oncolytic virus oncolytic virus an oncolytic virus is a virus that preferentially infects and kills cancer cells. as the infected cancer cells are destroyed by oncolysis, they release new infectious virus particles or virions to help destroy the remaining tumour. oncolytic viruses are thought not only to cause direct destruction of the tumour cells, but also to stimulate host anti-tumour immune system responses. oncolytic viruses also have the ability to affect the tumor micro-environment in multiples ways. 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. a number of viruses including adenovirus, reovirus, measles, herpes simplex, newcastle disease virus, and vaccinia have been clinically tested as oncolytic agents. most current oncolytic viruses are engineered for tumour selectivity, although there are naturally occurring examples such as reovirus and the senecavirus, resulting in clinical trials. the first oncolytic virus to be approved by a national regulatory agency was genetically unmodified echo-7 strain enterovirus rigvir, which was approved in latvia in 2004 for the treatment of skin melanoma; the approval was withdrawn in 2019. an oncolytic adenovirus, a genetically modified adenovirus named h101, was approved in china in 2005 for the treatment of head and neck cancer. in 2015, talimogene laherparepvec (oncovex, t-vec), an oncolytic herpes virus which is a modified herpes simplex virus, became the first oncolytic virus to be approved for use in the u.s. and european union, for the treatment of advanced inoperable melanoma. 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. ￼ history a connection between cancer regression and viruses has long been theorised, and case reports of regression noted in cervical cancer, burkitt lymphoma, and hodgkin lymphoma, after immunisation or infection with an unrelated virus appeared at the beginning of the 20th century. efforts to treat cancer through immunisation or virotherapy (deliberate infection with a virus), began in the mid-20th century. as the technology to create a custom virus did not exist, all early efforts focused on finding natural oncolytic viruses. during the 1960s, promising research involved using poliovirus, adenovirus, coxsackie virus, echo enterovirus rigvir, and others. the early complications were occasional cases of uncontrolled infection (resulting in significant morbidity and mortality); an immune response would also frequently develop. while not directly harmful to the patient, the response destroyed the virus thus preventing it from destroying the cancer. early efforts also found that only certain cancers could be treated through virotherapy. even when a response was seen, these responses were neither complete nor durable. the field of virotherapy was nearly abandoned for a time, as the technology required to modify viruses didn't exist whereas chemotherapy and radiotherapy technology enjoyed early success. however, now that these technologies have been thoroughly developed and cancer remains a major cause of mortality, there is still a need for novel cancer therapies, garnering this once-sidelined therapy renewed interest. herpes simplex virus main article: oncolytic herpes virus herpes simplex virus (hsv) was one of the first viruses to be adapted to attack cancer cells selectively, because it was well understood, easy to manipulate and relatively harmless in its natural state (merely causing cold sores) so likely to pose fewer risks. the herpes simplex virus type 1 (hsv-1) mutant 1716 lacks both copies of the icp34.5 gene, and as a result is no longer able to replicate in terminally differentiated and non-dividing cells but will infect and cause lysis very efficiently in cancer cells, and this has proved to be an effective tumour-targeting strategy. in a wide range of in vivo cancer models, the hsv1716 virus has induced tumour regression and increased survival times. in 1996, the first approval was given in europe for a clinical trial using the oncolytic virus hsv1716. from 1997 to 2003, strain hsv1716 was injected into tumours of patients with glioblastoma multiforme, a highly malignant brain tumour, with no evidence of toxicity or side effects, and some long-term survivors. other safety trials have used hsv1716 to treat patients with melanoma and squamous-cell carcinoma of head and neck. since then other studies have shown that the outer coating of hsv1716 variants can be targeted to specific types of cancer cells, and can be used to deliver a variety of additional genes into cancer cells, such as genes to split a harmless prodrug inside cancer cells to release toxic chemotherapy, or genes which command infected cancer cells to concentrate protein tagged with radioactive iodine, so that individual cancer cells are killed by micro-dose radiation as well as by virus-induced cell lysis. other oncolytic viruses based on hsv have also been developed and are in clinical trials. one that has been approved by the fda for advanced melanoma is amgen's talimogene laherparepvec. oncorine (h101) 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. 