An oncolytic virus is a virus that preferentially infects and kills cancer cells. As the infected cancer cells are destroyed by lysis, they release new infectious virus particles 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 responses.
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 now 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 Seneca Valley virus.
As of 2011, only limited human trials had been performed. Nevertheless, in January 2011, the oncolytic virus company BioVex Inc was purchased by Amgen for $1 billion because of encouraging results for talimogene laherparepvec in clinical trials. This drug recently reported the first positive interim Phase III trial results for an oncolytic virus, making it likely that talimogene laherparepvec will also be the first one approved for use (for the treatment of advanced melanoma). However, skeptics have questioned the clinical relevance of this interim data citing that the awaited overall survival data will be the final judgement and that it is likely that patient benefit will be maximised in combination with other therapies, which this trial did not test.
- 1 History
- 2 Possible applications
- 3 Oncolytic behaviour of wild-type viruses
- 4 Engineering oncolytic viruses
- 5 Interactions with host immunity
- 6 Oncolytic viruses in conjunction with existing cancer therapies
- 7 Clinical research
- 8 In fiction
- 9 See also
- 10 Further reading
- 11 External links
- 12 References
A connection between cancer regression and viruses has long been theorized, and case reports of regression (cervical cancer, Burkitt lymphoma, Hodgkin lymphoma) after immunization or infection with an unrelated virus appeared at the beginning of the 20th century. Efforts to treat cancer through immunization or deliberate infection with a virus began in the mid-20th century. 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, adenovirus, Coxsackie virus, and others. 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, destroyed the virus and thus prevented it from destroying the cancer. Only certain cancers could be treated through virotherapy was also recognized very early. 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 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, hence the return to this sidelined therapy now using the recently developed genetic technology required to engineer viruses.
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. 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, most notably OncoVex GM-CSF, developed by Amgen, which has successfully completed a pivotal Phase III trial for advanced melanoma. This study met its primary endpoint (durable response rate) with a very high degree of statistical significance in March 2013, the first positive phase 3 study for an oncolytic virus in the western world.
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 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.
The specificity and flexibility of oncolytic viruses means they have the potential to treat cancers that are unresponsive to other forms of treatment like surgery, chemotherapy, or radiation. The benefit of using oncolytic viral therapy is that viruses can naturally, or be engineered to, target tumor cells specifically based on their expression of certain growth factors or receptors. Animal models are currently being used to study the effect of viruses, such as the Herpes simplex virus (HSV), genetically modified to secrete certain growth factors or molecules (e.g. interleukin 12 or IL-12) that cause tumor cell death. In the case of glioblastomal cells, it has been shown that in mice, the injection of IL-12 enhanced HSV not only has oncolytic effects, but it also has antiangiogenic effects, thus decreasing the blood flow to the tumor.
Viral agents administered intravenously have the potential to be effective against metastatic cancers, which are especially difficult to treat conventionally, although none have been so far. However, blood-borne viruses can be deactivated by antibodies and cleared from the blood quickly e.g. by Kupffer cells (extremely active phagocytic cells in the liver, which are responsible for adenovirus clearance).
Oncolytic behaviour of wild-type viruses
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.
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) 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, an acronym for Respiratory Enteric Orphan virus, generally infects 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.
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.
Engineering oncolytic viruses
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. 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. These enzymes also exist in the genomes of certain viruses (E.g. HSV, vaccinia) and allow viral replication in quiescent(non-replicating) cells, so if they are inactivated by mutation the virus will only be able to replicate in proliferating cells, such as cancer cells.
There are two main approaches for generating tumour selectivity: transductional and non-transductional targeting.
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.
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. 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.
Double targeting with both transductional and non-transductional targeting methods is more effective than any one form of targeting alone.
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. 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. 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.
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.
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. 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.
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.
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. This approach has been used successfully preclinically with adenovirus, measles virus and vaccinia virus.
Interactions with host immunity
Immunity as an obstacle
A major obstacle to the success of oncolytic viruses is the patient immune system which naturally attempts to inactivate 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. However, some studies have shown that pre-immunity to oncolytic viruses doesn't cause a significant reduction in efficacy.
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. 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. 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.
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.
Chen et al. (2001) 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.
