Oncolytic virus Article

From Wikipedia, the free encyclopedia
Jump to navigation Jump to search

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. [1] [2] Oncolytic viruses are thought not only to cause direct destruction of the tumour cells, but also to stimulate host anti-tumour immune responses. [3] [4]

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. [5] A number of viruses including adenovirus, reovirus, measles, herpes simplex, Newcastle disease virus and vaccinia have now been clinically tested as oncolytic agents. [6] Most current oncolytic viruses are engineered for tumour selectivity, although there are naturally occurring examples such as reovirus and the senecavirus, [7] resulting in clinical trials. [8]

The first oncolytic virus approved by a national regulatory agency is genetically not modified ECHO-7 strain enterovirus RIGVIR, approved in Latvia in 2004 for treatment of skin melanoma. [9] Later (in 2015 and 2016 respectively) it was also approved in Georgia [10] and Armenia. [11] In 2005 Chinese company, Shanghai Sunway Biotech registered an oncolytic adenovirus, a genetically modified adenovirus named H101. It gained regulatory approval in 2005 from the CFDA, for the treatment of head and neck cancer. [12] The drug talimogene laherparepvec (OncoVex, T-VEC) was the first oncolytic herpes virus (a modified herpes simplex virus), approved for use by the US FDA and by the EMA in the EU in 2015 for the treatment of advanced inoperable melanoma. In a combined decision, members of the FDA's Oncology Drug Advisory Committee and Cellular, Tissue and Gene Therapies Advisory Committee voted 22-1 to recommend approval of the oncolytic immunotherapy. [13]


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. [14] Efforts to treat cancer through immunisation or virotherapy (deliberate infection with a virus), began in the mid-20th century. [14] [15] As the technology for creating a custom virus did not exist, all early efforts focused on finding natural oncolytic viruses. During the 1960s, promising research involved using poliovirus, [16] adenovirus, [14] Coxsackie virus, [17] ECHO enterovirus RIGVIR [18] and others. [15] The early complications were occasional cases of uncontrolled infection, resulting in significant morbidity and mortality; the very frequent development of an immune response, while harmless to the patient, [14] destroyed the virus and thus prevented it from destroying the cancer. [16] Only certain cancers could be treated through virotherapy was also recognised very early. [17] Even when a response was seen, these responses were neither complete nor durable. [14] The field of virotherapy was nearly abandoned for a time, as the technology required to modify viruses didn't exist and chemotherapy and radiotherapy technology enjoyed early success. However, now these technologies have been thoroughly developed, cancer is still a major cause of mortality and there is still a need for novel cancer therapies, this sidelined therapy has now gained renewed interest. [14] [19]

Herpes simplex 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. [20] [21] In a wide range of in vivo cancer models, the HSV1716 virus has induced tumour regression and increased survival times. [22] [23] [24]

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. [25] [26] [27] Other safety trials have used HSV1716 to treat patients with melanoma and squamous-cell carcinoma of head and neck. [28] [29] Since then other studies have shown that the outer coating of HSV1716 variants can be targeted to specific types of cancer cells, [30] 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, [31] 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. [32]

Other oncolytic viruses based on HSV have also been developed and are in clinical trials. [33] One that has been approved by the FDA for advanced melanoma is Amgen's talimogene laherparepvec. [34]

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. [12] [35] Sunway's H101 and the very similar Onyx-15 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. [35] Despite the promises of early in vivo lab work, these viruses do not specifically infect cancer cells, but they still kill cancer cells preferentially. [35] While overall survival rates are not known, short-term response rates are approximately doubled for H101 plus chemotherapy when compared to chemotherapy alone. [35] It appears to work best when injected directly into a tumour, and when any resulting fever is not suppressed. [35] Systemic therapy (such as through infusion through an intravenous line) is desirable for treating metastatic disease. [36] It is now marketed under the brand name Oncorine. [37]

Mechanisms of action


With advances in cancer immunotherapy such as immune checkpoint inhibitors, increased attention has been given to using oncolytic viruses to increase antitumor immunity. [38] 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. [39] It has been shown that immunosuppression by chemotherapy and inhibition of the complement system can enhance oncolytic virus therapy. [40] [41] [42]

Pre-existing immunity can be partly avoided by using viruses that are not common human pathogens. However, this does not avoid subsequent antibody generation. However, some studies have shown that pre-immunity to oncolytic viruses doesn't cause a significant reduction in efficacy. [43]

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. [44]

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. [45]

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. [46] [47] This essentially produces a personalised Cancer vaccine.

Many cases of spontaneous remission of cancer have been recorded, though not fully understood, they are thought likely to be a result of a sudden immune response or infection. [48] 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. [49] 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. [50] [51]

Viruses selectively infect tumor cells because of their defective anti-viral response. [38] Imlygic, an attenuated herpes simplex virus, has been genetically engineered to replicate preferentially within tumor cells and to generate antigens that illicit an immune response. [38]

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. [52] 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. [53] [54] [55] [56] 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. [53]

Recent research has shown that this virus has the potential to cure brain tumours, thanks to its oncolytic properties. [57]


Poliovirus is a natural neuropathogen, 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) [58] 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. [59]


Reoviruses, an acronym for respiratory enteric orphan virus, generally infect mammalian respiratory and bowel systems. Most people have been exposed to reovirus by adulthood; however, the infection does not typically produce symptoms. The link to the reovirus' oncolytic ability was established after it was discovered to reproduce well in various cancer cell lines and lyses these cells. [60]

