Virotherapy

Oncolytic virotherapy is not a new idea – as early as the mid 1950s doctors were noticing that cancer patients who suffered a non-related viral infection, or who had been vaccinated recently, showed signs of improvement;[2] this has been largely attributed to the production of interferon and tumour necrosis factors in response to viral infection, but oncolytic viruses are being designed that selectively target and lyse only cancerous cells.

In the 1940s and 1950s, studies were conducted in animal models to evaluate the use of viruses in the treatment of tumours.[3] In the 1940s–1950s some of the earliest human clinical trials with oncolytic viruses were started.[4][5]

In 2015 the FDA approved the marketing of talimogene laherparepvec, a genetically engineered herpes virus, to treat melanoma lesions that cannot be operated on; it is injected directly into the lesion.[6] As of 2016 there was no evidence that it extends the life of people with melanoma, or that it prevents metastasis.[7] Two genes were removed from the virus – one that shuts down an individual cell's defenses, and another that helps the virus evade the immune system – and a gene for human GM-CSF was added. The drug works by replicating in cancer cells, causing them to burst; it was also designed to stimulate an immune response but as of 2016, there was no evidence of this.[8][6] The drug was created and initially developed by BioVex, Inc. and was continued by Amgen, which acquired BioVex in 2011.[9] It was the first oncolytic virus approved in the West.[8]

Viral gene therapy uses genetically engineered viral vectors to deliver a gene of interest to target cells. An AAV-based vector is shown in this example.

Viral gene therapy uses genetically engineered viral vectors to deliver therapeutic genes to cells with genetic malfunctions[10]. Typically, the virus is administered to patients intravenously or by direct injection into target tissues[10]. The molecular mechanisms of gene delivery and/or integration into cells vary based on the viral vector that is used[10].

There are many targets of viral gene therapy. While some therapies target the missing or mutated genes of inherited genetic disorders, others seek to deliver new genes to cancer cells in order to destroy tumors[11][12].

Currently, immune responses to viral gene therapies pose a challenge to successful treatment[13]. However, responses to viral vectors at immune privileged sites such as the eye may be reduced compared to other sites of the body[13][14].

Unlike traditional vaccines, in which attenuated or killed virus/bacteria is used to generate an immune response, viral immunotherapy uses genetically engineered viruses to present a specific antigen to the immune system. That antigen could be from any species of virus/bacteria or even human disease antigens, for example cancer antigens.

Vaccines are another method of virotherapy that use attenuated or inactivated viruses to develop immunity to disease. An attenuated virus is a weakened virus that incites a natural immune response in the host that is often undetectable. The host also develops potentially life-long immunity due to the attenuated virus’s similarity to the actual virus. Inactivated viruses are killed viruses that present a form of the antigen to the host. However, long-term immune response is limited.[15]

There are two general approaches to develop these viruses using applied evolutionary techniques: Jennerian and Pastorian. The Jennerian method involves selecting similar viruses from non-human organisms to protect against a human virus while Pastorian methods use serial passage. This Pastorian method is very similar to directive evolution of oncolytic viruses. Selected viruses that target humans are passed through multiple non-human organisms for multiple generations. Over time the viruses adapt to the foreign environments of their new hosts. These now maladapted viruses have minimal capacity for harming humans and are used as attenuated viruses for clinical use.[16] An important consideration is to not reduce the replicative ability of the virus beyond the point where the immune system response will be compromised. A secondary immune response would therefore be insufficient to provide protection against the live virus should it be reintroduced to the host.

Chester M. Southam, a researcher at Memorial Sloan Kettering Cancer Center, pioneered the study of viruses as potential agents to treat cancer.[36]

• Cancer
• Gene therapy
• Oncolytic virus
• Vector
• Virosome, using modified viruses for drug delivery

• Ring, Christopher J. A.; Blair, Edward D. (2000). Genetically engineered viruses: development and applications. Oxford: Bios. ISBN 978-1859961032. OCLC 45828140.