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.
- Oncorine, by Shanghai Sunway Biotech, was approved in China for Head and neck cancer in 2005. It is based on the adenovirus H101.
- Talimogene laherparepvec (OncoVEX GM-CSF), by Amgen, successfully completed phase III trials for advanced melanoma in March 2013. It is therefore likely to become the first approved oncolytic agent in the western world. It is based on herpes simplex (HSV-1) and was developed by BioVex, before that company was purchased by Amgen for $1 billion in 2011. 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.
- Reolysin, by Oncolytics Biotech, is in phase III for head and neck cancer. An interim data release showed that this phase III had already obtained statisically significant tumor shrinkage in patients at their 6-week scan, although the trial will not be complete until the overall survival data matures. Encouraging early results in colorectal cancer. In total there are 31 clinical studies either completed or ongoing, including many testing Reolysin alongside standard chemotherapies in a variety of solid cancers.
- JX-594, by Jennerex, is currently in phase II for hepatocellular carcinoma. JX-594 is a thymidine kinase-deleted Vaccinia virus plus GM-CSF.
- Seneca Valley virus (NTX-010), an oncolytic picornavirus, is in phase II for small cell lung cancer and neuroblastoma.
- SEPREHVIR (HSV-1716), by Virttu Biologics, completed phase I in glioblastoma, in squamous cell carcinoma of head and neck, and in melanoma. Ongoing phase I dose escalation study of intratumoral HSV-1716 in pediatric/young adult patients with non–central nervous system solid tumours and a new phase I/IIa study in mesothelioma commenced in 2012.
- CGTG-102 (Ad5/3-D24-GMCSF), by Oncos Therapeutics, while in phase I was already used to treat 200 advanced cancer patients in the company's Advanced Therapy Access Program.
- GL-ONC1, by Genelux, is in phase I administered intravenously for solid tumours. Additional trials are ongoing utilising alternative methods of administration including intrapleural administration for patients with malignant pleural effusion, intraperitoneal injection for patients with advanced peritoneal carcinomatosis, and in combination therapy in head and neck cancers.
- Cavatak is a coxsackie virus which is in phase II clinical trials for the treatment of malignant melanoma.
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. Dragon's Island is also known for being the source of the term "genetic engineering".
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.
- Harrington, Vile, Pandha (2008). Viral Therapy of Cancer. Hoboken, N.J.: Wiley. ISBN 0470019220.
- Thorne, Kirn, Liu (2011). Oncolytic Viruses: Methods and Protocols (Methods in Molecular Biology). New York: Humana Press. ISBN 1617793396.
- Sinkovics (2005). Viral therapy of human cancers. New York, NY: Dekker. ISBN 0824759133.
- A number of oncolytic viruses were discussed on Columbia University Professor Vincent Racaniello's "This week in virology" podcast, including episodes on myxoma virus, reovirus, picornavirus, and poxvirus.
- Nemunaitis, J (1999). "Oncolytic viruses.". Investigational new drugs 17 (4): 375–86. PMID 10759404.
- Ferguson, Mark S.; Lemoine, Nicholas R.; Wang, Yaohe (1 January 2012). "Systemic Delivery of Oncolytic Viruses: Hopes and Hurdles". Advances in Virology 2012: 1–14. doi:10.1155/2012/805629. PMC 3287020.
- Melcher, Alan; Parato, Kelley; Rooney, Cliona M; Bell, John C (19 April 2011). "Thunder and Lightning: Immunotherapy and Oncolytic Viruses Collide". Molecular Therapy 19 (6): 1008–1016. doi:10.1038/mt.2011.65. PMC 3129809.
- Alemany, R. (10 November 2012). "Viruses in cancer treatment". Clinical and Translational Oncology 15 (3): 182–188. doi:10.1007/s12094-012-0951-7. PMID 23143950.
- Donnelly, OG; Errington-Mais, F; Prestwich, R; Harrington, K; Pandha, H; Vile, R; Melcher, AA (2012 Jul). "Recent clinical experience with oncolytic viruses.". Current pharmaceutical biotechnology 13 (9): 1834–41. PMID 21740364.
