Oncolytic virus

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

An oncolytic virus is a virus that preferentially infects and kills cancer cells.[1][2] As the infected cancer cells are destroyed by oncolysis, they release new infectious virus particles or virions to help destroy the remaining tumour.[3][4] Oncolytic viruses are thought not only to cause direct destruction of the tumour cells, but also to stimulate host anti-tumour immune responses.[5][6]

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.[7] A number of viruses including adenovirus, reovirus, measles, herpes simplex, Newcastle disease virus and vaccinia have now been clinically tested as oncolytic agents.[8] Most current oncolytic viruses are engineered for tumour selectivity, although there are naturally occurring examples such as reovirus and the senecavirus,[9] resulting in clinical trials.[10]

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.[11] Later (in 2015 and 2016 respectively) it was also approved in Georgia (country)[12] and Armenia. 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.[13] The drug talimogene laherparepvec (OncoVex, T-VEC) was the first oncolytic herpes virus ( a modified herpes simplex virus), approved for use by the USFDA 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.[14]


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.[15] Efforts to treat cancer through immunisation or virotherapy (deliberate infection with a virus), began in the mid-20th century.[15][16] 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,[17] adenovirus,[15] Coxsackie virus,[18] ECHO enterovirus RIGVIR[19] and others.[16] 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,[15] destroyed the virus and thus prevented it from destroying the cancer.[17] Only certain cancers could be treated through virotherapy was also recognised very early.[18] Even when a response was seen, these responses were neither complete nor durable.[15] 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.[15][20]

Herpes simplex virus[edit]

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.[21][22] In a wide range of in vivo cancer models, the HSV1716 virus has induced tumour regression and increased survival times.[23][24][25]

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.[26][27][28] Other safety trials have used HSV1716 to treat patients with melanoma and squamous-cell carcinoma of head and neck.[29][30] Since then other studies have shown that the outer coating of HSV1716 variants can be targeted to specific types of cancer cells,[31] 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,[32] 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.[33]

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.[citation needed]

Oncorine (H101)[edit]

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.[13][34] 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.[34] Despite the promises of early in vivo lab work, these viruses do not specifically infect cancer cells, but they still kill cancer cells preferentially.[34] While overall survival rates are not known, short-term response rates are approximately doubled for H101 plus chemotherapy when compared to chemotherapy alone.[34] It appears to work best when injected directly into a tumour, and when any resulting fever is not suppressed.[34] Systemic therapy (such as through infusion through an intravenous line) is desirable for treating metastatic disease.[35] It is now marketed under the brand name Oncorine.[36]

Mechanisms of action[edit]

Direct oncolysis[edit]

Direct oncolysis, the cell killing effect produced by viral infection of cancer cells, was the original concept of oncolytic viruses.[1][37] By specific infection of a tumour cell, the virus multiplies within it until it causes cell lysis, releasing a second generation of virus to then infect surrounding cells.[3]


With advances in cancer immunotherapy such as immune checkpoint inhibitors, increased interest was given to the prospect of oncolytic viruses as immunotherapies. There are two main considerations of the interaction between oncolytic viruses and the immune system.

Immunity as an obstacle[edit]

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.[38] It has been shown that immunosuppression by chemotherapy and inhibition of the complement system can enhance oncolytic virus therapy.[39][40][41]

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.[42]

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.[43]

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.[44]

Immunity as an ally[edit]

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.[45][46] 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.[47] 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.[48] 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.[49]

Oncolytic behaviour of wild-type viruses[edit]

Vesicular stomatitis virus[edit]

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.[50] 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.[51][52][53][54] 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.[51]

Recent research has shown that this virus has the potential to cure brain tumours, thanks to its oncolytic properties.[55]


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)[56] 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.[57]


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.[58]

Reolysin is a formulation of reovirus that is currently in clinical trials for the treatment of various cancers.[59]


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.


In the 1960s, a group of scientists in Latvia led by Dr. Aina Muceniece studied oncolytic activity of ECHO viruses, but in 1968 a clinical trial of 5 ECHO enterovirus strains began (in trials participated stage-IV cancer patients volunteers). Scientists decided to continue researching ECHO-7 strain of ECHO virus (later called RIGVIR), because it showed the most pronounced oncolytic properties. III-phase trials started in 1988 with the aim to compare effect of RIGVIR therapy with results of chemotherapy and radiation therapy. In 2004 RIGVIR was patented and registered in Latvia and since then it has been used in cancer therapy.[19] RIGVIR virus was approved in Georgia in February 2015,[12] but in 2016 it was approved also in Armenia. Recent retrospective study published in Melanoma Research revealed that IB-IIC melanoma patients treated with oncolytic virus RIGVIR were 4.39–6.57-fold lower mortality than those, who according to melanoma treatment guidelines did not receive virotherapy and were only observed.[60] In 2015 Rigvir was included into the Latvian National guidelines for treatment of skin cancer and melanoma, developed by the Riga Eastern Clinical University Hospital Task Force.[61] In July 2016 three case reports results were published in APMIS journal about RIGVIR efficacy in treatment of lung cancer and histiocytic sarcoma.[62]

Semliki Forest virus[edit]

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.[63] The modified virus was also found to efficiently kill human glioblastoma tumour cell lines.[63]


The maraba virus, first identified in Brazilian sandflies, is being tested clinically.[64][65]

Engineering oncolytic viruses[edit]

Directed evolution[edit]

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.[66]

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.[66]


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.[67] 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.[68] These enzymes also exist in the genomes of certain viruses (E.g. HSV, vaccinia) and allow viral replication in quiescent(non-replicating) cells,[69] so if they are inactivated by mutation the virus will only be able to replicate in proliferating cells, such as cancer cells.

