Oncolytic virus
Encyclopedia
An oncolytic virus is a virus
that preferentially infects and lyses
cancer cells; these have obvious functions for cancer therapy, both by direct destruction of the tumour cells, and, if modified, as vectors enabling genes expressing anticancer proteins to be delivered specifically to the tumor site.
Most current oncolytic viruses are engineered for tumour selectivity, though there are a few naturally occurring ones such as the Seneca Valley virus.
, 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 in 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.
With the later development of advanced genetic engineering
techniques, researchers gained the ability to deliberately modify existing viruses, or to create new ones. All modern research on oncolytic viruses involves viruses that have been modified to be less susceptible to immune suppression, to more specifically target particular classes of cancer cells, or to express desired cancer-suppressing genes.
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 works best when injected directly into a tumor, and when any resulting fever
is not suppressed. Systemic therapy (such as through infusion through an intravenous line) is desirable for treating metastatic disease.
has never been used successfully against cancer, mainly due to poor transduction
of cells. This problem is solved by oncolytic viruses. The use of viral agents to treat cancer is now a real possibility, and several very promising advances have been made, e.g. ONYX-015 and MV-ERV. The most advanced oncolytic virus, based on herpes simplex is OncoVEX GM-CSF which is in Phase 3 clinical trials in melanoma
and head and neck cancer
. This virus has given a 20% complete response rate in melanoma, a level of efficacy which has never been seen by any agent in melanoma before.
Viral agents administered intravenously can be particularly effective against metastatic cancers, which are especially difficult to treat conventionally. However, blood-borne viruses can be deactivated by antibodies and cleared from the blood stream quickly e.g. by Kupffer cells (extremely active phagocytic cells in the liver, which are responsible for adenovirus clearance). Avoidance of the immune system until the tumour is destroyed could be the biggest obstacle to the success of oncolytic virus therapy. To date, no technique used to evade the immune system is entirely satisfactory. 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. An exception to each of these points is again provided by OncoVEX GM-CSF (BioVex Inc, Woburn MA), the efficacy of which has been found not to be compromised by host immunity, and with which stand alone therapy has provided an approximately 30% response rate (PR + CR) against systemic disease, following local injection into accessible tumors. This is because this virus stimulates a systemic anti-tumor immune response enhanced through the expression of GM-CSF in the dying tumor micro-environment. OncoVEX GM-CSF is currently completing a pivotal Phase 3 trial in melanoma, the first pivotal trial with an oncolytic virus to ever be conducted, and a phase 3 trial in head and neck cancer is also underway. (The developer of OncoVEX GM-CSF, BioVex Inc, was purchased by Amgen for $1 billion in January 2011.)
The specificity and flexibility of oncolytic viruses means they have the potential to treat a wide range of cancers with minimal side effect
s. However, altering the host range or tissue specificity of any virus has significant safety implications.
Non-oncolytic viral therapy :
ONYX-015 has undergone trials in conjunction with chemotherapy. The combined treatment gave a greater response than either treatment alone, but the results have not been entirely conclusive. ONYX-015 has shown promise in conjunction with radiotherapy. Abandoned in 2000.
is advantageous because it has greater stability during storage, which reduces the chances of hazardous mutations. Viruses like adenoviruses and herpes simplex virus
are the most suitable, and have been the most extensively studied.
targeting, where genes
essential for viral replication
are placed under the control of a tumour-specific promoter, or by attenuation
, which involves introducing deletions into the viral genome that eliminate functions that are dispensable in cancer cells, but not in normal cells. There are also other, slightly more obscure methods.
The most commonly used group of adenoviruses is serotype
5 (Ad5), whose binding to host
cells is initiated by interactions between the cellular coxsackievirus and adenovirus receptor
(CAR), and the knob domain of the adenovirus coat protein trimer
. Li et al. (1999) showed that CAR is necessary for adenovirus infection by showing that CAR-negative cells could be made adenovirus-sensitive by transfection
with CAR cDNA. Virus internalisation depends on an Arginine
-Glycine
-Asparagine
(RGD) motif at the base of adenovirus coat protein that binds to integrin
s, causing endocytosis
. It has been suggested that CAR has a role in cell adhesion, and possibly tumour suppression. Although expressed widely in epithelial cells, CAR expression in tumours is extremely variable, leading to resistance to Ad5 infection. Retargeting of Ad5 from CAR, to another receptor that is ubiquitously expressed on cancer cells, enables reduction of Ad5 tropism
, enhancing infection of CAR deficient target cells. This can be done in one of two ways:
Bi-specific adapter molecules can be administered along with the virus to redirect viral coat protein tropism. These molecules are fusion protein
s that are made up of an antibody
raised against the knob domain of the adenovirus coat protein, fused to a natural ligand
for a cell-surface receptor. The use of adapter molecules has been shown to increase viral transduction. However, adapters add complexity to the system, and the effect of adapter molecule binding on the stability of the virus is uncertain.