- Roberts, MS; Lorence, RM; Groene, WS; Bamat, MK (2006 Aug). "Naturally oncolytic viruses.". Current opinion in molecular therapeutics 8 (4): 314–21. PMID 16955694.
- Bourke, M.G.; Salwa, S.; Harrington, K.J.; Kucharczyk, M.J.; Forde, P.F.; de Kruijf, M.; Soden, D.; Tangney, M.; Collins, J.K.; O’Sullivan, G.C. (1 December 2011). "The emerging role of viruses in the treatment of solid tumours". Cancer Treatment Reviews 37 (8): 618–632. doi:10.1016/j.ctrv.2010.12.003. PMID 21232872.
- "Amgen, Form 8-K, Current Report, Filing Date Jan 26, 2012". secdatabase.com. Retrieved Jan 8, 2013.
- Sheridan, Cormac (9 June 2013). "Amgen announces oncolytic virus shrinks tumors". Nature Biotechnology 31 (6): 471–472. doi:10.1038/nbt0613-471.
- Kuruppu, Darshini; Tanabe, Kenneth K. (2005). "Viral oncolysis by herpes simplex virus and other viruses". Cancer Biology & Therapy 4 (5): 524–31. doi:10.4161/cbt.4.5.1820.
- Voroshilova, MK (1989). "Potential use of nonpathogenic enteroviruses for control of human disease". Progress in medical virology 36: 191–202. PMID 2555836.
- Pond, AR; Manuelidis, EE (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.
- Kunin, CM (1964). "CELLULAR SUSCEPTIBILITY TO ENTEROVIRUSES". Bacteriological reviews 28 (4): 382–90. PMC 441234. PMID 14244713.
- Kelly, E; Russell, SJ (2007 Apr). "History of oncolytic viruses: genesis to genetic engineering.". Molecular therapy : the journal of the American Society of Gene Therapy 15 (4): 651–9. doi:10.1038/sj.mt.6300108. PMID 17299401.
- MacLean, A. R.; ul-Fareed, M.; Robertson, L.; Harland, J.; Brown, S. M. (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.". Journal of General Virology 72 (3): 631–9. doi:10.1099/0022-1317-72-3-631. PMID 1848598.
- Brown, S. M.; Harland, J.; MacLean, A. R.; Podlech, J.; Clements, J. B. (1994). "Cell type and cell state determine differential in vitro growth of non-neurovirulent ICP34.5-negative herpes simplex virus types 1 and 2.". Journal of General Virology 75 (9): 2367–77. doi:10.1099/0022-1317-75-9-2367. PMID 8077935.
- Kesari, S.; Randazzo, B. P.; Valyi-Nagy, T.; Huang, Q. S.; Brown, S. M.; MacLean, A. R.; Lee, V. M.; Trojanowski, J. Q. et al. (1995). "Therapy of experimental human brain tumors using a neuroattenuated herpes simplex virus mutant.". Laboratory Investigation 73 (5): 636–48. PMID 7474937.
- McKie, E. A.; MacLean, A. R.; Lewis, A. D.; Cruickshank, G.; Rampling, R.; Barnett, S. C.; Kennedy, P. G.; S. M., Brown (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.
- Randazzo, B. P.; Bhat, M. G.; Kesari, S.; Fraser, N. W.; Brown, S. M. (1997). "Treatment of experimental subcutaneous human melanoma with a replication-restricted herpes simplex virus mutant.". Journal of Investigative Dermatology 108 (6): 933–7. doi:10.1111/1523-1747.ep12295238. PMID 9182825.
- Rampling, R, Cruikshank, G, et al. (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) 859-866.
- Papanastassiou, V, Rampling, R, et al. (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.
- Harrow, S, Papanastassiou, V, et al. (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, 1648-1658.
- MacKie, RM, Stewart, B and Brown, SM. (2001) "Intralesional injection of herpes simplex virus 1716 in metastatic melanoma." The Lancet 357, 525-526.
- Mace, AT, Ganly, I et al. (2008) "Potential for efficacy of the oncolytic herpes simplex virus 1716 in patients with oral squamous cell carcinoma." Head & Neck 30(8): 1045-1051.
- Conner, J, Braidwood, L and Brown, SM. (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): 1579-1592.
