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.