This method involves genetically modifying the fiber knob domain of the viral coat protein to alter its specificity. Wickham et al. (2003) added short peptide
s to the C-terminal end of the coat protein, which successfully altered viral tropism. The addition of larger peptides to the C-terminus is not viable because it reduces adenovirus integrity, possibly due to an effect on fiber trimerisation. The fiber protein also contains an HI-loop structure, which can tolerate peptide insertions of up to 100 residues without any negative effects on adenovirus integrity. Davydova et al. (2004) inserted an RGD motif in the HI loop of the fiber knob protein, shifting specificity toward integrin
s, which are frequently over-expressed in Oesophageal Adenocarcinoma. When combined with a form of non-transductional targeting, these viruses proved to be effective and selective therapeutic agents for Oesophageal Adenocarcinoma.
Transcriptional targeting places an essential viral gene under the control of a tumour-specific promoter, meaning the gene is only expressed in cell types where all the transcription factor
s required for promoter function are active. 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.
Cyclooxygenase-2 enzyme
(Cox-2) expression is elevated in a range of cancers, and has low liver expression, making it a suitable tumour-specific promoter. Davydova et al. (2004) targeted AdCox2Lluc, a conditionally replicating adenovirus (CRAd), against Oesophageal Adenocarcinoma by placing the early genes under the control of a Cox-2 promoter (adenoviruses have two early genes, E1A and E1B, that are essential for replication). When combined with transductional targeting, AdCox2Lluc showed potential for treatment of Oesophageal Adenocarcinoma. Cox-2 is also a possible tumour-specific promoter candidate for other cancer types, including ovarian cancer.
A suitable tumour-specific promoter for prostate cancer
is prostate-specific antigen
(PSA), whose expression is greatly elevated in prostate cancer. CN706 is a CRAd with a PSA tumour-specific promoter driving expression of the adenoviral E1A gene, required for viral replication. Rodriguez et al. (1997) showed that the CN706 titre is significantly greater in PSA-positive cells.
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. Attenuation involves deleting viral genes, or gene regions, to eliminate viral functions that are expendable in tumour cell, but not in normal cells.
For adenovirus replication to occur, the host cell must be induced into S-phase by viral proteins interfering with cell cycle proteins. The adenoviral E1A gene is responsible for inactivation of several proteins, including Retinoblastoma
, allowing entry into S-phase. The adenovirus E1B55kDa gene cooperates with another adenoviral product, E4ORF6, to inactivate p53
, thus preventing apoptosis
. It was initially proposed that an Adenovirus mutant
lacking the E1B55kDa gene, dl1520 (ONYX-015), could replicate selectively in p53
deficient cells. ONYX-015 was subsequently elevated into clinical trials in patients with advanced head and neck cancer, however the outcomes were marginal. ONYX-015 when combined with chemotherapy
, however, proved reasonably effective in a proportion of cases. During these trials a plethora of reports emerged challenging the underlying p53-selectivity, with some reports showing that in some cancers with a wild-type p53 ONYX-015 actually did better than in their mutant p53 counterparts. These reports slowed the advancement through Phase III trials in the US, however recently China licensed ONYX-015 for therapeutin use as H101. Outside of China, the push to the clinic for ONYX-015 has been largely been discontinued for financial reasons and until a real mechanism can be found.
Carette et al. (2004) used Ad5- Δ24E3, a CRAd with a 24 base pair
deletion in the retinoblastoma
-binding domain of the E1A protein
, making it unable to silence retinoblastoma
, and therefore unable to induce S-phase in host cells. This means Ad5-Δ24E3 is only able to replicate in proliferating cells, such as tumour cells. The adenovirus was used to deliver short hairpin RNA, which was able to reduce expression of the luciferase
target gene in target cells to 30%, relative to the control, by RNA interference
.
The herpes simplex virus genome contains the enzymes thymidine kinase and ribonucleotide reductase, whose cellular forms are responsible for the production of dNTP’s required for DNA synthesis
and are only expressed during the G1 and S phases of the cell cycle. These enzymes allow herpes simplex virus replication in quiescent
cells, so if they are inactivated by mutation the herpes simplex virus will only be able to replicate in proliferating cells, such as cancer cells. The G207 herpes simplex virus mutant contains a LacZ insertion, inactivating ribonucleotide reductase, as well as deletion of a virulence
gene for safety's sake, has progressed to clinical trials for the treatment in brain cancer.