- Braidwood, L, Dunn, PD et al. (2009) "Antitumor activity of a selectively replication competent herpes simplex virus (HSV) with enzyme prodrug therapy." Anticancer Research 29(6): 2159-2166.
- Sorensen, A, Mairs, RJ et al. (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): 647-654.
- Frew, Sarah E; Sammut, Stephen M; Shore, Alysha F; Ramjist, Joshua K; Al-Bader, Sara; Rezaie, Rahim; Daar, Abdallah S; Singer, Peter A (2008). "Chinese health biotech and the billion-patient market". Nature Biotechnology 26 (1): 37–53. doi:10.1038/nbt0108-37. PMID 18183014.
- Garber, K. (2006). "China Approves World's First Oncolytic Virus Therapy for Cancer Treatment". JNCI Journal of the National Cancer Institute 98 (5): 298–300. doi:10.1093/jnci/djj111. PMID 16507823.
- Ayllón Barbellido, S; Campo Trapero, J; Cano Sánchez, J; Perea García, MA; Escudero Castaño, N; Bascones Martínez, A (2008). "Gene therapy in the management of oral cancer: Review of the literature". Medicina oral, patologia oral y cirugia bucal 13 (1): E15–21. PMID 18167474.
- Guo, J; Xin, H (2006 Nov 24). "Chinese gene therapy. Splicing out the West?". Science 314 (5803): 1232–5. doi:10.1126/science.314.5803.1232. PMID 17124300.
- Cheema, T, Wakimoto, H, Fecci, PE, Ning, J, Kuroda, T, Jeyaretna, DS, Martuza, RL, Rabkin, SD, "Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model." PNAS, 2013.
- Roy, Dominic, Bell, John C, "Cell carriers for oncolytic viruses: current challenges and future directions." Oncolytic Virotherapy, 2:47-56, 2013.
- Bell, John C.; Stojdl, David F.; Lichty, Brian; Knowles, Shane; Marius, Ricardo; Atkins, Harold; Sonenberg, Nahum (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.
- Stojdl, David F; Lichty, Brian D; Tenoever, Benjamin R; Paterson, Jennifer M; Power, Anthony T; Knowles, Shane; Marius, Ricardo; Reynard, Jennifer et al. (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.
- Ahmed, M; Cramer, S; Lyles, D (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.
- Ebert, Oliver; Harbaran, Sonal; Shinozaki, Katsunori; Woo, Savio L C (2004). "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.
- Porosnicu, M; Mian, A; Barber, GN (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.
- Bridle, B. W.; Stephenson, K. B.; Boudreau, J. E.; Koshy, S.; Kazdhan, N.; Pullenayegum, E.; Brunellière, J.; Bramson, J. L.; Lichty, B. D.; Wan, Y. (2010). "Potentiating cancer immunotherapy using an oncolytic virus.". Molecular Therapy 18 (8): 1430–9. doi:10.1038/mt.2010.98. PMC 2927075. PMID 20551919.
- Gromeier, M. (2000). "Intergeneric poliovirus recombinants for the treatment of malignant glioma". Proceedings of the National Academy of Sciences 97 (12): 6803–8. doi:10.1073/pnas.97.12.6803.
- Goetz, C; Gromeier, M (2010 Apr-Jun). "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. PMID 20299272.
- Lal, R; Harris, D; Postel-Vinay, S; De Bono, J (2009). "Reovirus: Rationale and clinical trial update". Current opinion in molecular therapeutics 11 (5): 532–9. PMID 19806501.
- Thirukkumaran, Chandini; Morris, Don G. (2009). Oncolytic Viral Therapy Using Reovirus. "Gene Therapy of Cancer". Methods in molecular biology (Clifton, N.J.). Methods in Molecular Biology 542: 607–34. doi:10.1007/978-1-59745-561-9_31. ISBN 978-1-934115-85-5. PMID 19565924.
- Chow, Amy. "Cell Cycle Control by Oncogenes and Tumor Suppressors: Driving the Transformation of Normal Cells into Cancerous Cells". Nature Education. Retrieved 5 April 2013.
- "Medical Dictionary". Merriam-Webster. Retrieved 5 April 2013.
