From the simplest to the most complex, viruses have evolved to multiply within a host cell. By harnessing the cell’s machinery, the virus is able to propagate, often causing illness within the infected organism. However, there are cases where the body may benefit from this seemingly parasitic relationship. This is where the oncolytic virus – a virus capable of killing cancerous cells – comes in.
The concept of an oncolytic virus has been around for a century. Although viruses were still poorly defined in the 1800s, cases were reported in which a viral infection correlated with the remission of cancer. This built the basis for the idea that a viral infection could be beneficial. Early clinical trials took place mid-20th century and some attempts to engineer better oncolytic viruses were made. One of these early trials, led by Dr. Hoster at Ohio State University, included infecting patients suffering from Hodgkin’s disease with human serum or tissue extract containing the Hepatitis B virus. One patient was confirmed to have died from the infection, and only seven saw some improvement of their disease.
Luckily, not all of the work done since has resembled the antics of mad scientists, and with technological advances in DNA manipulation and genetic engineering, the field saw a resurge in research interest in the early 1990s. Over 20 different viruses and their potential for cancer treatment have now been studied, with 19 clinical trials currently underway. In May 2015, the largest phase 3 trial so far completed testing a herpesvirus-based therapy to treat melanoma. The results look promising, as patient survival was increased, and the virus called T-Vec is well on its way to receive FDA approval. To date, only one other virus-based cancer therapy has been approved for use in treating head and neck cancer (since 2005 in China); its efficacy proved to be too low for other countries to approve its use.
How does a virus become oncolytic? When a virus infects a cell, it hijacks the cell’s machinery to make copies of itself. In some cases, the cell ends up bursting and releasing the new virus; in others, the virus has more sophisticated ways to kill its host cell or doesn’t kill the cell at all. As the name suggests, an oncolytic virus only kills cancerous cells. It may do this by preferring to bind molecular structures that are on the outside of the cancer cell and not on a healthy cell. These structures act like a doorknob: if the virus can turn the doorknob, it can enter the cell. The term for this is tissue tropism. An oncolytic virus is not always restricted to entering tumour cells, though. In this case, a virus used for cancer treatments should only be able to multiply in and kill the cancerous cell and not any healthy cells it may enter. This is partially made possible by a decreased antiviral response in the cancer cells.
While cancerous cells have mastered hiding from the immune system, oncolytic viruses can counteract this mechanism by acting like a vaccine, boosting the anti-cancer immune response.”
The ability of cancer cells to continuously proliferate can also be used by the virus to replicate. The genetically engineered respiratory enteric orphan virus (reovirus), called Reolysin® and developed by Oncolytics Biotech Inc., is an excellent example of this concept. It is able to infect humans, but has only been associated with mild disease and was long neglected in research labs. Through a lucky discovery, Dr. Matt Coffey, co-founder of Oncolytics Biotech Inc., was able to identify a reovirus as an oncolytic virus during his PhD at the University of Calgary. He found that cancerous cell lines infected with the virus would die, while healthy cells would live. Further work showed that the healthy cells combatted viral replication by undergoing an antiviral response. The cancerous cells were susceptible if they contained a mutation in the RAS pathway. The RAS pathway is part of the cell cycle, and if components of this pathway are mutated, it can lead to continuous cell growth, causing the cell to become cancerous. Additionally, in the presence of such mutations, the antiviral response is perturbed and the cell is not able to contain the virus, ultimately leading to its death. Reolysin® was given the Orphan Drug Designation by the FDA in May 2015 for the treatment of gastric cancers; it is now licensed to be used in the treatment of this rare disease and is being assessed for use with other cancers in a number of clinical trials.
Another bonus to oncolytic viruses is that they can travel to metastases throughout the body, killing these as well. Furthermore, while cancerous cells have mastered hiding from the immune system, oncolytic viruses can counteract this mechanism by acting like a vaccine, boosting the anti-cancer immune response. Similar to reovirus, some viruses are naturally oncolytic, while others can be manipulated in the lab via genetic engineering, as was done with the herpes simplex virus to create T-Vec. A virus that normally infects multiple cell types can also be changed so that it becomes cancer-specific. For example, poliovirus has been manipulated in such a way that it may be safely used in the treatment of brain tumours.
Despite the advances seen in recent years, a number of problems must be resolved before oncolytic viruses can become standard therapy. For one, a virus does not always infect all tumour cells, which may allow some cells to escape the therapy. Then there is the continuing tug-of-war between the virus and the cancer. Cancer cells want to survive and propagate, and so due to their inherent instability as well as the selective pressure of the virus, they can acquire mutations that will outcompete the infection. Furthermore, the immune system can develop neutralizing antibodies to the virus and prevent it from infecting cells. Strategies to avoid this include using healthy cells, such as mesenchymal stem cells, to transport the virus directly to the tumour. The purposeful infection of an individual who is already immunosuppressed also poses a risk, although so far only comparatively mild side effects have been observed in patients receiving this kind of therapy. Another risk factor is the spread of the virus; it is important that individuals such as medical staff and family members are continuously observed for signs of infection. However, the evidence currently suggests that others cannot become infected with oncolytic viruses.
Aside from the medical limitations, there are practical impediments to using oncolytic viruses. While pharmaceutical companies are readily invested in the development of these therapies, there are concerns regarding production of the virus and its associated costs. It takes considerable effort to produce large amounts of high quality virus. There is the problem of logistics: where in the hospital will the virus be stored and where will the treatments take place? Furthermore, current evaluations of whether a patient is responding to therapy are based on the available treatments, such as radiation. These evaluations need to be adapted to viral therapy to provide a more accurate assessment of clinical outcome.
It is a long way to go from a virus that kills tumour cells in a petri dish to a virus that can be given to patients. Nevertheless, if the indications are correct, we appear to be close to using oncolytic viruses in the clinic. Along with other immunotherapies, oncolytic viral technology is helping to push cancer treatment towards more directed treatment tactics.
References
1. Brown, M.C., Bryant, J.D., Dobrikova, E.Y., Shveygert, M., Bradrick, S.S., Chandramohan, V., Bigner, D.D., Gromeier, N. (2014). Induction of Viral, 7-Methyl-Guanosine Cap-Independent Translation and Oncolysis by Mitogen-Activated Protein Kinase-Interacting Kinase-Mediated Effects on the Serine/Arginine-Rich Protein Kinase. Journal of Virology. 88(22): 13135-13148.
2. Chakratabarty, R., Tran, H., Selvaggi, G., Hagerman, A., Thompson, B., Coffey, M. (2015). The oncolytic virus, pelareorep, as a novel anticancer agent: a review. Investigational New Drugs. 33(3): 761-774.
3. Donnelly, O., Harrington, K., Melcher, A., Pandha, H. (2013). Live viruses to treat cancer. Journal of the Royal Society of Medicine. 106(8): 310-314.
4. Hoster, H.A., Zanes, R.P., Jr., von Haam, E. (1949). Studies in Hodgkin’s Sydrome: IX. The Association of “Viral” Hepatitis and Hodgkin’s Disease (A Preliminary Report). Cancer Research. 9:473-480.
5. Kelly, E., Russell, S.J. (2007). History of Oncolytic Viruses: Genesis to Genetic Engineering. Molecular Therapy. 15(4):651-659.
6. Pol, J., Bloy, N., Obrist, F., Eggermont, A., Galon, J., Cremer, I., Erbs, P., Limacher, J., Preville, X., Zitovel, L., Kroemer, G., Galluzzi, L. (2014). Trial Watch: Oncolytic Viruses for Cancer Therapy. Oncoimmunology. 3: e28694-1-13.
Elisabeth Foerster
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