, blocking DNA synthesis. The tumour selectivity of oncolytic viruses ensures that the suicide genes are only expressed in cancer cells.
(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 vector
s, 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 antitumor activities have been demonstrated in a recombinant vaccinia virus encoding anti-angiogenic therapeutic antibody.
However, since viruses are normal human pathogens, they induce an immune response, which reduces their effectiveness. Increased antibody
titers could deactivate viruses before the tumour has been destroyed. This can be partly overcome by using parental viruses that are not normal human pathogens, thereby avoiding any pre-existing immunity. However, this does not avoid subsequent antibody
generation. 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. Deactivation of the immune system
is not desirable, since it has a positive effect on tumour necrosis.
(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 and 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 (Stojdl et al., 2003, Ahmed et al., 2004, Ebert et al. 2005 and Porosnicu et al., 2003 have gone on to show that systemically administered VSV can be delivered to a tumor 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 tumor cells is unaffected (Stojdl et al., 2003).
Recent research has shown that this virus has the potential to cure brain tumors, thanks to its oncolytic properties.
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 ribosomal 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.
, 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.
Reolysin
is a formulation of reovirus that is currently in clinical trials for the treatment of various cancers.
, 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 Hollywood film I Am Legend
is based on the premise that a worldwide epidemic was caused by a viral cure for cancer. This fictional tale emphasizes a major concern with oncolytic viruses: that mutations could possibly destroy the host.
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
that preferentially infects and lyses
Lysis
Lysis refers to the breaking down of a cell, often by viral, enzymic, or osmotic mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a "lysate"....
cancer cells; these have obvious functions for cancer therapy, both by direct destruction of the tumour cells, and, if modified, as vectors enabling genes expressing anticancer proteins to be delivered specifically to the tumor site.
Most current oncolytic viruses are engineered for tumour selectivity, though there are a few naturally occurring ones such as the Seneca Valley virus.
History
A connection between cancer and viruses has long been theorized, and case reports of cancer regression (cervical cancerCervical cancer
Cervical cancer is malignant neoplasm of the cervix uteri or cervical area. One of the most common symptoms is abnormal vaginal bleeding, but in some cases there may be no obvious symptoms until the cancer is in its advanced stages...
, 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
Immunization
Immunization, or immunisation, is the process by which an individual's immune system becomes fortified against an agent ....
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 in using poliovirus
Poliovirus
Poliovirus, the causative agent of poliomyelitis, is a human enterovirus and member of the family of Picornaviridae.Poliovirus is composed of an RNA genome and a protein capsid. The genome is a single-stranded positive-sense RNA genome that is about 7500 nucleotides long. The viral particle is...
, 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
Virotherapy
Virotherapy is a treatment using biotechnology to convert viruses into cancer-fighting agents by reprogramming viruses to attack cancerous cells, while healthy cells remained relatively undamaged...
was also recognized very early. Even when a response was seen, these responses were neither complete nor durable. The field of virotherapy
Virotherapy
Virotherapy is a treatment using biotechnology to convert viruses into cancer-fighting agents by reprogramming viruses to attack cancerous cells, while healthy cells remained relatively undamaged...
was nearly abandoned for a time.
With the later development of advanced genetic engineering
Genetic engineering
Genetic engineering, also called genetic modification, is the direct human manipulation of an organism's genome using modern DNA technology. It involves the introduction of foreign DNA or synthetic genes into the organism of interest...
techniques, researchers gained the ability to deliberately modify existing viruses, or to create new ones. All modern research on oncolytic viruses involves viruses that have been modified to be less susceptible to immune suppression, to more specifically target particular classes of cancer cells, or to express desired cancer-suppressing genes.
H101
The first oncolytic virus to be approved by a regulatory agency was a genetically modified adenovirus named H101 by Shanghai Sunway Biotech. It gained regulatory approval in 2005 from China's State Food and Drug Administration (SFDA) for the treatment of head and neck cancer. Sunway's H101 and the very similar Onyx-15Onyx-15
Onyx-015 is an experimental oncolytic virus created by genetically engineering an adenovirus. It has been trialed as a possible treatment for cancer...
have been engineered to remove a viral defense mechanism that interacts with a normal human gene p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
, 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 works best when injected directly into a tumor, and when any resulting fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
is not suppressed. Systemic therapy (such as through infusion through an intravenous line) is desirable for treating metastatic disease.