- Gentry, GA (1992). "Viral thymidine kinases and their relatives.". Pharmacology & therapeutics 54 (3): 319–55. PMID 1334563.
- Davydova, J.; Le, LP; Gavrikova, T; Wang, M; Krasnykh, V; Yamamoto, M (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.
- 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). "Imaging characteristics, tissue distribution, and spread of a novel oncolytic vaccinia virus carrying the human sodium iodide symporter.". PLoS ONE 7 (8): e41647. doi:10.1371/journal.pone.0041647. PMC 3422353. PMID 22912675.
- Poirier, JT; Reddy, PS; Idamakanti, N; Li, SS; Stump, KL; Burroughs, KD; Hallenbeck, PL; Rudin, CM (2012 Dec). "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.
- Yu, YA; Shabahang, S; Timiryasova, TM; Zhang, Q; Beltz, R; Gentschev, I; Goebel, W; Szalay, AA (2004 Mar). "Visualization of tumors and metastases in live animals with bacteria and vaccinia virus encoding light-emitting proteins". Nat Biotechnol 22 (3): 313–20. doi:10.1038/nbt937. PMID 14990953.
- Freeman, SM; Whartenby, KA; Freeman, JL; Abboud, CN; Marrogi, AJ (1996 Feb). "In situ use of suicide genes for cancer therapy.". Seminars in oncology 23 (1): 31–45. PMID 8607030.
- Duarte, S; Carle, G; Faneca, H; de Lima, MC; Pierrefite-Carle, V (2012 Nov 28). "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.
- Frentzen, A.; Yu, Y. A.; Chen, N.; Zhang, Q.; Weibel, S.; Raab, V.; Szalay, A. A. (2009). "Anti-VEGF single-chain antibody GLAF-1 encoded by oncolytic vaccinia virus significantly enhances antitumor therapy". Proceedings of the National Academy of Sciences 106 (31): 12915–20. doi:10.1073/pnas.0900660106.
- Conner, J; Braidwood, L (18 May 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. Retrieved 31 May 2013.
- Haddad, Dana; Chen, Chun-Hao; Carlin, Sean; Silberhumer, Gerd; Chen, Nanhai G.; Zhang, Qian; Longo, Valerie; Carpenter, Susanne G.; Mittra, Arjun; Carson, Joshua; Au, Joyce; Gonen, Mithat; Zanzonico, Pat B.; Szalay, Aladar A.; Fong, Yuman; Gelovani, Juri G. (16 August 2012). "Imaging Characteristics, Tissue Distribution, and Spread of a Novel Oncolytic Vaccinia Virus Carrying the Human Sodium Iodide Symporter". PLoS ONE 7 (8): e41647. doi:10.1371/journal.pone.0041647. PMC 3422353. PMID 22912675.
- Grünwald, GK; Klutz, K; Willhauck, MJ; Schwenk, N; Senekowitsch-Schmidtke, R; Schwaiger, M; Zach, C; Göke, B; Holm, PS; Spitzweg, C (2012 Oct 4). "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. Retrieved 31 May 2013.
- Penheiter, AR; Wegman, TR; Classic, KL; Dingli, D; Bender, CE; Russell, SJ; Carlson, SK (2010 Aug). "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.
- Li, H; Peng, K-W; Dingli, D; Kratzke, R A; Russell, S J (9 April 2010). "Oncolytic measles viruses encoding interferon β and the thyroidal sodium iodide symporter gene for mesothelioma virotherapy". Cancer Gene Therapy 17 (8): 550–558. doi:10.1038/cgt.2010.10. PMC 2907639. PMID 20379224.
- Schmidt, C (6 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.
- Kottke, T; Thompson, J; Diaz, RM; Pulido, J; Willmon, C; Coffey, M; Selby, P; Melcher, A; Harrington, K; Vile, RG (2009 Jan 15). "Improved systemic delivery of oncolytic reovirus to established tumors using preconditioning with cyclophosphamide-mediated Treg modulation and interleukin-2.". Clinical cancer research : an official journal of the American Association for Cancer Research 15 (2): 561–9. doi:10.1158/1078-0432.CCR-08-1688. PMC 3046733. PMID 19147761.