Reolysin is a formulation of reovirus that is currently in clinical trials for the treatment of various cancers. [61]


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 is a drug that was approved by the State Agency of Medicines of the Republic of Latvia in 2004. [62] It is wild type ECHO-7, a member of echovirus family. [63] The potential use of echovirus as an oncolytic virus to treat cancer was discovered by Latvian scientist Aina Muceniece in the 1960s and 1970s. [63] The data used to register the drug in Latvia is not sufficient to obtain approval to use it in the US, Europe, or Japan. [63] [64] As of 2017 there was no good evidence that RIGVIR is an effective cancer treatment. [65] [66]

Semliki Forest virus

Semliki Forest virus (SFV) is a virus that naturally infects cells of the central nervous system and causes encephalitis. A genetically engineered form has been pre-clinically tested as an oncolytic virus against the severe brain tumour type glioblastoma. The SFV was genetically modified with microRNA target sequences so that it only replicated in brain tumour cells and not in normal brain cells. The modified virus reduced tumour growth and prolonged survival of mice with brain tumours. [67] The modified virus was also found to efficiently kill human glioblastoma tumour cell lines. [67]


The maraba virus, first identified in Brazilian sandflies, is being tested clinically. [68]

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. [69]

Directed evolution was applied on human adenovirus, one of many viruses that are being developed as oncolytic agents, to create a highly selective and yet potent oncolytic vaccine. As a result of this process, ColoAd1 (a novel chimeric member of the group B adenoviruses) was generated. This hybrid of adenovirus serotypes Ad11p and Ad3 shows much higher potency and tumour selectivity than the control viruses (including Ad5, Ad11p and Ad3) and was confirmed to generate approximately two logs more viral progeny on freshly isolated human colon tumour tissue than on matching normal tissue. [69]


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. [70] 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.

The enzymes thymidine kinase and ribonucleotide reductase in cells are responsible for DNA synthesis and are only expressed in cells which are actively replicating. [71] These enzymes also exist in the genomes of certain viruses (E.g. HSV, vaccinia) and allow viral replication in quiescent(non-replicating) cells, [72] 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. [73]

  • 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. [73]
  • 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. [73]
    • Transcription targeting can also be used, where critical parts of the viral genome are placed under the control of a tumour-specific promoter. A suitable promoter should be active in the tumour but inactive in the majority of normal tissue, particularly the liver, which is the organ that is most exposed to blood born viruses. Many such promoters have been identified and studied for the treatment of a range of cancers. [73]
    • 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.

Double targeting with both transductional and non-transductional targeting methods is more effective than any one form of targeting alone. [74]

Reporter genes

Viral luciferase expression in a mouse tumour

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. [75] [76] 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. [77] 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. [75]

Vaccinia virus infected cells expressing beta-glucuronidase (blue colour)

The E. coli enzymes beta-glucuronidase and beta-galactosidase can also be encoded by some viruses. These enzymes, in the presence of certain substrates, can produce intense colored compounds useful for visualizing infected cells and also for quantifying gene expression.

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 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. The herpes simplex virus thymidine kinase phosphorylates the pro-drug, ganciclovir, which is then incorporated into DNA, blocking DNA synthesis. [78] The tumour selectivity of oncolytic viruses ensures that the suicide genes are only expressed in cancer cells, however a 'bystander effect' on surrounding tumour cells has been described with several suicide gene systems. [79]

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. [80] [81]


Adenoviral NIS gene expression in a mouse tumour (Located at the crosshairs) following intravenous delivery of virus (Left) compared to an uninfected control mouse (Right)

Addition of the sodium-iodide symporter (NIS) gene to the viral genome causes infected tumour cells to express NIS and accumulate iodine. When combined with radioiodine therapy it allows local radiotherapy of the tumour, as used to treat thyroid cancer. The radioiodine can also be used to visualise viral replication within the body by the use of a gamma camera. [75] This approach has been used successfully preclinically with adenovirus, measles virus and vaccinia virus. [82] [83] [84]

Approved therapeutic agents

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. [90]

Clinical trials

Onyx-015 underwent trials in conjunction with chemotherapy before it was abandoned in the early 2000s. The combined treatment gave a greater response than either treatment alone, but the results were not entirely conclusive. [91] 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. [92] Herpes simplex virus, adenovirus, reovirus and murine leukemia virus are also undergoing clinical trials as a part of combination therapies. [93]

Pre-clinical research

Chen et al. (2001) [94] used CV706, a prostate-specific adenovirus, in conjunction with radiotherapy on prostate cancer in mice. The combined treatment resulted in a synergistic increase in cell death, as well as a significant increase in viral burst size (the number of virus particles released from each cell lysis). No alteration in viral specificity was observed.

SEPREHVIR (HSV-1716) has also shown synergy in pre-clinical research when used in combination with several cancer chemotherapies. [95] [96]

The anti- angiogenesis drug Bevacizumab (anti- VEGF antibody) has been shown to reduce the inflammatory response to oncolytic HSV and improve virotherapy in mice. [97] 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. [98]

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. [99] Dragon's Island is also known for being the source of the term " genetic engineering". [100]

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. [101]

In the Fox Broadcasting Company Tv series House (TV series) Season 2 Episode 19, a strain of Herpes simplex virus is shown to have shrunk a hepatic tumor.

