Oncolytic virus
An oncolytic virus is a
The potential of viruses as anti-cancer agents was first realised in the early twentieth century, although coordinated research efforts did not begin until the 1960s.
The first oncolytic virus to be approved by a national regulatory agency was genetically unmodified ECHO-7 strain enterovirus
On December 16, 2022, the Food and Drug Administration approved nadofaragene firadenovec-vncg (Adstiladrin, Ferring Pharmaceuticals) for adult patients with high-risk Bacillus Calmette-Guérin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors. [14]
History
A connection between cancer
Herpes simplex virus
In 1996, the first approval was given in Europe for a
Other oncolytic viruses based on HSV have also been developed and are in clinical trials.[34] One that has been approved by the FDA for advanced melanoma is Amgen's talimogene laherparepvec.[35]
Oncorine (H101)
The first oncolytic virus to be approved by a regulatory agency was a genetically modified adenovirus named
Mechanisms of action
Immunotherapy
With advances in
Immunity as an obstacle
A major obstacle to the success of oncolytic viruses is the patient immune system which naturally attempts to deactivate any virus. This can be a particular problem for intravenous injection, where the virus must first survive interactions with the blood complement and neutralising antibodies.[40] It has been shown that immunosuppression by chemotherapy and inhibition of the complement system can enhance oncolytic virus therapy.[41][42][43]
Pre-existing immunity can be partly avoided by using viruses that are not common human pathogens. However, this does not avoid subsequent antibody generation. Yet, some studies have shown that pre-immunity to oncolytic viruses doesn't cause a significant reduction in efficacy.[44]
Alternatively, the viral vector can be coated with a polymer such as polyethylene glycol, shielding it from antibodies, but this also prevents viral coat proteins adhering to host cells.[45]
Another way to help oncolytic viruses reach cancer growths after intravenous injection, is to hide them inside macrophages (a type of white blood cell). Macrophages automatically migrate to areas of tissue destruction, especially where oxygen levels are low, characteristic of cancer growths, and have been used successfully to deliver oncolytic viruses to prostate cancer in animals.[46]
Immunity as an ally
Although it poses a hurdle by inactivating viruses, the patient's immune system can also act as an ally against tumors; infection attracts the attention of the immune system to the tumour and may help to generate useful and long-lasting antitumor immunity.[47][48] One important mechanism is the release of substances by tumor lysis, such as tumor-associated antigens and danger associated-molecular patterns (DAMPs), which can elicit an antitumor immune response.[49] This essentially produces a personalised cancer vaccine.
Many cases of spontaneous remission of cancer have been recorded. Though the cause is not fully understood, they are thought likely to be a result of a sudden immune response or infection.
Viruses selectively infect tumor cells because of their defective anti-viral response.
Oncolytic behaviour of wild-type viruses
Vaccinia virus
Vesicular stomatitis virus
Recent research has shown that this virus has the potential to cure brain tumours, thanks to its oncolytic properties.[60]
Poliovirus
Reovirus
Senecavirus
RIGVIR
Semliki Forest virus
Other
The maraba virus, first identified in Brazilian sandflies, is being tested clinically.[76]
Coxsackievirus A21 is being developed by Viralytics under trade name Cavatak.[77] Coxsackievirus A21 belongs to Enterovirus C species.[78]
Engineering oncolytic viruses
Directed evolution
An innovative approach of drug development termed "directed evolution" involves the creation of new viral variants or serotypes specifically directed against tumour cells via rounds of directed selection using large populations of randomly generated recombinant precursor viruses. The increased biodiversity produced by the initial homologous recombination step provides a large random pool of viral candidates which can then be passed through a series of selection steps designed to lead towards a pre-specified outcome (e.g. higher tumor specific activity) without requiring any previous knowledge of the resultant viral mechanisms that are responsible for that outcome. The pool of resultant oncolytic viruses can then be further screened in pre-clinical models to select an oncolytic virus with the desired therapeutic characteristics.[81]
Directed evolution was applied on human
Attenuation
Attenuation involves deleting viral genes, or gene regions, to eliminate viral functions that are expendable in tumour cells, but not in normal cells, thus making the virus safer and more tumour-specific. Cancer cells and virus-infected cells have similar alterations in their cell signalling pathways, particularly those that govern progression through the cell cycle.[82] A viral gene whose function is to alter a pathway is dispensable in cells where the pathway is defective, but not in cells where the pathway is active.[citation needed]
The enzymes thymidine kinase and ribonucleotide reductase in cells are responsible for DNA synthesis and are only expressed in cells which are actively replicating.[83] These enzymes also exist in the genomes of certain viruses (E.g. HSV, vaccinia) and allow viral replication in quiescent(non-replicating) cells,[84] so if they are inactivated by mutation the virus will only be able to replicate in proliferating cells, such as cancer cells.