Possible applications
Virus gene therapyGene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
has never been used successfully against cancer, mainly due to poor transduction
Transduction (genetics)
Transduction is the process by which DNA is transferred from one bacterium to another by a virus. It also refers to the process whereby foreign DNA is introduced into another cell via a viral vector. Transduction does not require cell-to-cell contact , and it is DNAase resistant...
of cells. This problem is solved by oncolytic viruses. The use of viral agents to treat cancer is now a real possibility, and several very promising advances have been made, e.g. ONYX-015 and MV-ERV. The most advanced oncolytic virus, based on herpes simplex is OncoVEX GM-CSF which is in Phase 3 clinical trials in melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
and head and neck cancer
Head and neck cancer
Head and neck cancer refers to a group of biologically similar cancers that start in the upper aerodigestive tract, including the lip, oral cavity , nasal cavity , paranasal sinuses, pharynx, and larynx. 90% of head and neck cancers are squamous cell carcinomas , originating from the mucosal lining...
. This virus has given a 20% complete response rate in melanoma, a level of efficacy which has never been seen by any agent in melanoma before.
Viral agents administered intravenously can be particularly effective against metastatic cancers, which are especially difficult to treat conventionally. However, blood-borne viruses can be deactivated by antibodies and cleared from the blood stream quickly e.g. by Kupffer cells (extremely active phagocytic cells in the liver, which are responsible for adenovirus clearance). Avoidance of the immune system until the tumour is destroyed could be the biggest obstacle to the success of oncolytic virus therapy. To date, no technique used to evade the immune system is entirely satisfactory. 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. An exception to each of these points is again provided by OncoVEX GM-CSF (BioVex Inc, Woburn MA), the efficacy of which has been found not to be compromised by host immunity, and with which stand alone therapy has provided an approximately 30% response rate (PR + CR) against systemic disease, following local injection into accessible tumors. This is because this virus stimulates a systemic anti-tumor immune response enhanced through the expression of GM-CSF in the dying tumor micro-environment. OncoVEX GM-CSF is currently completing a pivotal Phase 3 trial in melanoma, the first pivotal trial with an oncolytic virus to ever be conducted, and a phase 3 trial in head and neck cancer is also underway. (The developer of OncoVEX GM-CSF, BioVex Inc, was purchased by Amgen for $1 billion in January 2011.)
The specificity and flexibility of oncolytic viruses means they have the potential to treat a wide range of cancers with minimal side effect
Adverse effect (medicine)
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
s. However, altering the host range or tissue specificity of any virus has significant safety implications.
Clinical research
- OncoVEX GM-CSF (see above) developed by BioVex is currently in phase III for advanced melanomaMelanomaMelanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
, and likely to become the first approved oncolytic agent in the western world. OncoVEX GM-CSF is also currently being tested in a pivotal phase 3 trial in head and neck cancer.
- REOLYSINReolysinReolysin is a formulation of reovirus that Oncolytics Biotech is developing for the treatment of various cancers and cell proliferative disorders. Reolysin is classified as a oncolytic virus, a virus that preferentially lyses cancer cells...
, in phase III for Head and neck cancer. Encouraging early results in colorectal cancer.
- JX-594JX-594JX-594 is an oncolytic virus that is developed by Jennerex and is designed to target and destroy cancer cells.JX-594 is a vaccinia poxvirus engineered to selectively replicate in tumor cells that have an activated EGFR/ Ras pathway, but not in normal tissue...
currently in phase II by Jennerex for hepatocellular carcinomaHepatocellular carcinomaHepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...
. JX-594 is a thymidine kinase-deleted Vaccinia virus plus GM-CSF. John Cameron Bell is the chief scientific officer for these trials. - JX-954
- NTX-010, in phase II for small cell lung cancer.
- CGTG-102 (Ad5/3-D24-GMCSF) by Oncos Therapeutics, while in phase I already used to treat 200 advanced cancer patients in company's Advanced Therapy Access Program.
- GL-ONC1 by Genelux is in phase I for solid tumors. Additional trials are being developed.
- Cavatak has a phase II study planned for malignant melanoma
- Oncorine, approved in China for Head and neck cancer. Based on H101 virus
Non-oncolytic viral therapy :
- TNFerade (a non replicating TNF gene therapy virus) failed a phase III trial for pancreatic cancerPancreatic cancerPancreatic cancer refers to a malignant neoplasm of the pancreas. The most common type of pancreatic cancer, accounting for 95% of these tumors is adenocarcinoma, which arises within the exocrine component of the pancreas. A minority arises from the islet cells and is classified as a...