See also


  1. ^ Ferguson MS, Lemoine NR, Wang Y (2012). "Systemic delivery of oncolytic viruses: hopes and hurdles". Advances in Virology. 2012: 805629. doi: 10.1155/2012/805629. PMID  22400027.
  2. ^ Casjens S (2010). "Oncolytic virus". In Mahy BW, Van Regenmortel MH. Desk Encyclopedia of General Virology. Boston: Academic Press. p. 167. ISBN  978-0-12-375146-1.
  3. ^ Melcher A, Parato K, Rooney CM, Bell JC (June 2011). "Thunder and lightning: immunotherapy and oncolytic viruses collide". Molecular Therapy. 19 (6): 1008–16. doi: 10.1038/mt.2011.65. PMC  3129809. PMID  21505424.
  4. ^ Lichty BD, Breitbach CJ, Stojdl DF, Bell JC (August 2014). "Going viral with cancer immunotherapy". Nature Reviews. Cancer. 14 (8): 559–67. doi: 10.1038/nrc3770. PMID  24990523.
  5. ^ Alemany R (March 2013). "Viruses in cancer treatment". Clinical & Translational Oncology. 15 (3): 182–8. doi: 10.1007/s12094-012-0951-7. PMID  23143950.
  6. ^ Donnelly OG, Errington-Mais F, Prestwich R, Harrington K, Pandha H, Vile R, Melcher AA (July 2012). "Recent clinical experience with oncolytic viruses". Current Pharmaceutical Biotechnology. 13 (9): 1834–41. doi: 10.2174/138920112800958904. PMID  21740364.
  7. ^ Roberts MS, Lorence RM, Groene WS, Bamat MK (August 2006). "Naturally oncolytic viruses". Current Opinion in Molecular Therapeutics. 8 (4): 314–21. PMID  16955694.
  8. ^ Rudin CM, Poirier JT, Senzer NN, Stephenson J, Loesch D, Burroughs KD, Reddy PS, Hann CL, Hallenbeck PL (February 2011). "Phase I clinical study of Seneca Valley Virus (SVV-001), a replication-competent picornavirus, in advanced solid tumors with neuroendocrine features". Clinical Cancer Research. 17 (4): 888–95. doi: 10.1158/1078-0432.CCR-10-1706. PMC  5317273. PMID  21304001.
  9. ^ "Rigvir šķīdums injekcijām". Medicinal product register of the Republic of Latvia. 2004-04-29. Retrieved 2016-12-08.
  10. ^ "Georgia Today".
  11. ^ "Latvian Rigvir anti-cancer medicine registered in Armenia". The Baltic Course. 11 May 2016. Retrieved 3 January 2018.
  12. ^ a b Frew SE, Sammut SM, Shore AF, Ramjist JK, Al-Bader S, Rezaie R, Daar AS, Singer PA (January 2008). "Chinese health biotech and the billion-patient market". Nature Biotechnology. 26 (1): 37–53. doi: 10.1038/nbt0108-37. PMID  18183014.
  13. ^ Broderick J. "FDA Panels Support Approval of T-VEC in Melanoma". OncLive. Retrieved 24 Aug 2015.
  14. ^ a b c d e f Kuruppu D, Tanabe KK (May 2005). "Viral oncolysis by herpes simplex virus and other viruses". Cancer Biology & Therapy. 4 (5): 524–31. doi: 10.4161/cbt.4.5.1820. PMID  15917655.
  15. ^ a b Voroshilova MK (1989). "Potential use of nonpathogenic enteroviruses for control of human disease". Progress in Medical Virology. Fortschritte Der Medizinischen Virusforschung. Progres en Virologie Medicale. 36: 191–202. PMID  2555836.
  16. ^ a b Pond AR, Manuelidis EE (August 1964). "Oncolytic Effect of Poliomyelitis Virus on Human Epidermoid Carcinoma (Hela Tumor) Heterologously Transplanted to Guinea Pigs". The American Journal of Pathology. 45 (2): 233–49. PMC  1907181. PMID  14202523.
  17. ^ a b Kunin CM (December 1964). "Cellular Susceptibility to Enteroviruses". Bacteriological Reviews. 28 (4): 382–90. PMC  441234. PMID  14244713.
  18. ^ Chumakov PM, Morozova VV, Babkin IV, Baĭkov IK, Netesov SV, Tikunova NV (2012). "[Oncolytic enteroviruses]". Molekuliarnaia Biologiia (in Russian). 46 (5): 712–25. doi: 10.1134/s0026893312050032. PMID  23156670.
  19. ^ Kelly E, Russell SJ (April 2007). "History of oncolytic viruses: genesis to genetic engineering". Molecular Therapy. 15 (4): 651–9. doi: 10.1038/sj.mt.6300108. PMID  17299401.
  20. ^ MacLean AR, ul-Fareed M, Robertson L, Harland J, Brown SM (March 1991). "Herpes simplex virus type 1 deletion variants 1714 and 1716 pinpoint neurovirulence-related sequences in Glasgow strain 17+ between immediate early gene 1 and the 'a' sequence". The Journal of General Virology. 72 ( Pt 3) (3): 631–9. doi: 10.1099/0022-1317-72-3-631. PMID  1848598.
  21. ^ Brown SM, Harland J, MacLean AR, Podlech J, Clements JB (September 1994). "Cell type and cell state determine differential in vitro growth of non-neurovirulent ICP34.5-negative herpes simplex virus types 1 and 2". The Journal of General Virology. 75 ( Pt 9) (9): 2367–77. doi: 10.1099/0022-1317-75-9-2367. PMID  8077935.
