Contributed by guest blogger: Brooke Schieffer ’12
In September of last year, a group of researchers infected cancer patients with a genetically engineered poxvirus. While this may sound like something out of a horror movie, it is actually quite the opposite: Breitbach et al. were performing a clinical trial to explore new, innovative ways to treat cancer tumors. Some people may be put off by the idea of having live viruses injected into their blood stream, but it’s actually not that uncommon. Indeed, many vaccines are actually live viruses. In fact, the vaccinia virus used in this clinical trial was derived from a vaccine for smallpox.
However, creating an attenuated virus to use as a vaccine and creating a virus that selectively infects and destroys cancer cells are two very different things. Before the scientists can create tumor-killing viruses, they first need to make sure that the virus can infect cancer cells while ignoring normal tissue cells in our body. To do this, they genetically engineered a poxvirus, called JX-594, that could replicate only in cells harboring activation of epidermal growth factor (EGFR)/Ras pathway (many epithelial cancers rely on this pathway). The virus, however, does not lyse the cell as this was only a trial to explore the possibilities of selectively cancer infection, not destruction.
The virus itself was chosen for several different reasons. Firstly, vaccinia (and, consequently, JX-594) is well adapted to intravenous transportation and displays some resistance to antibody neutralization in the blood stream. It can also spread quickly within tissues, making it ideal for infecting tumors (especially solid metastatic tumors). Finally, JX-594 replication is dependent on a commonly activated signaling pathway in epithelial cancers: the EGFR/Ras pathway. Furthermore, to determine if JX-594 was selectively infecting and replicating within cancer cells, the researchers incorporated the lacZ transgene (which encodes β-galactosidase) into the viral genome. They then could track β-galactosidase expression via immunohistochemical staining or tagged antibodies to see where the viruses were replicating in human tissue.
To test the effects of their virus, Breitbach et al. conducted a clinical trial with 23 cancer patients by intravenously injecting them with different concentrations of JX-594. They found their results to be quite promising: in the higher dose groups, they observed selective infection in tumor cells and expression of the β-galactosidase protein. And all with little apparent side effects—the worst of which were symptoms typical of a 24-hour flu. This is the first experiment in which an intravenously injected virus was able to selectively replicate in tumor cells and express a transgene. Of course, this is just the first step on the road to effective treatment. First off, this was only a preliminary study to determine if the virus could selectively infect cancer cells, they did not engineer the virus to kill the cells yet. As of now, it is simply a possible delivery method, not a way to kill cancer cells. But the researchers are hopeful that viruses such as JX-594 will eventually be customizable with proteins or siRNA to treat different types of cancer.
However, there are still many questions to keep in mind moving forward. Will we be able to insert a gene into these viral vectors that only destroys tumor cells? Can this delivery system be modified to infect cancers that do not use the EGFR/Ras pathway? What about the possibility of viral mutations that would allow the virus to infect healthy tissue? And what about the immune system’s role? How will multiple treatments work given the fact that the immune system will build up immunity against the virus because it is invading the body? Even with these questions, this clinical trial was still an innovative and interesting new approach to cancer treatment.
Link:
http://www.nature.com/nature/journal/v477/n7362/full/nature10358.html#/affil-auth
Brooke Schieffer is a senior at Vassar College, majoring in Drama.
I think the idea of treating cancer with a virus is pretty brilliant. Like Alix, I am also curious as to how far away a treatment using these methods could be. Has there been any more recent developments and how hard is it to inset a gene in the virus that would be able to destroy the cancerous cells.
This is an amazing discovery. Many of my initial questions were already answered, however while the only affects studied in the patients by researchers were symptoms typical of a 24-hour flu, I think that a long term study of these patients needs to verify that there are no negative long term symptoms/affects that can take place. Additionally, cancer cells multiply at a fast rate so wouldn’t the virus have to infect the cells at an even faster rate than the cells are dividing to have a significant effect? Finally, being that viruses mutate and the immune system will eventually kill the virus, this would clearly be a temporary treatment so how long would this treatment last and wouldn’t the patient ultimately have to resort to chemotherapy anyway?
This research has a lot of potential; it seems that many questions have been answered here. A good point is made by Brooke in the last paragraph, how would the researchers prevent mutations in the virus and negative side effects from occurring in the patients? Is there a way to effectively use this in conjunction with other treatments to eliminate the cancer cells in the body since the virus only kills the cancer cells and doesn’t prevent them from growing? What would happen if patients had viral therapy and chemotherapy? Further research is needed.
This research seems very promising. The question about how the body’s immune system might react, and how it might render the treatment ineffective after one trial due to antibodies etc, made me think about, and see the beneficial possibilities of, the earlier articles we looked at in class about virologists engineering extremely dangerous viruses. To me it seems that the development of genetically-engineered deadly viruses could only lead to negative outcomes (accidental release/biological warfare). However, after reading this, it made me think that the development of a virus that could evade the immune system could have positive abilities. If the virus could be engineered to only kill cancer cells and effectively escape the immune system then there could finally be a cure for cancer.