.
Oncolytic viruses in conjunction with existing cancer therapies
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.ONYX-015 has undergone trials in conjunction with chemotherapy. The combined treatment gave a greater response than either treatment alone, but the results have not been entirely conclusive. ONYX-015 has shown promise in conjunction with radiotherapy. Abandoned in 2000.
Selection criteria
The virus should be able to tolerate storage and production at high titres. A double-stranded DNA genomeGenome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
is advantageous because it has greater stability during storage, which reduces the chances of hazardous mutations. Viruses like adenoviruses and herpes simplex virus
Herpes simplex virus
Herpes simplex virus 1 and 2 , also known as Human herpes virus 1 and 2 , are two members of the herpes virus family, Herpesviridae, that infect humans. Both HSV-1 and HSV-2 are ubiquitous and contagious...
are the most suitable, and have been the most extensively studied.
Generating tumour selectivity
There are two main approaches for generating tumour selectivity: transductional and non-transductional targeting. Transductional targeting involves modifying the specificity of viral coat protein, thus increasing entry into target cells while reducing entry to non-target cells. Non-transductional targeting involves altering the genome of the virus so it can only replicate in cancer cells. This can be done by either transcriptionTranscription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
targeting, where genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
essential for viral replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
are placed under the control of a tumour-specific promoter, or by attenuation
Attenuation
In physics, attenuation is the gradual loss in intensity of any kind of flux through a medium. For instance, sunlight is attenuated by dark glasses, X-rays are attenuated by lead, and light and sound are attenuated by water.In electrical engineering and telecommunications, attenuation affects the...
, which involves introducing deletions into the viral genome that eliminate functions that are dispensable in cancer cells, but not in normal cells. There are also other, slightly more obscure methods.
Transductional targeting
This approach to tumour selectivity has mainly focused on adenoviruses, although it is entirely viable with other viruses. However, it should be recognised that increasing the host tissue range of a virus has serious safety implications.The most commonly used group of adenoviruses is serotype
Serotype
Serotype or serovar refers to distinct variations within a subspecies of bacteria or viruses. These microorganisms, viruses, or cells are classified together based on their cell surface antigens...
5 (Ad5), whose binding to host
Host (biology)
In biology, a host is an organism that harbors a parasite, or a mutual or commensal symbiont, typically providing nourishment and shelter. In botany, a host plant is one that supplies food resources and substrate for certain insects or other fauna...
cells is initiated by interactions between the cellular coxsackievirus and adenovirus receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
(CAR), and the knob domain of the adenovirus coat protein trimer
Trimer (biochemistry)
In biochemistry, a trimer is a macromolecular complex formed by three, usually non-covalently bound, macromolecules like proteins or nucleic acids. A homo-trimer would be formed by three identical molecules. A hetero-trimer would be formed by three different macromolecules. Collagen is an example...
. Li et al. (1999) showed that CAR is necessary for adenovirus infection by showing that CAR-negative cells could be made adenovirus-sensitive by transfection
Transfection
Transfection is the process of deliberately introducing nucleic acids into cells. The term is used notably for non-viral methods in eukaryotic cells...
with CAR cDNA. Virus internalisation depends on an Arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
-Glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
-Asparagine
Asparagine
Asparagine is one of the 20 most common natural amino acids on Earth. It has carboxamide as the side-chain's functional group. It is not an essential amino acid...
(RGD) motif at the base of adenovirus coat protein that binds to integrin
Integrin
Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
s, causing endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
. It has been suggested that CAR has a role in cell adhesion, and possibly tumour suppression. Although expressed widely in epithelial cells, CAR expression in tumours is extremely variable, leading to resistance to Ad5 infection. Retargeting of Ad5 from CAR, to another receptor that is ubiquitously expressed on cancer cells, enables reduction of Ad5 tropism
Tropism
A tropism is a biological phenomenon, indicating growth or turning movement of a biological organism, usually a plant, in response to an environmental stimulus. In tropisms, this response is dependent on the direction of the stimulus...
, enhancing infection of CAR deficient target cells. This can be done in one of two ways:
Adapter molecules
Bi-specific adapter molecules can be administered along with the virus to redirect viral coat protein tropism. These molecules are fusion protein
Fusion protein
Fusion proteins or chimeric proteins are proteins created through the joining of two or more genes which originally coded for separate proteins. Translation of this fusion gene results in a single polypeptide with functional properties derived from each of the original proteins...
s that are made up of an antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
raised against the knob domain of the adenovirus coat protein, fused to a natural ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
for a cell-surface receptor. The use of adapter molecules has been shown to increase viral transduction. However, adapters add complexity to the system, and the effect of adapter molecule binding on the stability of the virus is uncertain.