  22. ^ Kesari S, Randazzo BP, Valyi-Nagy T, Huang QS, Brown SM, MacLean AR, Lee VM, Trojanowski JQ, Fraser NW (November 1995). "Therapy of experimental human brain tumors using a neuroattenuated herpes simplex virus mutant". Laboratory Investigation; A Journal of Technical Methods and Pathology. 73 (5): 636–48. PMID  7474937.
  23. ^ McKie EA, MacLean AR, Lewis AD, Cruickshank G, Rampling R, Barnett SC, Kennedy PG, Brown SM (September 1996). "Selective in vitro replication of herpes simplex virus type 1 (HSV-1) ICP34.5 null mutants in primary human CNS tumours--evaluation of a potentially effective clinical therapy". British Journal of Cancer. 74 (5): 745–52. doi: 10.1038/bjc.1996.431. PMC  2074706. PMID  8795577.
  24. ^ Randazzo BP, Bhat MG, Kesari S, Fraser NW, Brown SM (June 1997). "Treatment of experimental subcutaneous human melanoma with a replication-restricted herpes simplex virus mutant". The Journal of Investigative Dermatology. 108 (6): 933–7. doi: 10.1111/1523-1747.ep12295238. PMID  9182825.
  25. ^ Rampling R, Cruickshank G, Papanastassiou V, Nicoll J, Hadley D, Brennan D, Petty R, MacLean A, Harland J, McKie E, Mabbs R, Brown M (May 2000). "Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma". Gene Therapy. 7 (10): 859–66. doi: 10.1038/sj.gt.3301184. PMID  10845724.
  26. ^ Papanastassiou V, Rampling R, Fraser M, Petty R, Hadley D, Nicoll J, Harland J, Mabbs R, Brown M (March 2002). "The potential for efficacy of the modified (ICP 34.5(-)) herpes simplex virus HSV1716 following intratumoural injection into human malignant glioma: a proof of principle study". Gene Therapy. 9 (6): 398–406. doi: 10.1038/sj.gt.3301664. PMID  11960316.
  27. ^ Harrow S, Papanastassiou V, Harland J, Mabbs R, Petty R, Fraser M, Hadley D, Patterson J, Brown SM, Rampling R (November 2004). "HSV1716 injection into the brain adjacent to tumour following surgical resection of high-grade glioma: safety data and long-term survival". Gene Therapy. 11 (22): 1648–58. doi: 10.1038/sj.gt.3302289. PMID  15334111.
  28. ^ MacKie RM, Stewart B, Brown SM (February 2001). "Intralesional injection of herpes simplex virus 1716 in metastatic melanoma". Lancet. 357 (9255): 525–6. doi: 10.1016/S0140-6736(00)04048-4. PMID  11229673.
  29. ^ Mace AT, Ganly I, Soutar DS, Brown SM (August 2008). "Potential for efficacy of the oncolytic Herpes simplex virus 1716 in patients with oral squamous cell carcinoma". Head & Neck. 30 (8): 1045–51. doi: 10.1002/hed.20840. PMID  18615711.
  30. ^ Conner J, Braidwood L, Brown SM (December 2008). "A strategy for systemic delivery of the oncolytic herpes virus HSV1716: redirected tropism by antibody-binding sites incorporated on the virion surface as a glycoprotein D fusion protein". Gene Therapy. 15 (24): 1579–92. doi: 10.1038/gt.2008.121. PMID  18701918.
  31. ^ Braidwood L, Dunn PD, Hardy S, Evans TR, Brown SM (June 2009). "Antitumor activity of a selectively replication competent herpes simplex virus (HSV) with enzyme prodrug therapy". Anticancer Research. 29 (6): 2159–66. PMID  19528476.
  32. ^ Sorensen A, Mairs RJ, Braidwood L, Joyce C, Conner J, Pimlott S, Brown M, Boyd M (April 2012). "In vivo evaluation of a cancer therapy strategy combining HSV1716-mediated oncolysis with gene transfer and targeted radiotherapy". Journal of Nuclear Medicine. 53 (4): 647–54. doi: 10.2967/jnumed.111.090886. PMID  22414636.
  33. ^ Turnbull S, West EJ, Scott KJ, Appleton E, Melcher A, Ralph C (December 2015). "Evidence for Oncolytic Virotherapy: Where Have We Got to and Where Are We Going?". Viruses. 7 (12): 6291–312. doi: 10.3390/v7122938. PMC  4690862. PMID  26633468.
  34. ^ Conry RM, Westbrook B, McKee S, Norwood TG (February 2018). "Talimogene laherparepvec: First in class oncolytic virotherapy". Human Vaccines & Immunotherapeutics: 1–8. doi: 10.1080/21645515.2017.1412896. PMID  29420123.
  35. ^ a b c d e Garber K (March 2006). "China approves world's first oncolytic virus therapy for cancer treatment". Journal of the National Cancer Institute. 98 (5): 298–300. doi: 10.1093/jnci/djj111. PMID  16507823.