Tumour targeting[edit]

There are two main approaches for generating tumour selectivity: transductional and non-transductional targeting.[citation needed]

  • 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.[citation needed]
  • 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.[citation needed]
    • 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.[citation needed]
    • 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.[70]

Reporter genes[edit]

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.[71][72] 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.[73] 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.[71]

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[edit]

Oncolytic viruses can be used against cancers in ways that are additional to lysis of infected cells.

Suicide genes[edit]

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.[74] 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.[75]

Suppression of angiogenesis[edit]

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.[76][77]


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.[71] This approach has been used successfully preclinically with adenovirus, measles virus and vaccinia virus.[78][79][80]

Approved therapeutic agents[edit]

Clinical research[edit]

In 2014-2016 period a number of clinical trials were initiated for a wide range of oncolytic virus products, reflecting the ongoing clinical development of this class of therapy.[86]

Agent Indication Phase Status Route Notes Ref
Ad5-yCD/mutTKSR39rep-hIL12 Prostate carcinoma I Recruiting Intraprostatic As single agent NCT02555397
Cavatak Bladder carcinoma I Recruiting Intravesical Optionally combined with low-dose mitomycin C NCT02316171
Melanoma I Recruiting Intratumoral Combined with ipilimumab NCT02307149
Combined with pembrolizumab NCT02565992
CG0070 Bladder carcinoma II No longer available Intravesical As single agent NCT02143804
Recruiting Intravesical As single agent NCT02365818
DNX-2401 Brain tumors I Recruiting Intratumoral Combined with IFNγ NCT02197169
G207 Brain tumors I Not yet recruiting Intratumoral Optionally combined with radiation therapy NCT02457845
GL-ONC1 Ovarian cancer Ib Recruiting Intraperitoneal As single agent NCT02759588
HF10 Melanoma II Recruiting Intratumoral Combined with ipilimumab NCT02272855
Solid tumors I Recruiting Intratumoral As single agent NCT02428036
Imlygic® Hepatocellular carcinoma I Not yet recruiting Intratumoral As single agent NCT02509507
Melanoma n.a. Enrolling by invitation Intratumoral As single agent NCT02173171
II Recruiting Intratumoral As single agent NCT02366195
Combined with surgery NCT02211131
III Active, not recruiting Intratumoral Combined with pembrolizumab NCT02263508
Available Intratumoral As single agent NCT02147951
Soft tissue sarcoma I/II Recruiting Intratumoral Combined with radiotherapy NCT02453191
JX-594 Hepatocellular carcinoma III Not yet recruiting Intratumoral Combined with sorafenib NCT02562755
MG1-MA3 Solid tumors I/II Recruiting Intravenous Combined with a MAGEA3-encoding adenovirus NCT02285816
MV-NIS Gynecological tumors II Recruiting Intraperitoneal As single agent NCT02364713
Multiple myeloma II Recruiting Intravenous Combined with cyclophosphamide NCT02192775
OBP-301 Solid tumors I Not yet recruiting Intratumoral As single agent NCT02293850
Reolysin® Brain tumors I Recruiting Intravenous Combined with GM-CSF s.c. NCT02444546
Multiple myeloma I Recruiting Intravenous Combined with dexamethasone plus a proteasomal inhibitor NCT02101944
Toca 511 Brain tumors II/III Not yet recruiting Intratumoral Combined with 5-FC and standard chemotherapy NCT02414165
Solid tumors I/II Recruiting Intratumoral Intravenous Combined with 5-FC NCT02576665

Abbreviations: 5-FC, 5-fluorocytosine; GM-CSF, granulocyte macrophage colony-stimulating factor; IFNγ, interferon γ; MAGEA3, melanoma antigen family A3; s.c., sub cutem.*initiated between 2014, March 1 and 2015, October 31.

Approved somewhere[edit]

  • Talimogene laherparepvec was approved by the US FDA in 2015, with the brand name Imlygic, for the treatment of melanoma in patients with inoperable tumors.[82] In Jan 2016 it was approved in Europe for some inoperable melanoma.[87]
  • Oncorine, by Shanghai Sunway Biotech, was approved in China for Head and neck cancer in 2005.[88] It is based on the adenovirus H101.
  • RIGVIR, approved for melanoma treatment in Latvia (2004), Georgia (2015) and Armenia (2016) for melanoma treatment.

Started phase III[edit]

  • Reolysin, by Oncolytics Biotech, is in phase III for head and neck cancer.[89] An interim data release showed that this phase III had already obtained statistically significant tumor shrinkage in patients at their 6-week scan,[90] although the trial will not be complete until the overall survival data matures. Encouraging early results in colorectal cancer.[91][92] In total there are 31 clinical studies either completed or ongoing, including many testing Reolysin alongside standard chemotherapies in a variety of solid cancers.[93]

Started phase II[edit]

  • JX-594, by Jennerex, is currently in phase II for hepatocellular carcinoma.[94] JX-594 is a thymidine kinase-deleted Vaccinia virus plus GM-CSF.[95][96]
  • Seneca Valley virus (NTX-010) and (SVV-001), oncolytic picornavirus, is in phase II for small cell lung cancer and neuroblastoma.[9][88][97][98]
  • ColoAd1 was developed by Psioxus Therapeutics Ltd using the process of directed evolution. ColoAd1 has successfully completed recruitment in a Phase I clinical trials of ColoAd1.[citation needed] The trial involved recruiting patients with metastatic solid tumours where no standard treatment options were applicable. Samples from these patients showed evidence of virus replication within tumour sites after intravenous delivery. The second phase of the ColoAd1 study is planned to commence in 2014 and will examine efficacy in patients with metastatic colorectal cancer. Unlike many other oncolytic viruses, ColoAd1 can be administered by intravenous injection rather than requiring intra-tumoral injection. A second trial is comparing the efficacy of the intravenous approach versus direct intra-tumoural injection to assess the most effective method of delivering ColoAd1 to cancer patients (see the EU Clinical Trials Register for further details). A third trial is examining the intra-peritoneal route of delivery for women with late stage ovarian cancer.
  • Cavatak[99][100] is a coxsackie virus which is in phase II clinical trials for the treatment of malignant melanoma.[101]
  • ONCOS-102 is an engineered human serotype 5/3 adenovirus coding for human GM-CSF optimized to induce systemic anti-tumor T cell response in cancer patients. It has started a phase II trial for Unresectable Malignant Pleural Mesothelioma.[102] It has completed a phase I trial and is starting another for malignant pleural mesothelioma (MPM).[103]