Tumour targeting
There are two main approaches for generating tumour selectivity: transductional and non-transductional targeting.[85]
- Transductional targeting involves modifying the viral coat proteins to target tumour cells while reducing entry to non-tumour cells. This approach to tumour selectivity has mainly focused on adenoviruses and HSV-1, although it is entirely viable with other viruses.[85]
- Non-transductional targeting involves altering the genome of the virus so it can only replicate in cancer cells, most frequently as part of the attenuation of the virus.[85]
- Similarly, viral replication can be finely tuned with the use of microRNAs (miRNA) artificial target sites or miRNA response elements (MREs). Differential expression of miRNAs between healthy tissues and tumors permit to engineer oncolytic viruses detargeted from certain tissues of interest while allowing its replication in the tumor cells.[citation needed]
Double targeting with both transductional and non-transductional targeting methods is more effective than any one form of targeting alone.[86]
Reporter genes
Both in the laboratory and in the clinic it is useful to have a simple means of identifying cells infected by the experimental virus. This can be done by equipping the virus with "reporter genes" not normally present in viral genomes, which encode easily identifiable protein markers. One example of such proteins is GFP (green fluorescent protein) which, when present in infected cells, will cause a fluorescent green light to be emitted when stimulated by blue light.[87][88] An advantage of this method is that it can be used on live cells and in patients with superficial infected lesions, it enables rapid non-invasive confirmation of viral infection.[89] Another example of a visual marker useful in living cells is luciferase, an enzyme from the firefly which in the presence of luciferin, emits light detectable by specialized cameras.[87]
The
Modifications to improve oncolytic activity
Oncolytic viruses can be used against cancers in ways that are additional to lysis of infected cells.
Suicide genes
Viruses can be used as vectors for delivery of suicide genes, encoding enzymes that can metabolise a separately administered non-toxic
Suppression of angiogenesis
Angiogenesis (blood vessel formation) is an essential part of the formation of large tumour masses. Angiogenesis can be inhibited by the expression of several genes, which can be delivered to cancer cells in viral vectors, resulting in suppression of angiogenesis, and oxygen starvation in the tumour. The infection of cells with viruses containing the genes for angiostatin and endostatin synthesis inhibited tumour growth in mice. Enhanced antitumour activities have been demonstrated in a recombinant vaccinia virus encoding anti-angiogenic therapeutic antibody and with an HSV1716 variant expressing an inhibitor of angiogenesis.[92][93]
Radioiodine
Addition of the
Approved therapeutic agents
- US FDA approved T-VEC, with the brand name Imlygic, for the treatment of melanoma in patients with inoperable tumors.[98] becoming the first approved oncolytic agent in the western world.[99] It is based on herpes simplex virus (HSV-1).[100] It has also been tested in a Phase I trial for pancreatic cancer and a Phase III trial in head and neck cancer together with cisplatin chemotherapy and radiotherapy.[101]
- Teserpaturev (G47∆), aka Delytact by Daiichi Sankyo is a first oncolytic virus therapy approved by Japan Ministry of Health, Labour and Welfare (MHLW). Delytact is a genetically engineered oncolytic herpes simplex virus type 1 (HSV-1) approved for treatment of malignant glioma in Japan.[102]
Oncolytic viruses in conjunction with existing cancer therapies
It is in conjunction with conventional cancer therapies that oncolytic viruses have often showed the most promise, since combined therapies operate synergistically with no apparent negative effects.[103]
Clinical trials
Pre-clinical research
Chen et al. (2001)
SEPREHVIR (HSV-1716) has also shown synergy in pre-clinical research when used in combination with several cancer chemotherapies.[108][109]
The anti-angiogenesis drug bevacizumab (anti-VEGF antibody) has been shown to reduce the inflammatory response to oncolytic HSV and improve virotherapy in mice.[110] A modified oncolytic vaccinia virus encoding a single-chain anti-VEGF antibody (mimicking bevacizumab) was shown to have significantly enhanced antitumor activities than parental virus in animal models.[111]
In fiction
In science fiction, the concept of an oncolytic virus was first introduced to the public in Jack Williamson's novel Dragon's Island, published in 1951, although Williamson's imaginary virus was based on a bacteriophage rather than a mammalian virus.[112] Dragon's Island is also known for being the source of the term "genetic engineering".[113]
The plot of the Hollywood film I Am Legend is based on the premise that a worldwide epidemic was caused by a viral cure for cancer.[114]
See also
- Measles virus encoding the human thyroidal sodium iodide symporter (MV-NIS)
- Oncolytic AAV
- Oncovirus, virus that can cause cancer
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Further reading
- Harrington KJ, Vile RG, Pandha HS (2008). Viral Therapy of Cancer. Hoboken, N.J.: Wiley. ISBN 978-0-470-01922-1.
- Kirn DH, Liu TC, Thorne SH, eds. (2011). Oncolytic Viruses: Methods and Protocols (Methods in Molecular Biology). New York: Humana Press. ISBN 978-1-61779-339-4.
- Sinkovics JG, Horvath J, eds. (2005). Viral therapy of human cancers. New York: Dekker. ISBN 978-0-8247-5913-1.