Coat-protein modification
This method involves genetically modifying the fiber knob domain of the viral coat protein to alter its specificity. Wickham et al. (2003) added short peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
s to the C-terminal end of the coat protein, which successfully altered viral tropism. The addition of larger peptides to the C-terminus is not viable because it reduces adenovirus integrity, possibly due to an effect on fiber trimerisation. The fiber protein also contains an HI-loop structure, which can tolerate peptide insertions of up to 100 residues without any negative effects on adenovirus integrity. Davydova et al. (2004) inserted an RGD motif in the HI loop of the fiber knob protein, shifting specificity toward integrin
Integrin
Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
s, which are frequently over-expressed in Oesophageal Adenocarcinoma. When combined with a form of non-transductional targeting, these viruses proved to be effective and selective therapeutic agents for Oesophageal Adenocarcinoma.
Transcriptional targeting
Transcriptional targeting places an essential viral gene under the control of a tumour-specific promoter, meaning the gene is only expressed in cell types where all the transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s required for promoter function are active. A suitable promoter should be active in the tumour but inactive in the majority of normal tissue, particularly the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, 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.
Cyclooxygenase-2 enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
(Cox-2) expression is elevated in a range of cancers, and has low liver expression, making it a suitable tumour-specific promoter. Davydova et al. (2004) targeted AdCox2Lluc, a conditionally replicating adenovirus (CRAd), against Oesophageal Adenocarcinoma by placing the early genes under the control of a Cox-2 promoter (adenoviruses have two early genes, E1A and E1B, that are essential for replication). When combined with transductional targeting, AdCox2Lluc showed potential for treatment of Oesophageal Adenocarcinoma. Cox-2 is also a possible tumour-specific promoter candidate for other cancer types, including ovarian cancer.
A suitable tumour-specific promoter for prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
is prostate-specific antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
(PSA), whose expression is greatly elevated in prostate cancer. CN706 is a CRAd with a PSA tumour-specific promoter driving expression of the adenoviral E1A gene, required for viral replication. Rodriguez et al. (1997) showed that the CN706 titre is significantly greater in PSA-positive cells.
Attenuation
Cancer cells and virus-infected cells have similar alterations in their cell signalling pathways, particularly those that govern progression through the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
. 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. Attenuation involves deleting viral genes, or gene regions, to eliminate viral functions that are expendable in tumour cell, but not in normal cells.
For adenovirus replication to occur, the host cell must be induced into S-phase by viral proteins interfering with cell cycle proteins. The adenoviral E1A gene is responsible for inactivation of several proteins, including Retinoblastoma
Retinoblastoma
Retinoblastoma is a rapidly developing cancer that develops in the cells of retina, the light-detecting tissue of the eye. In the developed world, Rb has one of the best cure rates of all childhood cancers , with more than nine out of every ten sufferers surviving into...
, allowing entry into S-phase. The adenovirus E1B55kDa gene cooperates with another adenoviral product, E4ORF6, to inactivate p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
, thus preventing apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. It was initially proposed that an Adenovirus mutant
Mutant
In biology and especially genetics, a mutant is an individual, organism, or new genetic character, arising or resulting from an instance of mutation, which is a base-pair sequence change within the DNA of a gene or chromosome of an organism resulting in the creation of a new character or trait not...
lacking the E1B55kDa gene, dl1520 (ONYX-015), could replicate selectively in p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
deficient cells. ONYX-015 was subsequently elevated into clinical trials in patients with advanced head and neck cancer, however the outcomes were marginal. ONYX-015 when combined with chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, however, proved reasonably effective in a proportion of cases. During these trials a plethora of reports emerged challenging the underlying p53-selectivity, with some reports showing that in some cancers with a wild-type p53 ONYX-015 actually did better than in their mutant p53 counterparts. These reports slowed the advancement through Phase III trials in the US, however recently China licensed ONYX-015 for therapeutin use as H101. Outside of China, the push to the clinic for ONYX-015 has been largely been discontinued for financial reasons and until a real mechanism can be found.