Started phase I[edit]

  • SEPREHVIR (HSV-1716), by Virttu Biologics,[104] 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.[105][106]
  • CGTG-102 (Ad5/3-D24-GMCSF), by Oncos Therapeutics,[107] while in phase I was already used to treat 200 advanced cancer patients in the company's Advanced Therapy Access Program.[108]
  • GL-ONC1, by Genelux, is in phase Ib administered intravenously for solid tumours.[109] Additional trials are ongoing utilising alternative methods of administration including intrapleural administration for patients with malignant pleural effusion,[110] intraperitoneal injection for patients with advanced peritoneal carcinomatosis,[111] intraperitoneal injection for recurrent ovarian cancer,[112] and intravenous injection in combination therapy in head and neck cancers.[113]
  • MV-NIS, an engineered measles virus has shown to be effective in targeted destruction of myeloma plasma cells. Radioactive Iodine imaging provides a novel technique for NIS gene expression monitoring.[114]
  • DNX-2401 is an oncolytic adenovirus with US Orphan drug status for glioma.[115]

Oncolytic viruses in conjunction with existing cancer therapies[edit]

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.[116]

Clinical trials[edit]

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.[117] Herpes simplex virus, adenovirus, reovirus and murine leukemia virus are also undergoing clinical trials as a part of combination therapies.[118]

Pre-clinical research[edit]

Chen et al. (2001)[119] 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.[120][121]

The anti-angiogenesis drug Bevacizumab (anti-VEGF antibody) has been shown to reduce the inflammatory response to oncolytic HSV and improve virotherapy in mice.[122]

In fiction[edit]

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.[123] Dragon's Island is also known for being the source of the term "genetic engineering".[124]

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.[citation needed]

See also[edit]


