Tuesday, 1 March 2016

Fighting cancer with a virus of plants: it's not a load of bull

If I ask you to think of a virus, I’m going to guess you’ll land on one of Zika, Ebola, HIV, Influenza or maybe at a push, Rhinovirus, the latter two of which you may be unfortunate enough to have recently experienced in the winter of the northern hemisphere. Viruses, and the infections they cause, are massive public health concerns, and for the most part this is what gets our attention. However, there is currently a vast amount of research going into the development of viruses as tools in the fight against cancer, and it’s some of this work I’d like to discuss in the blog post.

The work I’m going to talk about was published in the journal Nature Nanotechnology and comes from the Geisel School of Medicine in New Hampshire, USA. The published article has the somewhat striking title of “in situ vaccination with cowpea mosaic virus nanoparticles suppresses metastatic cancer.”

Let’s break that down. Our immune system has the capacity to destroy cancer cells, this is in fact one of the major hurdles a mutant cell needs to overcome in order to develop into a cancer. In order to escape the immune response, mutated cells need to develop ways in which to protect themselves, for instance, by releasing molecules that act to suppress the the immune system - in a sense, camouflaging themselves. This kind of immunosuppression by cells is nothing strange in our body, it’s part of a normal response to stop your immune system attacking your own body. However, cancer cells develop the ability, through mutation, to subvert this system to aid their own growth. As such, an idea that has starting to come to the front of cancer research is so called cancer immunotherapy; stimulating the immune response to fight against cancerous tissue, while leaving normal tissue untouched. So to break down the first part of the paper’s title, “in situ vaccination” is the idea of directly supplying something to trigger an immune response at the site of a cancer. The “something” that is being supplied into cancerous tissue in the case of this work, is cowpea mosaic virus nanoparticles.  
Cowpea peas
I’m guessing that cowpea mosaic virus isn’t something you’ve come across before (I certainly hadn’t). By way of background, cowpea mosaic virus, is a virus that infects the cowpea plant, and causes a mosaic pattern on the leaves (to state something you’d probably guessed). In this study of cowpea mosaic virus as an anti-cancer agent, the group work with “nanoparticles," which can also be called "virus-like particles." If you consider a virus particle, such as the one depicted for cowpea mosaic virus (below), that 3D shape is made up by very few proteins. A virus structure is essentially just a protein case for the genetic material. A virus-like particle is simply just this casing with nothing inside (literally a shell of it’s former self). Without the genetic material, these particles are no longer able to infect cells. An analogy for this could be a laptop that has had all of the internal circuit boards removed. From the outside it still looks like a laptop, but try and turn it on, and nothing will happen. Virus-like particles are of very little danger because they cannot infect cells, however, the immune system isn’t able to detect this. The cells of the immune system only ever see the outer casing of a virus and treat this as a threat - thus virus-like particles can stimulate an immune response just like a real virus (from the outside a laptop without circuit boards still looks like a laptop). And this is the basis of some vaccines, most notably of which is the vaccine against human papillomaviruses, which some readers may have received. 
Cowpea mosaic virus structure (from Wikipedia)

We can now get to the meat of the paper. To jump to the punchline, the group were able to show that injecting mice with cowpea mosaic virus-like particles could stimulate an immune response, that resulted in suppression of cancers in mice. Initially the group determined that treating cells with the virus-like particles was capable of triggering an immune response in a dish, and moreover, found that this treatment didn’t cause the cells to die. The group moved on to have mice inhale preparations of cowpea mosaic virus-like particles. In mice with no tumours, this inhalation resulted in activation of the immune system, which could be detected by an increase in the number of neutrophils (one class of immune cells) in the lungs. And indeed, collecting neutrophils from these mice showed that the virus-like particles had been taken up into these cells, thus activating them - the neutrophils treated the virus-like particles as a true threat and attempted to remove them. Importantly, this inhalation of the virus-like particles to healthy mice didn’t cause any adverse side effects or damage to the lungs.

The next experiment was to give the virus preparation to mice with tumours. It was found that before the inhalation, the immune cells in the lungs of these mice was very different to that of healthy mice. There were far more cells associated with immunosuppression (as a result of the cancer). Upon giving virus-like particles by inhalation to these mice, it was seen that there was a large increase in the number of activated immune cells capable of tackling cancer (again, a large increase in the number of neutrophils, for instance). So far then, everything seems to be going to plan for using cowpea mosaic virus to activate an anti-cancer immune response.

Next, the group started to give mice injections of the virus-like particles instead of allowing them to inhale. They found that injecting mice with cowpea mosaic virus-like particles resulted in a decreased number of tumours in the lungs. Importantly, the researchers nicely demonstrated that this reduction in tumour number was due to an immune response but using mutant mice that don’t have a functional immune system - these mice showed no change in their tumour burden.

The tumours that were being tested to this point were melanomas growing in the lungs. But it wasn’t just melanomas that showed sensitivity to the immune response triggered by cowpea mosaic virus-like particles. In one set of experiments, mice were injected with cancerous tissue in their fat pads, which then spontaneously metastasis to the lungs 16 days later. The mice given injection of virus-like particles all showed delayed onset of lung tumour formation, and survived the treatement. Similarly, mice with tumours in their colons could also be protected by treatment with the virus-like particles. 

Finally, the group tested whether injections of virus-like particles could protect against melanomas growing in the skin. Once again, they found that cowpea mosaic virus-like particles could protect the mice, and half of the mice injected completely cleared their tumours after only two injections of virus preparations. Moreover, this anti-tumour immune response was found to be long lasting, since when mice that had previously cleared tumours were injected with more cancerous tissue at a later date, 3 out of 4 completely rejected the implanted cancer (while this cancer grew in all non-vaccinated mice). 

Overall this work has nicely demonstrated the potential for the use of cowpea mosaic virus-like particles in the battle against cancer. These virus-like particles could be tolerated in mice and were seen to trigger an immune response, which resulted in clearance of cancerous tissue. The virus-like particles showed no major side effects, and even seemed to provide long lasting immunity against the cancers used in the work. The next step for cowpea mosaic virus will probably be to test safety in humans. It will take a long time, and many more studies, but perhaps a virus that infects plants could one day be used to treat cancers in humans.

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