  36. ^ Ayllón Barbellido S, Campo Trapero J, Cano Sánchez J, Perea García MA, Escudero Castaño N, Bascones Martínez A (January 2008). "Gene therapy in the management of oral cancer: review of the literature" (PDF). Medicina Oral, Patologia Oral Y Cirugia Bucal. 13 (1): E15–21. PMID  18167474.
  37. ^ Guo J, Xin H (November 2006). "Chinese gene therapy. Splicing out the West?". Science. 314 (5803): 1232–5. doi: 10.1126/science.314.5803.1232. PMID  17124300.
  38. ^ a b c Marin-Acevedo JA, Soyano AE, Dholaria B, Knutson KL, Lou Y (January 2018). "Cancer immunotherapy beyond immune checkpoint inhibitors". Journal of Hematology & Oncology. 11 (1): 8. doi: 10.1186/s13045-017-0552-6. PMC  5767051. PMID  29329556.
  39. ^ Schmidt C (May 2013). "Awaiting a moment of truth for oncolytic viruses". Journal of the National Cancer Institute. 105 (10): 675–6. doi: 10.1093/jnci/djt111. PMID  23650626.
  40. ^ Kottke T, Thompson J, Diaz RM, Pulido J, Willmon C, Coffey M, Selby P, Melcher A, Harrington K, Vile RG (January 2009). "Improved systemic delivery of oncolytic reovirus to established tumors using preconditioning with cyclophosphamide-mediated Treg modulation and interleukin-2". Clinical Cancer Research. 15 (2): 561–9. doi: 10.1158/1078-0432.CCR-08-1688. PMC  3046733. PMID  19147761.
  41. ^ Lolkema MP, Arkenau HT, Harrington K, Roxburgh P, Morrison R, Roulstone V, Twigger K, Coffey M, Mettinger K, Gill G, Evans TR, de Bono JS (February 2011). "A phase I study of the combination of intravenous reovirus type 3 Dearing and gemcitabine in patients with advanced cancer". Clinical Cancer Research. 17 (3): 581–8. doi: 10.1158/1078-0432.CCR-10-2159. PMID  21106728.
  42. ^ Magge D, Guo ZS, O'Malley ME, Francis L, Ravindranathan R, Bartlett DL (June 2013). "Inhibitors of C5 complement enhance vaccinia virus oncolysis". Cancer Gene Therapy. 20 (6): 342–50. doi: 10.1038/cgt.2013.26. PMC  4060830. PMID  23661042.
  43. ^ Heo J, Reid T, Ruo L, Breitbach CJ, Rose S, Bloomston M, Cho M, Lim HY, Chung HC, Kim CW, Burke J, Lencioni R, Hickman T, Moon A, Lee YS, Kim MK, Daneshmand M, Dubois K, Longpre L, Ngo M, Rooney C, Bell JC, Rhee BG, Patt R, Hwang TH, Kirn DH (March 2013). "Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer". Nature Medicine. 19 (3): 329–36. doi: 10.1038/nm.3089. PMC  4268543. PMID  23396206.
  44. ^ Wonganan P, Croyle MA (February 2010). "PEGylated Adenoviruses: From Mice to Monkeys". Viruses. 2 (2): 468–502. doi: 10.3390/v2020468. PMC  3185605. PMID  21994645.
  45. ^ Muthana M, Rodrigues S, Chen YY, Welford A, Hughes R, Tazzyman S, Essand M, Morrow F, Lewis CE, Marniemi J, Parkki MG (September 1975). "Radiochemical assay of glutathione S-epoxide transferase and its enhancement by phenobarbital in rat liver in vivo". Biochemical Pharmacology. 24 (17): 1569–72. doi: 10.1158/0008-5472.CAN-12-3056. PMID  23172310.
  46. ^ Tong AW, Senzer N, Cerullo V, Templeton NS, Hemminki A, Nemunaitis J (July 2012). "Oncolytic viruses for induction of anti-tumor immunity". Current Pharmaceutical Biotechnology. 13 (9): 1750–60. doi: 10.2174/138920112800958913. PMID  21740355.
  47. ^ Naik JD, Twelves CJ, Selby PJ, Vile RG, Chester JD (July 2011). "Immune recruitment and therapeutic synergy: keys to optimizing oncolytic viral therapy?". Clinical Cancer Research. 17 (13): 4214–24. doi: 10.1158/1078-0432.CCR-10-2848. PMC  3131422. PMID  21576084.
  48. ^ O'Regan B, Hirshberg C (1993). Spontaneous Remission: An Annotated Bibliography. Sausalito, California: Institute of Noetic Sciences. ISBN  978-0-943951-17-1.[ page needed]
  49. ^ Lattime E (2013). Gene Therapy of Cancer: Translational Approaches from Preclinical Studies to Clinical Implementation. Academic Press. ISBN  978-0-12-394295-1.[ page needed]
  50. ^ Mastrangelo MJ, Lattime EC (December 2002). "Virotherapy clinical trials for regional disease: in situ immune modulation using recombinant poxvirus vectors". Cancer Gene Therapy. 9 (12): 1013–21. doi: 10.1038/sj.cgt.7700538. PMID  12522440.
  51. ^ Lundstrom K (2018). "New frontiers in oncolytic viruses: optimizing and selecting for virus strains with improved efficacy". Biologics: Targets & Therapy. 12: 43–60. doi: 10.2147/BTT.S140114. PMC  5810530. PMID  29445265.
  52. ^ Stojdl DF, Lichty B, Knowles S, Marius R, Atkins H, Sonenberg N, Bell JC (July 2000). "Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus". Nature Medicine. 6 (7): 821–5. doi: 10.1038/77558. PMID  10888934.