  1. ^ a b Nemunaitis, John (1999). "Oncolytic viruses". Investigational New Drugs. 17 (4): 375–86. PMID 10759404. doi:10.1023/A:1006334404767. 
  2. ^ Fillat, Cristina (2010). "Controlling Adenoviral Replication to Induce Oncolytic Efficacy" (PDF). The Open Gene Therapy Journal. 3: 15–23. doi:10.2174/1875037001003010015. 
  3. ^ a b Ferguson, Mark S.; Lemoine, Nicholas R.; Wang, Yaohe (2012). "Systemic Delivery of Oncolytic Viruses: Hopes and Hurdles". Advances in Virology. 2012: 1–14. doi:10.1155/2012/805629. 
  4. ^ Casjens S. In: Mahy BWJ and Van Regenmortel MHV. Desk Encyclopedia of General Virology. Boston: Academic Press; 2010. ISBN 0-12-375146-2. p. 167.
  5. ^ Melcher, Alan; Parato, Kelley; Rooney, Cliona M; Bell, John C (2011). "Thunder and Lightning: Immunotherapy and Oncolytic Viruses Collide". Molecular Therapy. 19 (6): 1008–16. PMC 3129809Freely accessible. PMID 21505424. doi:10.1038/mt.2011.65. 
  6. ^ Lichty, Brian D.; Breitbach, Caroline J.; Stojdl, David F.; Bell, John C. (2014). "Going viral with cancer immunotherapy". Nat Rev Cancer. 14 (8): 559–67. PMID 24990523. doi:10.1038/nrc3770. 
  7. ^ Alemany, R. (2012). "Viruses in cancer treatment". Clinical and Translational Oncology. 15 (3): 182–8. PMID 23143950. doi:10.1007/s12094-012-0951-7. 
  8. ^ g. Donnelly, O.; Errington-Mais, F.; Prestwich, R.; Harrington, K.; Pandha, H.; Vile, R.; Melcher, A. (2012). "Recent Clinical Experience with Oncolytic Viruses". Current Pharmaceutical Biotechnology. 13 (9): 1834–41. PMID 21740364. doi:10.2174/138920112800958904. 
  9. ^ a b Roberts, MS; Lorence, RM; Groene, WS; Bamat, MK (2006). "Naturally oncolytic viruses". Current opinion in molecular therapeutics. 8 (4): 314–21. PMID 16955694. 
  10. ^ Rudin, Charles M.; John T. Poirier; Neil N. Senzer; Joseph Stephenson; David Loesch; Kevin D. Burroughs; P. Seshidhar Reddy; Christine L. Hann; Paul L. Hallenbeck (2011-02-15). "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): 888–895. ISSN 1078-0432. PMID 21304001. doi:10.1158/1078-0432.CCR-10-1706. 
  11. ^ "Rigvir šķīdums injekcijām". Medicinal product register of the Republic of Latvia. 2004-04-29. Retrieved 2016-12-08. 
  12. ^ a b "Georgia Today". 
  13. ^ a b 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. PMID 18183014. doi:10.1038/nbt0108-37. 
  14. ^ Broderick, Jason. "FDA Panels Support Approval of T-VEC in Melanoma". OncLive. Retrieved 24 Aug 2015. 
  15. ^ a b c d e f Kuruppu, Darshini; Tanabe, Kenneth K. (2005). "Viral oncolysis by herpes simplex virus and other viruses". Cancer Biology & Therapy. 4 (5): 524–31. PMID 15917655. doi:10.4161/cbt.4.5.1820. 
  16. ^ a b Voroshilova, MK (1989). "Potential use of nonpathogenic enteroviruses for control of human disease". Progress in medical virology. 36: 191–202. PMID 2555836. 
  17. ^ a b 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 1907181Freely accessible. PMID 14202523. 
  18. ^ a b Kunin, CM (1964). "Cellular Susceptibility to Enterovirus". Bacteriological reviews. 28 (4): 382–90. PMC 441234Freely accessible. PMID 14244713. 
  19. ^ a b Chumakov P, Morozova V, Babkin I, Baikov I, Netesov S, Tikunova N (2012). "Oncolytic enteroviruses" (PDF). Molecular Biology. 46 (5): 639–650. doi:10.1134/s0026893312050032. 
  20. ^ Kelly, Elizabeth; Russell, Stephen J (2007). "History of Oncolytic Viruses: Genesis to Genetic Engineering". Molecular Therapy. 15 (4): 651–9. PMID 17299401. doi:10.1038/sj.mt.6300108. 
  21. ^ 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): 631–639. PMID 1848598. doi:10.1099/0022-1317-72-3-631. 
  22. ^ 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): 2367–2377. PMID 8077935. doi:10.1099/0022-1317-75-9-2367. 
  23. ^ Kesari, S; Randazzo, BP; Valyi-Nagy, T; Huang, QS; Brown, SM; MacLean, AR; Lee, VM; Trojanowski, JQ; Fraser, NW (1995). "Therapy of experimental human brain tumors using a neuroattenuated herpes simplex virus mutant". Laboratory Investigation. 73 (5): 636–48. PMID 7474937. 
  24. ^ McKie, EA; MacLean, AR; Lewis, AD; Cruickshank, G; Rampling, R; Barnett, SC; Kennedy, PGE; Brown, SM (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. PMC 2074706Freely accessible. PMID 8795577. doi:10.1038/bjc.1996.431. 
  25. ^ Randazzo, Bruce P; Bhat, Mulki G; Kesari, Santosh; Fraser, Nigel W; Brown, S Moira (1997). "Treatment of Experimental Subcutaneous Human Melanoma with a Replication-Restricted Herpes Simplex Virus Mutant". Journal of Investigative Dermatology. 108 (6): 933–7. PMID 9182825. doi:10.1111/1523-1747.ep12295238. 
  26. ^ Rampling, R; Cruickshank, G; Papanastassiou, V; Nicoll, J; Hadley, D; Brennan, D; Petty, R; MacLean, A; Harland, J; McKie, E; Mabbs, R; Brown, M (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. PMID 10845724. doi:10.1038/sj.gt.3301184. 
  27. ^ Papanastassiou, V; Rampling, R; Fraser, M; Petty, R; Hadley, D; Nicoll, J; Harland, J; Mabbs, R; Brown, M (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. PMID 11960316. doi:10.1038/sj.gt.3301664. 