Do you think this type of viral treatment will be put into effect soon? Or is it still a ways away?
On another note, isn’t there still a possibility of this virus mutating and becoming dangerous after the cancer cells are gone? Recently a family friend of mine finally beat cancer after two years of treatment, only to die a month later from complications from chemo. It seems possible that this type of treatment could also potentially have detrimental effects.
There is a normal immune response to cancer, which may seem counter-intuitive since, as you point out, it is self. However, our immune system is capable of detecting differences between normal and cancerous cells. Obviously it is imperfect since cancer does develop.
The idea of using viruses for cancer therapy has been around for a while in various forms using a variety of different viruses. Check out TWiV podcast #131 and #142 for example.
As for participating in a study like this, being injected by an experimental treatment, you also need to consider that the people selected for participating in novel cancer therapies are the people for whom all other standard therapies have failed and are at a very advanced stage. At that point, people are willing to try just about anything. Unfortunately that really stacks the odds against the new treatment, since it is not being tested early after diagnosis when many treatment options might be available, but at the end, where it may seem hopeless.
As Zoe points out, some viruses do cause cancer (HPV for example)…those would not be good candidates for oncolytic therapy, unless its oncogenic potential were in some way inactivated.
Great questions Cass! Allow me to try and fill in the blanks for you.
First, you asked if the virus would follow a path other than the same EGFR/Ras pathway the cancer took. The EGFR/Ras pathway is not a physical path but rather a process that only cancer cells activate. And this virus is specifically designed to only be able to infect cells that are undergoing that process. Imagine the virus is a police officer that is only allowed to arrest people that are vandalizing and imagine that all the cells in your body are people. Now, the police officer sees tons of people all over the place but cannot arrest just anyone; he can only arrest someone caught in the act of vandalizing. In a similar way, the virus can only infect cells that are actively utilizing an EGFR/Ras pathway. On that same vein, you asked what changes the virus used in this experiment would have to undergo to be able to kill cancer cells. In theory, to make a virus that destroys cancer cells scientists would only need to take out the β-galactosidase gene that makes the virus easy to track and replace it with a gene that lyses (destroys) the cell its infecting instead. And since the virus can only infect cancer cells, you wouldn’t have to worry about it infecting healthy, normal tissue. Of course, it’s rarely that simply in reality, but that’s the basic theory/ideal this whole project is based on.
As far as how the scientists measured the effectiveness of JX-594, they did many experiments (some of which are, quite honestly, a little over my head). But the one that made the most sense to me was that they put a handy marker in its DNA. For this experiment, they used the β-galactosidase as that marker which is easily traceable. And since viruses can only replicate (and therefore express the β-galactosidase marker) is if they infect a cell. So all the scientists had to do to see where the virus was infecting was to track where β-galactosidase was being made.
You seemed doubtful that anyone would willingly be injected with virus that may make them sick. But don’t be so sure! I’ll bet you’ve been injected with live virus several times in your life for various vaccines. And even though this is admittedly a different ballgame, 23 patients already did it for this first clinical trial! And look at chemotherapy. It is one of the most debilitating treatments we have to combat cancer and has the worst side effects imaginable, yet a vast majority of cancer patients gladly accept it. The worst side effects of getting injected with this virus were symptoms of a 24 hour flu. I’d take that over chemo any day.
Finally, you asked an intriguing question about merging virus and cancer cells to trick the immune system into destroying the cancer cells. That’s a really interesting thought. And, in fact, if the virus infects the cancer cells the immune system alone should eventually kill the cell if the virus doesn’t. The only problem is when the immune system gets good at fighting the infection, it will kill the virus before it can infect the cell, making multiple treatments difficult. Although it didn’t seem to present a problem in this experiment, the researchers admit that it may present a challenge in future trials.
Thanks for you great questions! I hope I cleared some things up for you. Let me know if you have any more questions.
Thanks for your comment Zoe! You are asking some great questions here—let me see if I can clear some of this up for you.
First off, you asked about how the virus would prevent uncontrollable growth. The virus itself isn’t targeting the cancer cells based on their growth rate per se, but rather it targets cells that have activated the EGFR/Ras pathway. The scientists specifically engineered the virus to only be able to infect cells that use this EGFR/Ras pathway. And since only epithelial cancer cells use this pathway, the virus can only infect those cancer cells, leaving all the other cells in our body (that don’t use that pathway) untouched. Obviously, making sure the virus ONLY infects cancer cells is a very important consideration, which is why this first clinical trial made sure the virus couldn’t harm any cells – it could infect them, but not destroy them. They didn’t want to inject patients with a virus that could kill cells it infected in case it didn’t only infect cancerous cells.