- 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 (2011 Feb 1). "A phase I study of the combination of intravenous reovirus type 3 Dearing and gemcitabine in patients with advanced cancer.". Clinical cancer research : an official journal of the American Association for Cancer Research 17 (3): 581–8. doi:10.1158/1078-0432.CCR-10-2159. PMID 21106728.
- Magge, D; Guo, ZS; O'Malley, ME; Francis, L; Ravindranathan, R; Bartlett, DL (2013 May 10). "Inhibitors of C5 complement enhance vaccinia virus oncolysis.". Cancer gene therapy 20 (6): 342–50. doi:10.1038/cgt.2013.26. PMID 23661042.
- 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 (2013 Feb 10). "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. PMID 23396206.
- Wonganan, P; Croyle, MA (2010 Feb). "PEGylated Adenoviruses: From Mice to Monkeys.". Viruses 2 (2): 468–502. doi:10.3390/v2020468. PMC 3185605. PMID 21994645.
- Muthana, M.; Rodrigues, S.; Chen, Y. -Y.; Welford, A.; Hughes, R.; Tazzyman, S.; Essand, M.; Morrow, F.; Lewis, C. E. (2012). "Macrophage Delivery of an Oncolytic Virus Abolishes Tumor Regrowth and Metastasis after Chemotherapy or Irradiation". Cancer Research 73 (2): 490–495. doi:10.1158/0008-5472.CAN-12-3056. PMID 23172310.
- Tong, AW; Senzer, N; Cerullo, V; Templeton, NS; Hemminki, A; Nemunaitis, J (2012 Jul). "Oncolytic viruses for induction of anti-tumor immunity.". Current pharmaceutical biotechnology 13 (9): 1750–60. PMID 21740355.
- Naik, JD; Twelves, CJ; Selby, PJ; Vile, RG; Chester, JD (2011 Jul 1). "Immune recruitment and therapeutic synergy: keys to optimizing oncolytic viral therapy?". Clinical cancer research : an official journal of the American Association for Cancer Research 17 (13): 4214–24. doi:10.1158/1078-0432.CCR-10-2848. PMID 21576084.
- O'Regan, Brendan; Hirshberg, Caryle (1993). Spontaneous remission : an annotated bibliography. Sausalito, CA: Institute of Noetic Sciences. ISBN 0943951178.
- Lattime, E (2013). Gene Therapy of Cancer: Translational Approaches from Preclinical Studies to Clinical Implementation. Academic Press. ISBN 0123942950.
- Mastrangelo, Michael J; Lattime, Edmund C (1 December 2002). "Virotherapy clinical trials for regional disease: In situ immune modulation using recombinant poxvirus vectors". Cancer Gene Therapy 9 (12): 1013–1021. doi:10.1038/sj.cgt.7700538.
- Ottolino-Perry, K; Diallo, JS; Lichty, BD; Bell, JC; McCart, JA (2010 Feb). "Intelligent design: combination therapy with oncolytic viruses.". Molecular therapy : the journal of the American Society of Gene Therapy 18 (2): 251–63. doi:10.1038/mt.2009.283. PMID 20029399.
- Chen, Y; Deweese, T; Dilley, J; Zhang, Y; Li, Y; Ramesh, N; Lee, J; Pennathur-Das, R et al. (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.
- Mace, AT, Harrow, S, et al. 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 2007;127: 880-887
- Toyoizumi, T, Mick, R et al. 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 1999;10: 3013-3029.
- Khuri, F.; Nemunaitis, J.; Ganly, I.; Arseneau, J.; Tannock, I.; Romel, L.; Gore, M.; Ironside, J.; MacDougall, R.; Heise, C.; Randlev, B.; Gillenwater, A. M.; Bruso, P.; Kaye, S. B.; Hong, W. K.; Kirn, D. H. (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): 879–885. doi:10.1038/78638. PMID 10932224.
- 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 (2013 Mar 12). "VEGF Blockade Enables Oncolytic Cancer Virotherapy in Part by Modulating Intratumoral Myeloid Cells.". Molecular therapy : the journal of the American Society of Gene Therapy 21 (5): 1014–23. doi:10.1038/mt.2013.39. PMID 23481323.