  53. ^ a b Stojdl DF, Lichty BD, tenOever BR, Paterson JM, Power AT, Knowles S, Marius R, Reynard J, Poliquin L, Atkins H, Brown EG, Durbin RK, Durbin JE, Hiscott J, Bell JC (October 2003). "VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents". Cancer Cell. 4 (4): 263–75. doi: 10.1016/S1535-6108(03)00241-1. PMID  14585354.
  54. ^ Ahmed M, Cramer SD, Lyles DS (December 2004). "Sensitivity of prostate tumors to wild type and M protein mutant vesicular stomatitis viruses". Virology. 330 (1): 34–49. doi: 10.1016/j.virol.2004.08.039. PMID  15527832.
  55. ^ Ebert O, Harbaran S, Shinozaki K, Woo SL (April 2005). "Systemic therapy of experimental breast cancer metastases by mutant vesicular stomatitis virus in immune-competent mice". Cancer Gene Therapy. 12 (4): 350–8. doi: 10.1038/sj.cgt.7700794. PMID  15565179.
  56. ^ Porosnicu M, Mian A, Barber GN (December 2003). "The oncolytic effect of recombinant vesicular stomatitis virus is enhanced by expression of the fusion cytosine deaminase/uracil phosphoribosyltransferase suicide gene". Cancer Research. 63 (23): 8366–76. PMID  14678998.
  57. ^ Bridle BW, Stephenson KB, Boudreau JE, Koshy S, Kazdhan N, Pullenayegum E, Brunellière J, Bramson JL, Lichty BD, Wan Y (August 2010). "Potentiating cancer immunotherapy using an oncolytic virus". Molecular Therapy. 18 (8): 1430–9. doi: 10.1038/mt.2010.98. PMC  2927075. PMID  20551919.
  58. ^ Gromeier M, Lachmann S, Rosenfeld MR, Gutin PH, Wimmer E (June 2000). "Intergeneric poliovirus recombinants for the treatment of malignant glioma". Proceedings of the National Academy of Sciences of the United States of America. 97 (12): 6803–8. Bibcode: 2000PNAS...97.6803G. doi: 10.1073/pnas.97.12.6803. JSTOR  122718. PMC  18745. PMID  10841575.
  59. ^ Goetz C, Gromeier M (2010). "Preparing an oncolytic poliovirus recombinant for clinical application against glioblastoma multiforme". Cytokine & Growth Factor Reviews. 21 (2–3): 197–203. doi: 10.1016/j.cytogfr.2010.02.005. PMC  2881183. PMID  20299272.
  60. ^ Lal R, Harris D, Postel-Vinay S, de Bono J (October 2009). "Reovirus: Rationale and clinical trial update". Current Opinion in Molecular Therapeutics. 11 (5): 532–9. PMID  19806501.
  61. ^ Thirukkumaran C, Morris DG (2009). "Oncolytic viral therapy using reovirus". Methods in Molecular Biology. Gene Therapy of Cancer. 542: 607–34. doi: 10.1007/978-1-59745-561-9_31. ISBN  978-1-934115-85-5. PMID  19565924.
  62. ^ "Latvijas Zāļu reģistrs". www.zva.gov.lv. Retrieved 2017-12-17.
  63. ^ a b c Babiker, HM; Riaz, IB; Husnain, M; Borad, MJ (2017). "Oncolytic virotherapy including Rigvir and standard therapies in malignant melanoma". Oncolytic virotherapy. 6: 11–18. doi: 10.2147/OV.S100072. PMC  5308590. PMID  28224120.
  64. ^ "Feasibility study for registration of medicine RIGVIR with the European Medicine Agency". European Commission. 2016-01-08. Archived from the original on 2016-11-02. Retrieved 2016-11-02. However, further use and commercialisation in the EU is prevented as EU regulations require cancer medicines to be registered centrally through the European Medicine Agency (EMA). National registrations are not considered.
  65. ^ Gorski D (18 September 2017). "Rigvir: Another unproven and dubious cancer therapy to be avoided". Science-Based Medicine.
  66. ^ Gorski, David (25 September 2017). "Ty Bollinger's "The Truth About Cancer" and the unethical marketing of the unproven cancer virotherapy Rigvir". Science-Based Medicine.
  67. ^ a b Ramachandran M, Yu D, Dyczynski M, Baskaran S, Zhang L, Lulla A, Lulla V, Saul S, Nelander S, Dimberg A, Merits A, Leja-Jarblad J, Essand M (March 2017). "Safe and Effective Treatment of Experimental Neuroblastoma and Glioblastoma Using Systemically Delivered Triple MicroRNA-Detargeted Oncolytic Semliki Forest Virus". Clinical Cancer Research. 23 (6): 1519–1530. doi: 10.1158/1078-0432.CCR-16-0925. PMID  27637889.
  68. ^ Clinical trial number NCT02285816 for "MG1 Maraba/MAGE-A3, With and Without Adenovirus Vaccine, With Transgenic MAGE-A3 Insertion in Patients With Incurable MAGE-A3-Expressing Solid Tumours (I214)" at ClinicalTrials.gov
