by Nishita Parnandi
figures by Krissy Lyon
One of the biggest challenges in treating cancer is to specifically target the cancerous site in a tissue without killing the surrounding normal cells. The use of oncolytic viruses is a new cancer treatment that is excellent at achieving just that. An oncolytic virus named ImlygicTM manufactured by Amgen recently received the stamp of approval from the FDA making exciting headlines in the research community across the globe.
An Oncolytic virus is a type of virus that is highly selective to tumor cells: it can replicate and spread within a tumor cell population without affecting normal tissue. Despite many advantages, doctors and scientists have been cautious about treating patients with viruses because there has always been considerable doubt as to how the patients’ immune system will respond to them. However, clinical trials of ImlygicTM have shown that the immune system actually acts synergistically with the drug to destroy tumor cells, making it a novel approach to cancer therapy.
The promises of a new therapy
How do oncolytic viruses kill cancer tissue but not the surrounding healthy tissue?
Some oncolytic viruses (OVs) have a natural preference for tumor cells such as coxsackie virus (known to cause sores on the mouth) and Measles virus, whereas others have to be engineered to replicate specifically in cancer cells such as adenovirus (Ad) and herpes simplex virus (HSV). Genetic engineering has enabled researchers to expand the range of OVs that could potentially be used in therapy by allowing scientists to reprogram several disease-causing viruses so that they can specifically target cancer cells. These disease-causing viruses are first weakened so as to prevent the patient’s immune system from reacting against the viruses, which could result in their destruction even before they can target tumor cells.
The specificity of OVs for cancerous tissue arises due to their ability to recognize and exploit certain traits that are unique to cancer cells. For instance, Coxsackie virus and Measles virus can naturally target tumor cells due to specific marker proteins that are only on the surface of cancer cells and not on other, healthy cells. In such a scenario, the outside of the virus has proteins that fit with these marker proteins like puzzle pieces. This allows the virus to infect the cancer cells (for more about virus biology see here). On the other hand, the specificity of HSV to attack cancer cells is engineered by scientists. These viruses are depleted of a certain enzyme that is highly abundant only in cancer cells, making these viruses depend on the cancer cells for their survival. .
The synergy between the immune system and the OVs arises once the cells are infected with the viruses. Cancer cells produce tumor antigens, which are proteins that can make cancer cells appear unhealthy to the immune system. The host immune system detects these antigens and naturally targets the cancer cells for destruction. In attempts to survive, some cancer cells reduce the expression of these antigens on the surface of the cell, making it difficult for the immune system to detect them. Once an oncolytic virus enters the host cell, the tumor cell is broken down and the tumor derived antigens present within the cell are released. As a result, the immune system is then activated and the tumor site is destroyed.
As with almost any new therapeutic strategy, there are several challenges in the field of oncolytic viral therapy. An important challenge to consider is the size of these viruses. Viruses are naturally larger than other anti-cancer agents such as chemicals and antibodies. Hence when viruses are injected into the tumor, effective spread of the virus could be impaired by the large number of different cells in the environment surrounding the tumor bed.
Another major weakness of OVs is that they can sometimes be targeted and destroyed by the host’s immune system. Delivery of the viruses is a major challenge as it is quite probable that the virus will be eliminated by the host antibodies and other immune cells even before it reaches the target site. Several methods have been proposed to overcome this particular problem. One example is the “Trojan Horse” method which has been tested in mice. In this method, instead of injecting the virus directly into the tumor, cells from the mouse are extracted and infected externally before being reintroduced into the mouse . The cells then act as delivery vehicle for antigens and carry the antigen to the environment surrounding the tumor.
What’s special about IMLYGIC?
Talimogene laherparepvec (Imlygic™) is an oncolytic virus being developed by Amgen for the intralesional treatment of various cancers, particularly malignant melanoma, a specific type of skin cancer. ImlygicTM is a genetically modified, live but weakened, herpes simplex virus (HSV) type 1 that is designed to promote an antitumor response by the immune system. In October 2015, it was tested for the local treatment of skin lesions in very severe cases of patients suffering from melanoma recurrent even after surgery. In these trials, it was not shown to improve overall survival or have an effect on the spread of cancer cells to other tissues. Currently, it is being evaluated in several countries for use as combination therapy with chemo- or radiotherapeutic agents in malignant melanoma ; it is also in development for liver cancer in the USA.
There are several advantages of using a modified HSV to other OVs. Firstly, it can infect a broad range of cancer cell types and has a type of replicative life cycle which results in host cell destruction. It is also very well studied: the genome of HSV is well characterized and contains many nonessential genes that can be replaced with several therapeutic genes. 
The modified HSV when injected directly into the tumors releases a protein that stimulates the host immune system. Subsequent to this, tumor cells are broken down and tumor-derived antigens are then released into the area around the tumor. This break down of the tumor cells coupled with the activation of the immune system is likely how the drug works, but this has yet to be confirmed by the drug manufacturer.
Need for further research
Despite the FDA approval, there are still several problems associated with this drug. For instance, herpetic infections such as cold sores have been reported in treated patients . It is unsuitable for immune-compromised individuals and the chance of accidental exposure during either preparation or administration can make the therapy quite risky.
All in all, although there is still much to be explored in the area of oncolytic viruses, the therapeutic strategy appears fascinating. The FDA approval can potentially promote further clinical trials of similar drugs and boost laboratory and clinical research in this area. For instance, a lot of ongoing research has been focused on New Castle Disease Virus, an additional potential oncolytic virus . If information from basic research and clinical trials can be implemented to overcome problems associated with efficacy and the host immune response, these drugs could serve as powerful agents to combat cancer.
Nishita Parnandi is a PhD student in the Biological and Biomedical Science program at Harvard University.
1. Thorne SH, Hwang TH, O’Gorman WE, Bartlett DL, Sei S, Kanji F, Brown C, Werier J, Cho JH, Lee DE, Wang Y, Bell J, Kirn DH. Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963. J Clin Invest. 2007 Nov; 117(11):3350-8.
2. Komarova S, Kawakami Y, Stoff-Khalili MA, Curiel DT, Pereboeva L. Mesenchymal progenitor cells as cellular vehicles for delivery of oncolytic adenoviruses. Mol Cancer Ther. 2006 Mar; 5(3):755-66.
3. Ryuichi Kanai, Hiroaki Wakimoto, Tooba Cheema, and Samuel D Rabkin. Oncolytic herpes simplex virus vectors and chemotherapy: are combinatorial strategies more effective for cancer? Future Oncol. 2010 Apr; 6(4): 619–634. doi: 10.2217/fon.10.18
4. Susan Varghese and Samuel D Rabkin. Oncolytic herpes simplex virus vectors for cancer virotherapy. Cancer Gene Therapy (2002) 9, 967–978. doi:10.1038/sj.cgt.7700537
5. FDA Approves IMLYGIC™ (Talimogene Laherparepvec) As First Oncolytic Viral Therapy In The US (http:// www.amgen.com/media/news-releases/2015/10/fda-approves-imlygic-talimogene-laherparepvec-as-first-oncolytic-viral-therapy-in-the-us/)
6. Newcastle Disease Virus–for health professionals (PDQ®) (http://www.cancer.gov/about-cancer/treatment/cam/hp/ndv-pdq )