Virotherapy
Virotherapy is a treatment using biotechnology to convert viruses into therapeutic agents by reprogramming viruses to treat diseases. There are three main branches of virotherapy: anti-cancer oncolytic viruses, viral vectors for gene therapy and viral immunotherapy. These branches use three different types of treatment methods: gene overexpression, gene knockout, and suicide gene delivery. Gene overexpression adds genetic sequences that compensate for low to zero levels of needed gene expression. Gene knockout uses RNA methods to silence or reduce expression of disease-causing genes. Suicide gene delivery introduces genetic sequences that induce an apoptotic response in cells, usually to kill cancerous growths.
History
Chester M. Southam, a researcher at Memorial Sloan Kettering Cancer Center, pioneered the study of viruses as potential agents to treat cancer.
Oncolytic 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;
In the 1940s and 1950s, studies were conducted in animal models to evaluate the use of viruses in the treatment of tumours.
Mechanism
It is believed that oncolytic virus achieve their goals by two mechanisms: selective killing of tumor cells as well as recruitment of host immune system.
Clinical development
As of 2019, there are over 100 clinical trials looking at different viruses, cancers, doses, routes and administrations. Most of the work has been done on herpesvirus, adenovirus, and vaccinia virus, but other viruses include measles virus, coxsackievirus, polio virus, newcastle disease virus, and more.
In 2015 the FDA approved the marketing of talimogene laherparepvec, a genetically engineered herpes virus, to treat melanoma lesions that cannot be operated on; as of 2019, it is the only oncolytic virus approved for clinical use. It is injected directly into the lesion.
RIGVIR is a virotherapy drug that was approved by the State Agency of Medicines of the Republic of Latvia in 2004.
Challenges and future prospective
Although oncolytic viruses are engineered to specifically target tumor cells, there is always the potential for off-target effects leading to symptoms that are usually associated with that virus.
Other challenges include developing an optimal method of delivery either directly to the tumor site or intravenously and allowing for target of multiple sites.
Another major challenge with using oncolytic viruses as therapy is avoiding the host's natural immune system which will prevent the virus from infecting the tumor cells.
Viral gene therapy
Viral gene therapy uses genetically engineered viral vectors to deliver therapeutic genes to cells with genetic malfunctions.
Mechanism
The use of viral material to deliver a gene starts with the engineering of the viral vector. Though the molecular mechanism of the viral vector differ from vector to vector, there are some general principles that are considered.
In diseases that are secondary to a genetic mutation that causes the lack of a gene, the gene is added back in.
Clinical development
There has been a few successful clinical use of viral gene therapy since the 2000s, specifically with adeno-associated virus vectors and chimeric antigen receptor T-cell therapy.
Vectors made from Adeno-associated virus are one of the most established products used in clinical trials today. It was initially attractive for the use of gene therapy due to it not being known to cause any disease along with several other features.
In additional, other clinical trials involving AAV-gene therapy looks to treat diseases such as Haemophilia along with various neurological, cardiovascular, and muscular diseases.
Chimeric antigen receptor T cell (CAR T cell) are a type of immunotherapy that makes use of viral gene editing. CAR T cell use an ex vivo method in which T lymphocytes are extracted and engineered with a virus typically gammaretrovirus or lentivirus to recognize specific proteins on cell surfaces.
In 2012 the European Commission approved Glybera, an AAV vector-based gene therapy product for the treatment of lipoprotein lipase deficiency in adults.
Challenges and future prospective
Currently, there are still many challenges of viral gene therapy. Immune responses to viral gene therapies pose a challenge to successful treatment.
Viral immunotherapy
Viral immunotherapy is the use of virus to stimulate the body's immune system. 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.
Cancer treatment
Viral immunotherapy in the context of cancer stimulates the body's immune system to better fight against cancer cells. Rather than preventing causes of cancer, as one would traditionally think in the context of vaccines, vaccines against cancer are used to treat cancer.