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. despite the promises of early in vivo lab work, these viruses do not specifically infect cancer cells, but they still kill cancer cells preferentially. while overall survival rates are not known, short-term response rates are approximately doubled for h101 plus chemotherapy when compared to chemotherapy alone. it appears to work best when injected directly into a tumour, and when any resulting fever is not suppressed. systemic therapy (such as through infusion through an intravenous line) is desirable for treating metastatic disease. it is now marketed under the brand name oncorine. mechanisms of action immunotherapy with advances in cancer immunotherapy such as immune checkpoint inhibitors, increased attention has been given to using oncolytic viruses to increase antitumor immunity. there are two main considerations of the interaction between oncolytic viruses and the immune system. 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. it has been shown that immunosuppression by chemotherapy and inhibition of the complement system can enhance oncolytic virus therapy. 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. 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. 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. 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. 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. 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. efforts to induce this phenomenon have used cancer vaccines (derived from cancer cells or selected cancer antigens), or direct treatment with immune-stimulating factors on skin cancers. some oncolytic viruses are very immunogenic and may by infection of the tumour, elicit an anti-tumor immune response, especially viruses delivering cytokines or other immune stimulating factors. viruses selectively infect tumor cells because of their defective anti-viral response. 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. oncolytic behaviour of wild-type viruses vaccinia virus 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. long before the smallpox eradication campaign was launched, vacv was exploited as a therapeutic agent for the treatment of cancer. in 1922, levaditi and nicolau reported that vacv was able to inhibit the growth of various tumors in mice and rats. this was the first demonstration of viral oncolysis in the laboratory. this virus was subsequently shown to selectively infect and destroy tumor cells with great potency, while sparing normal cells, both in cell cultures and in animal models. since vaccinia virus has long been recognized as an ideal backbone for vaccines due to its potent antigen presentation capability, this combines well with its natural oncolytic activities as an oncolytic virus for cancer immunotherapy. vesicular stomatitis virus vesicular stomatitis virus (vsv) is a rhabdovirus, consisting of 5 genes encoded by a negative sense, single-stranded rna genome. in nature, vsv infects insects as well as livestock, where it causes a relatively localized and non-fatal illness. 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. 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. vsv is therefore highly suitable for therapeutic application, and several groups have gone on to show that systemically administered vsv can be delivered to a tumour site, where it replicates and induces disease regression, often leading to durable cures. 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. recent research has shown that this virus has the potential to cure brain tumours, thanks to its oncolytic properties. poliovirus main article: pvsripo poliovirus is a natural invasive neurotropic virus, making it the obvious choice for selective replication in tumours derived from neuronal cells. poliovirus has a plus-strand rna genome, the translation of which depends on a tissue-specific internal ribosome entry site (ires) within the 5' untranslated region of the viral genome, which is active in cells of neuronal origin and allows translation of the viral genome without a 5' cap. gromeier et al. (2000) replaced the normal poliovirus ires with a rhinovirus ires, altering tissue specificity. the resulting pv1(ripo) virus was able to selectively destroy malignant glioma cells, while leaving normal neuronal cells untouched. reovirus reoviruses generally infect mammalian respiratory and bowel systems (the name deriving from an acronym, respiratory enteric orphan virus). most people have been exposed to reovirus by adulthood; however, the infection does not typically produce symptoms. the reovirus' oncolytic potential was established after they were discovered to reproduce well in various cancer cell lines, lysing these cells. reolysin is a formulation of reovirus intended to treat various cancers currently undergoing clinical trials. senecavirus 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. the initial isolate, svv-001, is being developed as an anti-cancer therapeutic by neotropix, inc. under the name ntx-010 for cancers with neuroendocrine features including small cell lung cancer and a variety of pediatric solid tumours. rigvir rigvir is a drug that was approved