Oncolytic virus
[1][2] Oncolytic viruses are thought not only to cause direct destruction of the tumour cells, but also to stimulate host anti-tumour immune system responses.
[8] Most current oncolytic viruses are engineered for tumour selectivity, although there are naturally occurring examples such as reovirus and the senecavirus,[9] resulting in clinical trials.
[13] On 16 December 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.
[16] The early complications were occasional cases of uncontrolled infection (resulting in significant morbidity and mortality); an immune response would also frequently develop.
[37] The first oncolytic virus to be approved by a regulatory agency was a genetically modified adenovirus named H101 by Shanghai Sunway Biotech.
It gained regulatory approval in 2005 from China's State Food and Drug Administration (SFDA) for the treatment of head and neck cancer.
[12][38] Sunway's H101 and the very similar Onyx-15 (dl1520) have been engineered to remove a viral defense mechanism that interacts with a normal human gene p53, which is very frequently dysregulated in cancer cells.
[47] Another way to help oncolytic viruses reach cancer growths after intravenous injection, is to hide them inside macrophages (a type of white blood cell).
[49][50] 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.
[41] Imlygic, an attenuated herpes simplex virus, has been genetically engineered to replicate preferentially within tumor cells and to generate antigens that elicit an immune response.
[41] Vaccinia virus (VACV) is arguably the most successful live biotherapeutic agent because of its critical role in the eradication of smallpox, one of the most deadly diseases in human history.
[56] Vesicular stomatitis virus (VSV) is a rhabdovirus, consisting of 5 genes encoded by a negative sense, single-stranded RNA genome.
The low pathogenicity of this virus is due in large part to its sensitivity to interferons, a class of proteins that are released into the tissues and bloodstream during infection.
These molecules activate genetic anti-viral defence programs that protect cells from infection and prevent spread of the virus.
However, in 2000, Stojdl, Lichty et al.[57] demonstrated that defects in these pathways render cancer cells unresponsive to the protective effects of interferons and therefore highly sensitive to infection with VSV.
Since VSV undergoes a rapid cytolytic replication cycle, infection leads to death of the malignant cell and roughly a 1000-fold amplification of virus within 24h.
[58][59][60][61] Attenuation of the virus by engineering a deletion of Met-51 of the matrix protein ablates virtually all infection of normal tissues, while replication in tumour cells is unaffected.
[62] Poliovirus is a natural invasive neurotropic virus, making it the obvious choice for selective replication in tumours derived from neuronal cells.
[66] Senecavirus, also known as Seneca Valley Virus, is a naturally occurring wild-type oncolytic picornavirus discovered in 2001 as a tissue culture contaminate at Genetic Therapy, Inc.
[72][73] On 19 March 2019, the manufacturer of ECHO-7, SIA LATIMA, announced the drug's removal from sale in Latvia, quoting financial and strategic reasons and insufficient profitability.
A genetically engineered form has been pre-clinically tested as an oncolytic virus against the severe brain tumour type glioblastoma.
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.
This can be done by equipping the virus with "reporter genes" not normally present in viral genomes, which encode easily identifiable protein markers.
[91] 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.
These enzymes, in the presence of certain substrates, can produce intense colored compounds useful for visualizing infected cells and also for quantifying gene expression.
Viruses can be used as vectors for delivery of suicide genes, encoding enzymes that can metabolise a separately administered non-toxic pro-drug into a potent cytotoxin, which can diffuse to and kill neighbouring cells.
One herpes simplex virus, encoding a thymidine kinase suicide gene, has progressed to phase III clinical trials.
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.
[106] Vaccinia virus GL-ONC1 was studied in a trial combined with chemo- and radiotherapy as Standard of Care for patients newly diagnosed with head & neck cancer.
[110][111] The anti-angiogenesis drug bevacizumab (anti-VEGF antibody) has been shown to reduce the inflammatory response to oncolytic HSV and improve virotherapy in mice.