  69. ^ a b Kuhn I, Harden P, Bauzon M, Chartier C, Nye J, Thorne S, Reid T, Ni S, Lieber A, Fisher K, Seymour L, Rubanyi GM, Harkins RN, Hermiston TW (June 2008). "Directed evolution generates a novel oncolytic virus for the treatment of colon cancer". PLOS One. 3 (6): e2409. Bibcode: 2008PLoSO...3.2409K. doi: 10.1371/journal.pone.0002409. PMC  2423470. PMID  18560559.
  70. ^ Chow AY. "Cell Cycle Control by Oncogenes and Tumor Suppressors: Driving the Transformation of Normal Cells into Cancerous Cells". Nature Education. Nature Education. 3 (9): 7. Retrieved 5 April 2013.
  71. ^ "Thymidine kinase". Medical Dictionary. Merriam-Webster. Retrieved 5 April 2013.
  72. ^ Gentry GA (1992). "Viral thymidine kinases and their relatives". Pharmacology & Therapeutics. 54 (3): 319–55. doi: 10.1016/0163-7258(92)90006-L. PMID  1334563.
  73. ^ a b c d Singh PK, Doley J, Kumar GR, Sahoo AP, Tiwari AK (October 2012). "Oncolytic viruses & their specific targeting to tumour cells". The Indian Journal of Medical Research. 136 (4): 571–84. PMC  3516024. PMID  23168697.
  74. ^ Davydova J, Le LP, Gavrikova T, Wang M, Krasnykh V, Yamamoto M (June 2004). "Infectivity-enhanced cyclooxygenase-2-based conditionally replicative adenoviruses for esophageal adenocarcinoma treatment". Cancer Research. 64 (12): 4319–27. doi: 10.1158/0008-5472.CAN-04-0064. PMID  15205347.
  75. ^ a b c Haddad D, Chen CH, Carlin S, Silberhumer G, Chen NG, Zhang Q, Longo V, Carpenter SG, Mittra A, Carson J, Au J, Gonen M, Zanzonico PB, Szalay AA, Fong Y (2012). Gelovani JG, ed. "Imaging characteristics, tissue distribution, and spread of a novel oncolytic vaccinia virus carrying the human sodium iodide symporter". PLOS One. 7 (8): e41647. Bibcode: 2012PLoSO...741647H. doi: 10.1371/journal.pone.0041647. PMC  3422353. PMID  22912675.
  76. ^ Poirier JT, Reddy PS, Idamakanti N, Li SS, Stump KL, Burroughs KD, Hallenbeck PL, Rudin CM (December 2012). "Characterization of a full-length infectious cDNA clone and a GFP reporter derivative of the oncolytic picornavirus SVV-001". The Journal of General Virology. 93 (Pt 12): 2606–13. doi: 10.1099/vir.0.046011-0. PMID  22971818.
  77. ^ Yu YA, Shabahang S, Timiryasova TM, Zhang Q, Beltz R, Gentschev I, Goebel W, Szalay AA (March 2004). "Visualization of tumors and metastases in live animals with bacteria and vaccinia virus encoding light-emitting proteins". Nature Biotechnology. 22 (3): 313–20. doi: 10.1038/nbt937. PMID  14990953.
  78. ^ Freeman SM, Whartenby KA, Freeman JL, Abboud CN, Marrogi AJ (February 1996). "In situ use of suicide genes for cancer therapy". Seminars in Oncology. 23 (1): 31–45. PMID  8607030.
  79. ^ Duarte S, Carle G, Faneca H, de Lima MC, Pierrefite-Carle V (November 2012). "Suicide gene therapy in cancer: where do we stand now?". Cancer Letters. 324 (2): 160–70. doi: 10.1016/j.canlet.2012.05.023. PMID  22634584.
  80. ^ Frentzen A, Yu YA, Chen N, Zhang Q, Weibel S, Raab V, Szalay AA (August 2009). "Anti-VEGF single-chain antibody GLAF-1 encoded by oncolytic vaccinia virus significantly enhances antitumor therapy". Proceedings of the National Academy of Sciences of the United States of America. 106 (31): 12915–20. Bibcode: 2009PNAS..10612915F. doi: 10.1073/pnas.0900660106. JSTOR  40484625. PMC  2722284. PMID  19617539.
  81. ^ Conner J, Braidwood L (July 2012). "Expression of inhibitor of growth 4 by HSV1716 improves oncolytic potency and enhances efficacy". Cancer Gene Therapy. 19 (7): 499–507. doi: 10.1038/cgt.2012.24. PMID  22595793.
  82. ^ Grünwald GK, Klutz K, Willhauck MJ, Schwenk N, Senekowitsch-Schmidtke R, Schwaiger M, Zach C, Göke B, Holm PS, Spitzweg C (June 2013). "Sodium iodide symporter (NIS)-mediated radiovirotherapy of hepatocellular cancer using a conditionally replicating adenovirus". Gene Therapy. 20 (6): 625–33. doi: 10.1038/gt.2012.79. PMID  23038026.
  83. ^ Penheiter AR, Wegman TR, Classic KL, Dingli D, Bender CE, Russell SJ, Carlson SK (August 2010). "Sodium iodide symporter (NIS)-mediated radiovirotherapy for pancreatic cancer". AJR. American Journal of Roentgenology. 195 (2): 341–9. doi: 10.2214/AJR.09.3672. PMC  3117397. PMID  20651188.
  84. ^ Li H, Peng KW, Dingli D, Kratzke RA, Russell SJ (August 2010). "Oncolytic measles viruses encoding interferon beta and the thyroidal sodium iodide symporter gene for mesothelioma virotherapy". Cancer Gene Therapy. 17 (8): 550–8. doi: 10.1038/cgt.2010.10. PMC  2907639. PMID  20379224.