  28. ^ Harrow, S; Papanastassiou, V; Harland, J; Mabbs, R; Petty, R; Fraser, M; Hadley, D; Patterson, J; Brown, S M; Rampling, R (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. PMID 15334111. doi:10.1038/sj.gt.3302289. 
  29. ^ MacKie, Rona M; Stewart, Barry; Brown, S Moira (2001). "Intralesional injection of herpes simplex virus 1716 in metastatic melanoma". The Lancet. 357 (9255): 525–6. PMID 11229673. doi:10.1016/S0140-6736(00)04048-4. 
  30. ^ Mace, Alastair T. M.; Ganly, Ian; Soutar, David S.; Brown, S. Moira (2008). "Potential for efficacy of the oncolytic Herpes simplex virus 1716 in patients with oral squamous cell carcinoma". Head & Neck. 30 (8): 1045–51. PMID 18615711. doi:10.1002/hed.20840. 
  31. ^ Conner, J; Braidwood, L; Brown, S M (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. PMID 18701918. doi:10.1038/gt.2008.121. 
  32. ^ Braidwood, L; Dunn, PD; Hardy, S; Evans, TR; Brown, SM (2009). "Antitumor activity of a selectively replication competent herpes simplex virus (HSV) with enzyme prodrug therapy". Anticancer research. 29 (6): 2159–66. PMID 19528476. 
  33. ^ Sorensen, A.; Mairs, R. J.; Braidwood, L.; Joyce, C.; Conner, J.; Pimlott, S.; Brown, M.; Boyd, M. (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. PMID 22414636. doi:10.2967/jnumed.111.090886. 
  34. ^ a b c d e 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. PMID 16507823. doi:10.1093/jnci/djj111. 
  35. ^ 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" (PDF). Medicina oral, patologia oral y cirugia bucal. 13 (1): E15–21. PMID 18167474. 
  36. ^ Guo, J.; Xin, H. (2006). "CHINESE GENE THERAPY: Splicing Out the West?". Science. 314 (5803): 1232–5. PMID 17124300. doi:10.1126/science.314.5803.1232. 
  37. ^ Fillat, Cristina (2010). "Controlling Adenoviral Replication to Induce Oncolytic Efficacy" (PDF). The Open Gene Therapy Journal. 3: 15–23. doi:10.2174/1875037001003010015. 
  38. ^ Schmidt, C. (2013). "Awaiting a Moment of Truth for Oncolytic Viruses". JNCI Journal of the National Cancer Institute. 105 (10): 675–6. PMID 23650626. doi:10.1093/jnci/djt111. 
  39. ^ Kottke, T.; Thompson, J.; Diaz, R. M.; Pulido, J.; Willmon, C.; Coffey, M.; Selby, P.; Melcher, A.; Harrington, K.; Vile, R. G. (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. PMC 3046733Freely accessible. PMID 19147761. doi:10.1158/1078-0432.CCR-08-1688. 
  40. ^ Lolkema, M. P.; Arkenau, H.-T.; Harrington, K.; Roxburgh, P.; Morrison, R.; Roulstone, V.; Twigger, K.; Coffey, M.; Mettinger, K.; Gill, G.; Evans, T. R. J.; De Bono, J. S. (2010). "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. PMID 21106728. doi:10.1158/1078-0432.CCR-10-2159. 
  41. ^ Magge, D; Guo, Z S; O'Malley, M E; Francis, L; Ravindranathan, R; Bartlett, D L (2013). "Inhibitors of C5 complement enhance vaccinia virus oncolysis". Cancer Gene Therapy. 20 (6): 342–50. PMC 4060830Freely accessible. PMID 23661042. doi:10.1038/cgt.2013.26. 
  42. ^ Heo, Jeong; Reid, Tony; Ruo, Leyo; Breitbach, Caroline J; Rose, Steven; Bloomston, Mark; Cho, Mong; Lim, Ho Yeong; Chung, Hyun Cheol; Kim, Chang Won; Burke, James; Lencioni, Riccardo; Hickman, Theresa; Moon, Anne; Lee, Yeon Sook; Kim, Mi Kyeong; Daneshmand, Manijeh; Dubois, Kara; Longpre, Lara; Ngo, Minhtran; Rooney, Cliona; Bell, John C; Rhee, Byung-Geon; Patt, Richard; Hwang, Tae-Ho; Kirn, David H (2013). "Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer". Nature Medicine. 19 (3): 329–36. PMC 4268543Freely accessible. PMID 23396206. doi:10.1038/nm.3089. 
  43. ^ Wonganan, Piyanuch; Croyle, Maria A. (2010). "PEGylated Adenoviruses: From Mice to Monkeys". Viruses. 2 (2): 468–502. PMC 3185605Freely accessible. PMID 21994645. doi:10.3390/v2020468. 
  44. ^ 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): 490–5. PMID 23172310. doi:10.1158/0008-5472.CAN-12-3056. 
  45. ^ w. Tong, Alex; Senzer, Neil; Cerullo, Vincenzo; Templeton, Nancy; Hemminki, Akseli; Nemunaitis, John (2012). "Oncolytic Viruses for Induction of Anti-Tumor Immunity". Current Pharmaceutical Biotechnology. 13 (9): 1750–60. PMID 21740355. doi:10.2174/138920112800958913. 
  46. ^ Naik, J. D.; Twelves, C. J.; Selby, P. J.; Vile, R. G.; Chester, J. D. (2011). "Immune Recruitment and Therapeutic Synergy: Keys to Optimizing Oncolytic Viral Therapy?". Clinical Cancer Research. 17 (13): 4214–24. PMC 3131422Freely accessible. PMID 21576084. doi:10.1158/1078-0432.CCR-10-2848. 
  47. ^ O'Regan, Brendan; Hirshberg, Caryle (1993). Spontaneous remission : an annotated bibliography. Sausalito, California: Institute of Noetic Sciences. ISBN 0943951178. [page needed]
  48. ^ Lattime, E (2013). Gene Therapy of Cancer: Translational Approaches from Preclinical Studies to Clinical Implementation. Academic Press. ISBN 0123942950. [page needed]
  49. ^ Mastrangelo, Michael J; Lattime, Edmund C (2002). "Virotherapy clinical trials for regional disease: In situ immune modulation using recombinant poxvirus vectors". Cancer Gene Therapy. 9 (12): 1013–21. PMID 12522440. doi:10.1038/sj.cgt.7700538. 
  50. ^ Bell, John C.; Lichty, David F.; Knowles, Brian; Marius, Shane; Atkins, Ricardo; Sonenberg, Harold; Bell, Nahum (2000). "Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus". Nature Medicine. 6 (7): 821–5. PMID 10888934. doi:10.1038/77558. 