- Schmidt, Charlie (2011). "Amgen spikes interest in live virus vaccines for hard-to-treat cancers". Nature Biotechnology 29 (4): 295–6. doi:10.1038/nbt0411-295. PMID 21478830.
- http://clinicaltrials.gov/ct2/show/NCT00769704%7Ctitle=Efficacy and Safety Study of OncoVEXGM-CSF Compared to GM-CSF in Melanoma|accessdate=31 May 2013
- "Study of Safety and Efficacy of OncoVEXGM-CSF With Cisplatin for Treatment of Locally Advanced Head and Neck Cancer". Retrieved 31 May 2013.
- "Intravenous Administration of REOLYSIN® in Combination with Paclitaxel and Carboplatin for Patients with Platinum-Refractory Head and Neck Cancers". Retrieved 31 May 2013.
- "Oncolytics Biotech® announces positive data from translational clinical trial investigating REOLYSIN® in Patients with Metastatic Colorectal Cancer" (Press release). Biofind. 21 April 2011. Retrieved 7 August 2011.
- Cell Carriage, Delivery, and Selective Replication of an Oncolytic Virus in Tumor in Patients, Science Translational Medicine (Vol. 4 Issue 138 138ra77), cited in "Oncolytics Biotech® Inc. Announces Publication of Translational Clinical Trial Results in Science Translational Medicine" (Press release). Biofind. 13 June 2012. Retrieved 16 June 2012.
- http://clinicaltrials.gov/ct2/results?term=reolysin%7Caccessdate=31 May 2013
- ClinicalTrials.gov NCT01387555 A Phase 2b Study of Vaccinia Virus to Treat Advanced Liver Cancer (TRAVERSE)
- ClinicalTrials.gov NCT00625456 Safety Study of Recombinant Vaccinia Virus to Treat Refractory Solid Tumors
- Breitbach, CJ; Thorne, SH; Bell, JC; Kirn, DH (2011). "Targeted and Armed Oncolytic Poxviruses for Cancer: The Lead Example of JX-594". Current pharmaceutical biotechnology. PMID 21740365.
- ClinicalTrials.gov NCT01048892 Seneca Valley Virus-001 and Cyclophosphamide in Treating Young Patients With Relapsed or Refractory Neuroblastoma, Rhabdomyosarcoma, or Rare Tumors With Neuroendocrine Features, October 2012
- "Seneca Valley Virus-001 After Chemotherapy in Treating Patients With Extensive-Stage Small Cell Lung Cancer".
- Seprehvir, Virttu Biologics
- Oncolytic Virus Specialist Virttu Biologics Initiates Phase I/II SEPREHVIR™ Study in Mesothelioma, BioSpace, 11 September 2012
- "Oncolytic viruses mediating anti-tumor immunity in human cancer patients" (Press release). Oncos Therapeutics. 19 May 2010.
- ClinicalTrials.gov NCT00794131 Safety Study of GL-ONC1, an Oncolytic Virus, in Patients With Advanced Solid Tumors
- "Intra-pleural Administration of GL-ONC1, a Genetically Modified Vaccinia Virus, in Patients With Malignant Pleural Effusion: Primary, Metastases and Mesothelioma". Retrieved 31 May 2013.
- "A Study of GL-ONC1, an Oncolytic Vaccinia Virus, in Patients With Advanced Peritoneal Carcinomatosis". Retrieved 31 May 2013.
- "Safety Study of Attenuated Vaccinia Virus (GL-ONC1)With Combination Therapy in Head & Neck Cancer".
- Oncolytic activity of Coxsackievirus A21 (CAVATAK™) in human pancreatic cancer. (June 2011 poster)
- ClinicalTrials.gov NCT00832559 A Study of the Intratumoural Administration of CAVATAK to Head and Neck Cancer Patients
- ClinicalTrials.gov NCT01227551 A Study of Intratumoral CAVATAK in Patients With Stage IIIc and Stage IV Malignant Melanoma
- Williamson, Jack (2002). Dragon's Island and other stories. Waterville, Me.: Five Star. ISBN 0786243147.
- Stableford, Brian M. (2004). Historical dictionary of science fiction literature. p. 133. ISBN 9780810849389