  85. ^ Clinical trial number NCT00769704 for "Efficacy and Safety Study of OncoVEXGM-CSF Compared to GM-CSF in Melanoma" at ClinicalTrials.gov
  86. ^ "FDA approves Amgen's Injected Immunotherapy for Melanoma". Reuters. 27 October 2015.
  87. ^ Sheridan C (June 2015). "First oncolytic virus edges towards approval in surprise vote". Nature Biotechnology. 33 (6): 569–70. doi: 10.1038/nbt0615-569. PMID  26057953.
  88. ^ "Amgen, Form 8-K, Current Report, Filing Date Jan 26, 2012" (PDF). secdatabase.com. Retrieved Jan 8, 2013.
  89. ^ Clinical trial number NCT01161498 for "Study of Safety and Efficacy of OncoVEXGM-CSF With Cisplatin for Treatment of Locally Advanced Head and Neck Cancer" at ClinicalTrials.gov
  90. ^ Ottolino-Perry K, Diallo JS, Lichty BD, Bell JC, McCart JA (February 2010). "Intelligent design: combination therapy with oncolytic viruses". Molecular Therapy. 18 (2): 251–63. doi: 10.1038/mt.2009.283. PMC  2839289. PMID  20029399.
  91. ^ Khuri FR, Nemunaitis J, Ganly I, Arseneau J, Tannock IF, Romel L, Gore M, Ironside J, MacDougall RH, Heise C, Randlev B, Gillenwater AM, Bruso P, Kaye SB, Hong WK, Kirn DH (August 2000). "a controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer". Nature Medicine. 6 (8): 879–85. doi: 10.1038/78638. PMID  10932224.
  92. ^ Mell LK, Brumund KT, Daniels GA, Advani SJ, Zakeri K, Wright ME, Onyeama SJ, Weisman RA, Sanghvi PR, Martin PJ, Szalay AA (October 2017). "Phase I Trial of Intravenous Oncolytic Vaccinia Virus (GL-ONC1) with Cisplatin and Radiotherapy in Patients with Locoregionally Advanced Head and Neck Carcinoma". Clinical Cancer Research. 23 (19): 5696–5702. doi: 10.1158/1078-0432.CCR-16-3232. PMID  28679776.
  93. ^ Suryawanshi YR, Zhang T, Essani K (March 2017). "Oncolytic viruses: emerging options for the treatment of breast cancer". Medical Oncology. 34 (3): 43. doi: 10.1007/s12032-017-0899-0. PMID  28185165.
  94. ^ Chen Y, DeWeese T, Dilley J, Zhang Y, Li Y, Ramesh N, Lee J, Pennathur-Das R, Radzyminski J, Wypych J, Brignetti D, Scott S, Stephens J, Karpf DB, Henderson DR, Yu DC (July 2001). "CV706, a prostate cancer-specific adenovirus variant, in combination with radiotherapy produces synergistic antitumor efficacy without increasing toxicity". Cancer Research. 61 (14): 5453–60. PMID  11454691.
  95. ^ Mace AT, Harrow SJ, Ganly I, Brown SM (August 2007). "Cytotoxic effects of the oncolytic herpes simplex virus HSV1716 alone and in combination with cisplatin in head and neck squamous cell carcinoma". Acta Oto-Laryngologica. 127 (8): 880–7. doi: 10.1080/00016480601075381. PMID  17763002.
  96. ^ Toyoizumi T, Mick R, Abbas AE, Kang EH, Kaiser LR, Molnar-Kimber KL (December 1999). "Combined therapy with chemotherapeutic agents and herpes simplex virus type 1 ICP34.5 mutant (HSV-1716) in human non-small cell lung cancer". Human Gene Therapy. 10 (18): 3013–29. doi: 10.1089/10430349950016410. PMID  10609661.
  97. ^ Currier MA, Eshun FK, Sholl A, Chernoguz A, Crawford K, Divanovic S, Boon L, Goins WF, Frischer JS, Collins MH, Leddon JL, Baird WH, Haseley A, Streby KA, Wang PY, Hendrickson BW, Brekken RA, Kaur B, Hildeman D, Cripe TP (May 2013). "VEGF blockade enables oncolytic cancer virotherapy in part by modulating intratumoral myeloid cells". Molecular Therapy. 21 (5): 1014–23. doi: 10.1038/mt.2013.39. PMC  3666636. PMID  23481323.
  98. ^ Frentzen A, Yu YA, Chen N, Zhang Q, Weibel S, Raab V, Szalay AA (August 2009). "Anti-VEGF single-chain antibody GLAF-1 encoded by oncolytic vaccinia virus significantly enhances antitumor therapy". Proceedings of the National Academy of Sciences of the United States of America. 106 (31): 12915–20. Bibcode: 2009PNAS..10612915F. doi: 10.1073/pnas.0900660106. PMC  2722284. PMID  19617539.
  99. ^ Williamson J (2002). Dragon's Island and other stories. Waterville, Me.: Five Star. ISBN  978-0-7862-4314-3.[ page needed]
  100. ^ Stableford BM (2004). Historical dictionary of science fiction literature. p. 133. ISBN  978-0-8108-4938-9.
  101. ^ Dalhousie University (9 May 2008). "A Real-life 'I Am Legend?' Researcher Champions Development Of 'Reovirus' As Potential Treatment For Cancer". Science Daily.

Further reading