilities of IFN proteins to stave off viruses of this sort but I am certainly skeptical at this point. It almost seems too good to be true.
- "Acute Lymphocytic Leukemia (ALL)." Medline Plus. U.S. National Library of Medicine, Web. 24 Apr. 2014. <http://www.nlm.nih.gov/medlineplus/acutelymphocyticleukemia.html>
- Batenchuk, C, F Le Boeuf, et al. "Non-replicating rhabdovirus-derived particles (NRRPs) eradicate acute leukemia by direct cytolysis and induction of antitumor immunity." Blood Cancer Journal 3.7 (2013): e123. Print.
- Chang, Wei-Li, and Kara Bischoff. "Rhabdoviridae." RHABDOVIRIDAE. Stranford University, Web. 24 Apr. 2014. <http://www.stanford.edu/group/virus/rhabdo/2004bischoffchang/Rhabdo.htm>
"Interferon (IFN)." Wikipedia. Wikimedia Foundation, 21 Apr. 2014. Web. 25 Apr. 2014. <http://en.wikipedia.org/wiki/Interferon>