You also asked about the possibility of the virus/cancer integration. I find it hard to believe that this virus would accidentally promote cancer growth. Viruses don’t help their cell hosts, they utilize their cellular machinery to replicate their genome and express their genes. If anything, they slow cell growth due to competition for common resources. Also, it is highly unlikely that some sort of cancer/virus mutant will emerge simply because poxviruses are not retroviruses: they do not insert their DNA into the host’s genome. And viruses like to keep their genomes as streamlined as possible so they don’t usually incorporate cellular DNA into their own. Therefore you don’t have to worry about the virus “inheriting” any cancerous traits or vice versa.
Also, the question you raised about immunity is an important one. The immune system fails to recognize cancer cells as threats because they still see the cells as “self” (after all, cancer cells are still YOUR cells, not pathogens like viruses or bacteria). Therefore, even if virus was to invade only the cancer cells, which we see as a good thing, the immune system still mounts a defense because it’s an “other” invading the “self.” However, it is worth noting that the virus they used for this experiment was derived from vaccinia virus, which is used as a vaccine against smallpox. And most of the patients that took part in the trial were older and had been infected with vaccinia when they were younger to protect them against smallpox. Therefore, those patients should have had an immune response yet there results were no different from that of other patients. While it didn’t seem to be too big of an issue at the time, the researchers admit it may pose a problem in the future.
Finally, you seemed doubtful that anyone would willingly be injected with virus that may make them sick. Don’t be so sure! I’ll bet you’ve been injected with live virus several times in your life for various vaccines. And even though this is admittedly a different ballgame, 23 patients already did it for this first clinical trial! And look at chemotherapy. It is one of the most debilitating treatments we have to combat cancer and has the worst side effects imaginable, yet a vast majority of cancer patients gladly accept it. The worst side effects of getting injected with this virus were symptoms of a 24 hour flu. I’d take that over chemo any day.
Hope that clears things up! Let me know if you have any other questions!
This research is really valuable and could have amazing potential in finding cures to cancer. I would be interested in reading more about previous experiments in using viruses in cancer treatment. Additionally, I think it would be worthwhile to know how the scientists investigating this experiment would add the poxvirus that would kill the cancer cells, versus just following the EGFR/Ras pathway. Furthermore, how would the addition of the poxvirus and it’s ability to harm the cancer cells change the results of the experiment. Would the virus possibly follow a path different than the same EGFR/Ras pathway the cancer took?
Also, how did the scientists measure the effectiveness JX-594 with different concentrations in the 23 patients?
Additionally, although this experiment had amazing results in theory–I wonder about the practicality of cancer patients agreeing to let a version of poxvirus be injected to them considering the detrimental results on their already deteriorating health and the possibility of a poxvirus outbreak.
Lastly, in response to Zoe’s comment about the role of antibodies in this process. I think it would be interesting to discover if the virus and cancer cells could somehow merge genetically so that the immune system might develop antibodies that recognize the poxvirus as harmful and thus, the cancer cell as well.
Using a virus to fight cancer is certainly an innovative and interesting idea. Viruses can be used to study diseases in many ways, and they often have brought to light the intricacies of how diseases infect humans and evolve.
Brooke brought up many interesting points about moving this “fighting fire with fire” research forward in the future. Firstly, the genetically engineered poxvirus, JX-594, does not lyse the tumor cells it is designated to infect. If a virus were to be engineered in a way that it could lyse cancer cells, wouldn’t this compromise the immune system as a whole? Because cancer cells are rapidly dividing (tumor suppressors fail to suppress cell growth during checkpoints in the cell cycle), how exactly would a virus contribute to preventing this uncontrollable growth? Also, conducting a clinical trial on a virus that is only claimed to lyse cancer cells would be very risky. What if the virus failed to lyse the cancer cells and instead contributed to further growth and replication of the cells (cells that are now not only cancerous but also filled with virus)? Even further, could the combination of a virus being integrated into a cancer cell express strange mutations in the virus’ genome? It is hard to believe that cancer patients would agree to participate in a trial where there is a potential risk of becoming even sicker.
Another interesting point that Brooke raised is the role of antibodies in recognizing the virus after continual treatments. Antibodies are essential to our immune system, but in patients with cancer who would potentially be infected by a virus to help stop cancer cell replication, antibodies pose as a problem. The virus, in this case, should be recognized by the body as a beneficial pathogen. It is unclear how only specific antibodies would cease to develop immunity without comprising other antibodies not related to the virus being used to treat the cancer.
Overall, it is compelling to look at a treatment for cancer from this angle; it pushes other researchers to explore innovative ways to treat a disease that has remained a large, frustrating mystery in the scientific field.