  51. ^ a b Stojdl, David F; Lichty, Brian D; Tenoever, Benjamin R; Paterson, Jennifer M; Power, Anthony T; Knowles, Shane; Marius, Ricardo; Reynard, Jennifer; Poliquin, Laurent; Atkins, Harold; Brown, Earl G; Durbin, Russell K; Durbin, Joan E; Hiscott, John; Bell, John C (2003). "VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents". Cancer Cell. 4 (4): 263–75. PMID 14585354. doi:10.1016/S1535-6108(03)00241-1. 
  52. ^ 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. PMID 15527832. doi:10.1016/j.virol.2004.08.039. 
  53. ^ 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. PMID 15565179. doi:10.1038/sj.cgt.7700794. 
  54. ^ 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. 
  55. ^ Bridle, Byram W; Stephenson, Kyle B; Boudreau, Jeanette E; Koshy, Sandeep; Kazdhan, Natasha; Pullenayegum, Eleanor; Brunellière, Jérôme; Bramson, Jonathan L; Lichty, Brian D; Wan, Yonghong (2010). "Potentiating Cancer Immunotherapy Using an Oncolytic Virus". Molecular Therapy. 18 (8): 1430–9. PMC 2927075Freely accessible. PMID 20551919. doi:10.1038/mt.2010.98. 
  56. ^ Gromeier, M.; Lachmann, S.; Rosenfeld, M. R.; Gutin, P. H.; Wimmer, E. (2000). "Intergeneric poliovirus recombinants for the treatment of malignant glioma". Proceedings of the National Academy of Sciences. 97 (12): 6803–8. Bibcode:2000PNAS...97.6803G. JSTOR 122718. PMC 18745Freely accessible. PMID 10841575. doi:10.1073/pnas.97.12.6803. 
  57. ^ Goetz, Christian; Gromeier, Matthias (2010). "Preparing an oncolytic poliovirus recombinant for clinical application against glioblastoma multiforme". Cytokine & Growth Factor Reviews. 21 (2–3): 197–203. PMID 20299272. doi:10.1016/j.cytogfr.2010.02.005. 
  58. ^ 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. 
  59. ^ Thirukkumaran, Chandini; Morris, Don G. (2009), "Oncolytic Viral Therapy Using Reovirus", Methods in molecular biology, Gene Therapy of Cancer, 542: 607–34, ISBN 978-1-934115-85-5, PMID 19565924, doi:10.1007/978-1-59745-561-9_31 
  60. ^ Doniņa, Simona; Strēle, Ieva; Proboka, Guna; Auziņš, Jurģis; Alberts, Pēteris; Jonsson, Björn; Venskus, Dite; Muceniece, Aina (2015). "Adapted ECHO-7 virus Rigvir immunotherapy (oncolytic virotherapy) prolongs survival in melanoma patients after surgical excision of the tumour in a retrospective study". Melanoma Research. 25 (5): 421–426. doi:10.1097/CMR.0000000000000180. 
  61. ^ Cancer Virotherapy Journal | https://www.cancervirotherapy.eu/cancer-virotherapy-pdf-version.php | accessed 23 November 2015
  62. ^ Alberts, Pēteris; Olmane, Evija; Brokāne, Linda; Krastiņa, Zanda; Romanovska, Māra; Kupčs, Kārlis; Isajevs, Sergejs; Proboka, Guna; Romualds, Erdmanis; Jurijs, Nazarovs; Dite, Venskus (2016). "Long-term treatment with the oncolytic ECHO-7 virus Rigvir of a melanoma stage IV M1c patient, a small cell lung cancer stage IIIA patient, and a histiocytic sarcoma stage IV patient-three case reports.". APMIS. 124 (9): 896–904. doi:10.1111/apm.12576. 
  63. ^ a b Ramachandran, Mohanraj; Yu, Di; Dyczynski, Matheus; Baskaran, Sathishkumar; Zhang, Lei; Saul, Sirle; Lulla, Aleksei; Lulla, Valeria; Nelander, Sven (2016-01-01). "Safe and effective treatment of experimental neuroblastoma and glioblastoma using systemically administered triple microRNA-detargeted oncolytic Semliki Forest virus". Clinical Cancer Research: clincanres.0925.2016. ISSN 1078-0432. PMID 27637889. doi:10.1158/1078-0432.CCR-16-0925. 
  64. ^ Ottawa research into cancer vaccine gets funding boost
  65. ^ MG1 Maraba/MAGE-A3, With and Without Adenovirus Vaccine, With Transgenic MAGE-A3 Insertion in Patients With Incurable MAGE-A3-Expressing Solid Tumours (I214)
  66. ^ 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 (2008). "Directed evolution generates a novel oncolytic virus for the treatment of colon cancer". PLoS ONE. 3 (6): e2409. PMC 2423470Freely accessible. PMID 18560559. doi:10.1371/journal.pone.0002409. 
  67. ^ 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. 
  68. ^ "Medical Dictionary". Merriam-Webster. Retrieved 5 April 2013. 
  69. ^ Gentry, Glenn A. (1992). "Viral thymidine kinases and their relatives". Pharmacology & Therapeutics. 54 (3): 319–355. doi:10.1016/0163-7258(92)90006-L. 
  70. ^ 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. PMID 15205347. doi:10.1158/0008-5472.CAN-04-0064. 
  71. ^ a b c 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 (2012). Gelovani, Juri G, ed. "Imaging Characteristics, Tissue Distribution, and Spread of a Novel Oncolytic Vaccinia Virus Carrying the Human Sodium Iodide Symporter". PLoS ONE. 7 (8): e41647. PMC 3422353Freely accessible. PMID 22912675. doi:10.1371/journal.pone.0041647. 
  72. ^ Poirier, J. T.; Reddy, P. S.; Idamakanti, N.; Li, S. S.; Stump, K. L.; Burroughs, K. D.; Hallenbeck, P. L.; Rudin, C. M. (2012). "Characterization of a full-length infectious cDNA clone and a GFP reporter derivative of the oncolytic picornavirus SVV-001". Journal of General Virology. 93 (Pt 12): 2606–13. PMID 22971818. doi:10.1099/vir.0.046011-0. 