Carette et al. (2004) used Ad5- Δ24E3, a CRAd with a 24 base pair
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
deletion in the retinoblastoma
Retinoblastoma
Retinoblastoma is a rapidly developing cancer that develops in the cells of retina, the light-detecting tissue of the eye. In the developed world, Rb has one of the best cure rates of all childhood cancers , with more than nine out of every ten sufferers surviving into...
-binding domain of the E1A protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
, making it unable to silence retinoblastoma
Retinoblastoma
Retinoblastoma is a rapidly developing cancer that develops in the cells of retina, the light-detecting tissue of the eye. In the developed world, Rb has one of the best cure rates of all childhood cancers , with more than nine out of every ten sufferers surviving into...
, and therefore unable to induce S-phase in host cells. This means Ad5-Δ24E3 is only able to replicate in proliferating cells, such as tumour cells. The adenovirus was used to deliver short hairpin RNA, which was able to reduce expression of the luciferase
Luciferase
Luciferase is a generic term for the class of oxidative enzymes used in bioluminescence and is distinct from a photoprotein. One famous example is the firefly luciferase from the firefly Photinus pyralis. "Firefly luciferase" as a laboratory reagent usually refers to P...
target gene in target cells to 30%, relative to the control, by RNA interference
RNA interference
RNA interference is a process within living cells that moderates the activity of their genes. Historically, it was known by other names, including co-suppression, post transcriptional gene silencing , and quelling. Only after these apparently unrelated processes were fully understood did it become...
.
The herpes simplex virus genome contains the enzymes thymidine kinase and ribonucleotide reductase, whose cellular forms are responsible for the production of dNTP’s required for DNA synthesis
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
and are only expressed during the G1 and S phases of the cell cycle. These enzymes allow herpes simplex virus replication in quiescent
G0 phase
The G0 phase is a period in the cell cycle in which cells exist in a quiescent state. G0 phase is viewed as either an extended G1 phase, where the cell is neither dividing nor preparing to divide, or a distinct quiescent stage that occurs outside of the cell cycle...
cells, so if they are inactivated by mutation the herpes simplex virus will only be able to replicate in proliferating cells, such as cancer cells. The G207 herpes simplex virus mutant contains a LacZ insertion, inactivating ribonucleotide reductase, as well as deletion of a virulence
Virulence
Virulence is by MeSH definition the degree of pathogenicity within a group or species of parasites as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. The pathogenicity of an organism - its ability to cause disease - is determined by its...
gene for safety's sake, has progressed to clinical trials for the treatment in brain cancer.
Double targeting
It is unlikely to be possible to make a virus entirely specific toward any tissue type by using just one form of targeting. Infection of normal tissue can result in adverse side effects. Double targeting with both transductional and non-transductional targeting methods is more effective than any one form of targeting alone. Davydova et al. (2004) combined transductional targeting with a tumour-specific promoter to successfully target an adenovirus against Oesophageal Adenocarcinoma.Suicide genes
Viruses can be used as vectors for delivery of suicide genes, encoding enzymes that can metabolise a separately administered non-toxic pro-drug into a potent cytotoxin, which can diffuse to and kill neighbouring cells. One herpes simplex virus, encoding a thymidine kinase suicide gene, has progressed to phase III clinical trials. The herpes simplex virus thymidine kinase phosphorylates the pro-drug, ganciclovir, which is then incorporated into DNADNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, blocking DNA synthesis. The tumour selectivity of oncolytic viruses ensures that the suicide genes are only expressed in cancer cells.
Suppression of angiogenesis
AngiogenesisAngiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
(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 vector
Viral vector
Viral vectors are a tool commonly used by molecular biologists to deliver genetic material into cells. This process can be performed inside a living organism or in cell culture . Viruses have evolved specialized molecular mechanisms to efficiently transport their genomes inside the cells they infect...
s, 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 antitumor activities have been demonstrated in a recombinant vaccinia virus encoding anti-angiogenic therapeutic antibody.
Immune response
In a number of cases, cancer cells exposed to viruses have experienced widespread necrosis, which cannot be entirely accounted for by viral replication alone. Cytotoxic T-cell responses directed against virus-infected cells have been identified as an important factor in tumour necrosis.However, since viruses are normal human pathogens, they induce an immune response, which reduces their effectiveness. Increased antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
titers could deactivate viruses before the tumour has been destroyed. This can be partly overcome by using parental viruses that are not normal human pathogens, thereby avoiding any pre-existing immunity. However, this does not avoid subsequent antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
generation. Alternatively, the viral vector can be coated with a polymer
Polymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...
such as polyethylene glycol
Polyethylene glycol
Polyethylene glycol is a polyether compound with many applications from industrial manufacturing to medicine. It has also been known as polyethylene oxide or polyoxyethylene , depending on its molecular weight, and under the tradename Carbowax.-Available forms:PEG, PEO, or POE refers to an...