  73. ^ Yu, Yong A; Shabahang, Shahrokh; Timiryasova, Tatyana M; Zhang, Qian; Beltz, Richard; Gentschev, Ivaylo; Goebel, Werner; Szalay, Aladar A (2004). "Visualization of tumors and metastases in live animals with bacteria and vaccinia virus encoding light-emitting proteins". Nature Biotechnology. 22 (3): 313–20. PMID 14990953. doi:10.1038/nbt937. 
  74. ^ Freeman, SM; Whartenby, KA; Freeman, JL; Abboud, CN; Marrogi, AJ (1996). "In situ use of suicide genes for cancer therapy". Seminars in oncology. 23 (1): 31–45. PMID 8607030. 
  75. ^ Duarte, Sónia; Carle, Georges; Faneca, Henrique; De Lima, Maria C. Pedroso de; Pierrefite-Carle, Valérie (2012). "Suicide gene therapy in cancer: Where do we stand now?". Cancer Letters. 324 (2): 160–70. PMID 22634584. doi:10.1016/j.canlet.2012.05.023. 
  76. ^ 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. Bibcode:2009PNAS..10612915F. JSTOR 40484625. PMC 2722284Freely accessible. PMID 19617539. doi:10.1073/pnas.0900660106. 
  77. ^ Conner, J; Braidwood, L (2012). "Expression of inhibitor of growth 4 by HSV1716 improves oncolytic potency and enhances efficacy". Cancer Gene Therapy. 19 (7): 499–507. PMID 22595793. doi:10.1038/cgt.2012.24. 
  78. ^ Grünwald, G K; Klutz, K; Willhauck, M J; Schwenk, N; Senekowitsch-Schmidtke, R; Schwaiger, M; Zach, C; Göke, B; Holm, P S; Spitzweg, C (2012). "Sodium iodide symporter (NIS)-mediated radiovirotherapy of hepatocellular cancer using a conditionally replicating adenovirus". Gene Therapy. 20 (6): 625–33. PMID 23038026. doi:10.1038/gt.2012.79. 
  79. ^ Penheiter, Alan R.; Wegman, Troy R.; Classic, Kelly L.; Dingli, David; Bender, Claire E.; Russell, Stephen J.; Carlson, Stephanie K. (2010). "Sodium Iodide Symporter (NIS)-Mediated Radiovirotherapy for Pancreatic Cancer". American Journal of Roentgenology. 195 (2): 341–9. PMC 3117397Freely accessible. PMID 20651188. doi:10.2214/AJR.09.3672. 
  80. ^ Li, H; Peng, K-W; Dingli, D; Kratzke, R A; Russell, S J (2010). "Oncolytic measles viruses encoding interferon β and the thyroidal sodium iodide symporter gene for mesothelioma virotherapy". Cancer Gene Therapy. 17 (8): 550–8. PMC 2907639Freely accessible. PMID 20379224. doi:10.1038/cgt.2010.10. 
  81. ^ Clinical trial number NCT00769704 for "Efficacy and Safety Study of OncoVEXGM-CSF Compared to GM-CSF in Melanoma" at ClinicalTrials.gov
  82. ^ a b "FDA approves Amgen's Injected Immunotherapy for Melanoma". Reuters. 27 October 2015. 
  83. ^ Sheridan, Cormac (2015). "First oncolytic virus edges towards approval in surprise vote". Nature Biotechnology. 33 (6): 569–570. ISSN 1087-0156. PMID 26057953. doi:10.1038/nbt0615-569. 
  84. ^ "Amgen, Form 8-K, Current Report, Filing Date Jan 26, 2012" (PDF). secdatabase.com. Retrieved Jan 8, 2013. 
  85. ^ 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
  86. ^ Pol, Jonathan; Buqué, Aitziber; Aranda, Fernando; Bloy, Norma; Cremer, Isabelle; Eggermont, Alexander; Erbs, Philippe; Fucikova, Jitka; Galon, Jérôme; Limacher, Jean-Marc; Preville, Xavier; Sautès-Fridman, Catherine; Spisek, Radek; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo (8 December 2015). "Trial Watch—Oncolytic viruses and cancer therapy". OncoImmunology. 5 (2): e1117740. PMID 27057469. doi:10.1080/2162402X.2015.1117740. 
  87. ^ Metastatic Melanoma Therapy, Imlygic, Now Available in EU
  88. ^ a b Schmidt, Charlie (2011). "Amgen spikes interest in live virus vaccines for hard-to-treat cancers". Nature Biotechnology. 29 (4): 295–6. PMID 21478830. doi:10.1038/nbt0411-295. 
  89. ^ "Intravenous Administration of REOLYSIN® in Combination with Paclitaxel and Carboplatin for Patients with Platinum-Refractory Head and Neck Cancers". Retrieved 31 May 2013. 
  90. ^ http://www.oncolytics.com/news_items/details?press_release_id=1916[full citation needed]
  91. ^ "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. 
  92. ^ Adair, R. A.; Roulstone, V.; Scott, K. J.; Morgan, R.; Nuovo, G. J.; Fuller, M.; Beirne, D.; West, E. J.; Jennings, V. A.; Rose, A.; Kyula, J.; Fraser, S.; Dave, R.; Anthoney, D. A.; Merrick, A.; Prestwich, R.; Aldouri, A.; Donnelly, O.; Pandha, H.; Coffey, M.; Selby, P.; Vile, R.; Toogood, G.; Harrington, K.; Melcher, A. A. (2012). "Cell Carriage, Delivery, and Selective Replication of an Oncolytic Virus in Tumor in Patients". Science Translational Medicine. 4 (138): 138ra77. PMC 3893925Freely accessible. PMID 22700953. doi:10.1126/scitranslmed.3003578. , 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. 
  93. ^ Reolysin Clinical Trials at NIH
  94. ^ Clinical trial number NCT01387555 for "A Phase 2b Study of Vaccinia Virus to Treat Advanced Liver Cancer (TRAVERSE)" at ClinicalTrials.gov
  95. ^ Clinical trial number NCT00625456 for "Safety Study of Recombinant Vaccinia Virus to Treat Refractory Solid Tumors" at ClinicalTrials.gov
  96. ^ j. Breitbach, Caroline; Thorne, Steve; Bell, John; Kirn, David (2012). "Targeted and Armed Oncolytic Poxviruses for Cancer: The Lead Example of JX-594". Current Pharmaceutical Biotechnology. 13 (9): 1768–72. PMID 21740365. doi:10.2174/138920112800958922. 
  97. ^ Clinical trial number NCT01048892 for "Seneca Valley Virus-001 and Cyclophosphamide in Treating Young Patients With Relapsed or Refractory Neuroblastoma, Rhabdomyosarcoma, or Rare Tumors With Neuroendocrine Features" at ClinicalTrials.gov, October 2012
  98. ^ Clinical trial number NCT01017601 for "Seneca Valley Virus-001 After Chemotherapy in Treating Patients With Extensive-Stage Small Cell Lung Cancer" at ClinicalTrials.gov
  99. ^ Oncolytic activity of Coxsackievirus A21 (CAVATAK™) in human pancreatic cancer. (June 2011 poster)
  100. ^ Clinical trial number NCT00832559 for "A Study of the Intratumoural Administration of CAVATAK to Head and Neck Cancer Patients" at ClinicalTrials.gov
  101. ^ Clinical trial number NCT01227551 for "A Study of Intratumoral CAVATAK in Patients With Stage IIIc and Stage IV Malignant Melanoma" at ClinicalTrials.gov
  102. ^ A Randomised Phase II Open-label Study With a Phase Ib Safety lead-in Cohort of ONCOS-102, an Immune-priming GM-CSF Coding Oncolytic Adenovirus, and Pemetrexed/Cisplatin in Patients With Unresectable Malignant Pleural Mesothelioma
  103. ^ Targovax recruits the first patient in a trial with the oncolytic virus ONCOS-102 in malignant pleural mesothelioma
  104. ^ "Virttu.com". 
  105. ^ Seprehvir, Virttu Biologics
  106. ^ Oncolytic Virus Specialist Virttu Biologics Initiates Phase I/II SEPREHVIR™ Study in Mesothelioma, BioSpace, 11 September 2012
  107. ^ "Oncos.net". 
  108. ^ "Oncolytic viruses mediating anti-tumor immunity in human cancer patients" (Press release). Oncos Therapeutics. 19 May 2010. 
  109. ^ Clinical trial number NCT00794131 for "Safety Study of GL-ONC1, an Oncolytic Virus, in Patients With Advanced Solid Tumors" at ClinicalTrials.gov
  110. ^ Clinical trial number NCT01766739 for "Intra-pleural Administration of GL-ONC1, a Genetically Modified Vaccinia Virus, in Patients With Malignant Pleural Effusion: Primary, Metastases and Mesothelioma" at ClinicalTrials.gov
  111. ^ Clinical trial number NCT01443260 for "A Study of GL-ONC1, an Oncolytic Vaccinia Virus, in Patients With Advanced Peritoneal Carcinomatosis" at ClinicalTrials.gov
  112. ^ [1]
  113. ^ Clinical trial number NCT01584284 for "Safety Study of Attenuated Vaccinia Virus (GL-ONC1)With Combination Therapy in Head & Neck Cancer" at ClinicalTrials.gov
  114. ^ Russell SJ, Federspiel MJ, Peng KW, Tong C, Dingli D, Morice WG, Lowe V, O'Connor MK, Kyle RA, Leung N, Buadi FK, Rajkumar SV, Gertz MA, Lacy MQ, Dispenzieri A (2014-07-01). "Remission of Disseminated Cancer After Systemic Oncolytic Virotherapy". Mayo Clinic Proceedings. 89 (7): 926–933. ISSN 0025-6196. PMC 4225126Freely accessible. PMID 24835528. doi:10.1016/j.mayocp.2014.04.003. Retrieved 2014-08-21. 
  115. ^ [2]
  116. ^ Ottolino-Perry, Kathryn; Diallo, Jean-Simon; Lichty, Brian D; Bell, John C; McCart, J (2009). "Intelligent Design: Combination Therapy with Oncolytic Viruses". Molecular Therapy. 18 (2): 251–63. PMC 2839289Freely accessible. PMID 20029399. doi:10.1038/mt.2009.283. 
  117. ^ Khuri, Fadlo R.; Nemunaitis, John; Ganly, Ian; Arseneau, James; Tannock, Ian F.; Romel, Larry; Gore, Martin; Ironside, Janet; MacDougall, R.H.; Heise, Carla; Randlev, Britta; Gillenwater, Ann M.; Bruso, Patricia; Kaye, Stanley B.; Hong, Waun Ki; Kirn, David 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): 879–85. PMID 10932224. doi:10.1038/78638. 
  118. ^ Suryawanshi, Yogesh R.; Zhang, Tiantian; Essani, Karim (2017-03-01). "Oncolytic viruses: emerging options for the treatment of breast cancer". Medical Oncology. 34 (3): 43. ISSN 1357-0560. doi:10.1007/s12032-017-0899-0. 
  119. ^ 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 (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. 
  120. ^ Mace, A.T.M.; Harrow, S.J.; Ganly, I.; Brown, S.M. (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. PMID 17763002. doi:10.1080/00016480601075381. 
  121. ^ Toyoizumi, Takane; Mick, Rosemarie; Abbas, Abbas E.; Kang, Eugene H.; Kaiser, Larry R.; Molnar-Kimber, Katherine L. (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. PMID 10609661. doi:10.1089/10430349950016410. 
  122. ^ Currier, Mark A; Eshun, Francis K; Sholl, Allyson; Chernoguz, Artur; Crawford, Kelly; Divanovic, Senad; Boon, Louis; Goins, William F; Frischer, Jason S; Collins, Margaret H; Leddon, Jennifer L; Baird, William H; Haseley, Amy; Streby, Keri A; Wang, Pin-Yi; Hendrickson, Brett W; Brekken, Rolf A; Kaur, Balveen; Hildeman, David; Cripe, Timothy P (2013). "VEGF Blockade Enables Oncolytic Cancer Virotherapy in Part by Modulating Intratumoral Myeloid Cells". Molecular Therapy. 21 (5): 1014–23. PMC 3666636Freely accessible. PMID 23481323. doi:10.1038/mt.2013.39. 
  123. ^ Williamson, Jack (2002). Dragon's Island and other stories. Waterville, Me.: Five Star. ISBN 0786243147. [page needed]
  124. ^ Stableford, Brian M. (2004). Historical dictionary of science fiction literature. p. 133. ISBN 9780810849389. 

Further reading[edit]

  • 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: Dekker. ISBN 0824759133. 

External links[edit]