, shielding it from antibodies, but this also prevents viral coat proteins adhering to host cells. Deactivation of the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
is not desirable, since it has a positive effect on tumour necrosis.
Vesicular Stomatitis Virus
Vesicular stomatitis virusVesicular stomatitis virus
Vesicular stomatitis Indiana virus is a virus in the family Rhabdoviridae; the well-known Rabies virus belongs to the same family. VSIV can infect insects, cattle, horses, pigs and humans. It has particular importance to farmers in certain regions of the world where it can infect cattle...
(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 and 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 (Stojdl et al., 2003, Ahmed et al., 2004, Ebert et al. 2005 and Porosnicu et al., 2003 have gone on to show that systemically administered VSV can be delivered to a tumor 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 tumor cells is unaffected (Stojdl et al., 2003).
Recent research has shown that this virus has the potential to cure brain tumors, thanks to its oncolytic properties.
Poliovirus
PoliovirusPoliovirus
Poliovirus, the causative agent of poliomyelitis, is a human enterovirus and member of the family of Picornaviridae.Poliovirus is composed of an RNA genome and a protein capsid. The genome is a single-stranded positive-sense RNA genome that is about 7500 nucleotides long. The viral particle is...
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
Translation
Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. Whereas interpreting undoubtedly antedates writing, translation began only after the appearance of written literature; there exist partial translations of the Sumerian Epic of...
of which depends on a tissue-specific internal ribosomal 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
Rhinovirus
Human rhinoviruses are the most common viral infective agents in humans and are the predominant cause of the common cold. Rhinovirus infection proliferates in temperatures between 33–35 °C , and this may be why it occurs primarily in the nose...
IRES, altering tissue specificity. The resulting PV1(RIPO) virus was able to selectively destroy malignant glioma cells, while leaving normal neuronal cells untouched.
Reovirus
ReovirusReoviridae
Reoviridae is a family of viruses that can affect the gastrointestinal system and respiratory tract. Viruses in the family Reoviridae have genomes consisting of segmented, double-stranded RNA...
, 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.
Reolysin
Reolysin
Reolysin is a formulation of reovirus that Oncolytics Biotech is developing for the treatment of various cancers and cell proliferative disorders. Reolysin is classified as a oncolytic virus, a virus that preferentially lyses cancer cells...
is a formulation of reovirus that is currently in clinical trials for the treatment of various cancers.
In fiction
In science fictionScience fiction
Science fiction is a genre of fiction dealing with imaginary but more or less plausible content such as future settings, futuristic science and technology, space travel, aliens, and paranormal abilities...
, the concept of an oncolytic virus was first introduced to the public in Jack Williamson
Jack Williamson
John Stewart Williamson , who wrote as Jack Williamson was a U.S. writer often referred to as the "Dean of Science Fiction" following the death in 1988 of Robert A...
's novel Dragon's Island, published in 1951, although Williamson's imaginary virus was based on a bacteriophage
Bacteriophage
A bacteriophage is any one of a number of viruses that infect bacteria. They do this by injecting genetic material, which they carry enclosed in an outer protein capsid...
rather than a mammalian virus. Dragon's Island is also known for being the source of the term "genetic engineering
Genetic engineering
Genetic engineering, also called genetic modification, is the direct human manipulation of an organism's genome using modern DNA technology. It involves the introduction of foreign DNA or synthetic genes into the organism of interest...
".
The Hollywood film I Am Legend
I Am Legend (film)
I Am Legend is a 2007 post-apocalyptic science fiction film directed by Francis Lawrence and starring Will Smith. It is the third feature film adaptation of Richard Matheson's 1954 novel of the same name, following 1964's The Last Man on Earth and 1971's The Omega Man. Smith plays virologist Robert...
is based on the premise that a worldwide epidemic was caused by a viral cure for cancer. This fictional tale emphasizes a major concern with oncolytic viruses: that mutations could possibly destroy the host.
External links
- Oncos Therapeutics - a biotech developing oncolytic virus therapeutics
- Jennerex - a biotech developing oncolytic virus therapeutics
- Biovex - a biotech developing oncolytic virus therapeutics
- Genelux - a biotech developing oncolytic virus therapeutics and diagnostics
- Onyx Pharmaceuticals - a biotech developing oncolytic virus therapeutics
- OncoLyticVirus.org website
- Oncolytics Biotech