Oncolytic virus

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

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.[6] A number of viruses including adenovirus, reovirus, measles, herpes simplex, Newcastle disease virus and vaccinia have now been clinically tested as oncolytic agents.[7] Most current oncolytic viruses are engineered for tumour selectivity, although there are naturally occurring examples such as reovirus and the SVV-001 Seneca Valley virus,[8] resulting in clinical trials.[9]

As of 2011, only limited human trials had been performed.[10] Nevertheless, the drug talimogene laherparepvec (OncoVex, T-VEC) recently (Jan 2012) reported the first positive interim Phase III clinical trial results for an oncolytic virus, making it likely that it will also be the first one approved for use (for the treatment of advanced melanoma). However, skeptics have questioned the clinical relevance of this interim data citing that the awaited overall survival data will be the final judgement and that it is likely that patient benefit will be maximised in combination with other therapies, which this trial did not test.[11][12] 2015 update: In a combined decision, members of the FDA’s Oncologic Drugs Advisory Committee (ODAC) and Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC) voted 22-1 to recommend approval of the oncolytic immunotherapy talimogene laherparepvec (T-VEC) as a treatment for patients with advanced melanoma. A final approval decision from the FDA is scheduled by October 27, 2015.[13] Approved in Latvia oncolytic virus RIGVIR was registered in Georgia in February 2015.[14] Melanoma Research published new data on RIGVIR efficacy, showing that early stage melanoma patients treated with oncolytic virus RIGVIR had 4.39–6.57-fold lower mortality than those, who according to melanoma treatment guidelines did not receive virotherapy and were only observed.[15]

History

A connection between cancer regression and viruses has long been theorized, and case reports of regression (cervical cancer, Burkitt lymphoma, Hodgkin lymphoma) after immunization or infection with an unrelated virus appeared at the beginning of the 20th century.[16] Efforts to treat cancer through immunization or deliberate infection with a virus began in the mid-20th century.[16][17] 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,[18] adenovirus,[16] Coxsackie virus,[19] ECHO enterovirus RIGVIR[20] and others.[17] 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,[16] destroyed the virus and thus prevented it from destroying the cancer.[18] Only certain cancers could be treated through virotherapy was also recognized very early.[19] Even when a response was seen, these responses were neither complete nor durable.[16] The field of virotherapy was nearly abandoned for a time, as the technology required to modify viruses didn't exist and chemotherapy and radiotherapy technology enjoyed early success. However, now these technologies have been thoroughly developed, cancer is still a major cause of mortality and there is still a need for novel cancer therapies, hence the return to this sidelined therapy now using the recently developed genetic technology required to engineer viruses.[16][21]

Herpes simplex virus

Herpes simplex virus (HSV) was one of the first viruses to be adapted to attack cancer cells selectively, because it was well understood, easy to manipulate and relatively harmless in its natural state (merely causing cold sores) so likely to pose fewer risks. The herpes simplex virus type 1 (HSV-1) mutant 1716 lacks both copies of the ICP34.5 gene, and as a result is no longer able to replicate in terminally differentiated and non-dividing cells but will infect and cause lysis very efficiently in cancer cells, and this has proved to be an effective tumour-targeting strategy.[22][23] In a wide range of in vivo cancer models, the HSV1716 virus has induced tumour regression and increased survival times.[24][25][26]

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.[27][28][29] Other safety trials have used HSV1716 to treat patients with melanoma and squamous-cell carcinoma of head and neck.[30][31] Since then other studies have shown that the outer coating of HSV1716 variants can be targeted to specific types of cancer cells,[32] 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,[33] 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.[34]

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.

Oncorine (H101)

The first oncolytic virus to be approved by a regulatory agency was a genetically modified adenovirus named H101 by Shanghai Sunway Biotech. It gained regulatory approval in 2005 from China's State Food and Drug Administration (SFDA) for the treatment of head and neck cancer.[35][36] 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.[36] Despite the promises of early in vivo lab work, these viruses do not specifically infect cancer cells, but they still kill cancer cells preferentially.[36] While overall survival rates are not known, short-term response rates are approximately doubled for H101 plus chemotherapy when compared to chemotherapy alone.[36] It appears to work best when injected directly into a tumour, and when any resulting fever is not suppressed.[36] Systemic therapy (such as through infusion through an intravenous line) is desirable for treating metastatic disease.[37] It is now marketed under the brand name Oncorine.[38]

Possible applications

Anti-cancer

The specificity and flexibility of oncolytic viruses means they have the potential to treat cancers that are unresponsive to other forms of treatment like surgery, chemotherapy, or radiation.[39] Though oncolytic viruses are an important area of research, it is likely that such therapies will not be licensed until experiments show that they both work, and importantly, are more efficacious than the existing treatment options. Thus the best opportunity is to research the use of oncolytic viruses against cancers that have been unresponsive to other treatments. The benefit of using oncolytic viral therapy is that viruses can naturally, or be engineered to, target tumor cells specifically based on their expression of certain growth factors or receptors.[39] Animal models are currently being used to study the effect of viruses, such as the Herpes simplex virus (HSV), genetically modified to secrete certain growth factors or molecules (e.g. interleukin 12 or IL-12) that cause tumor cell death. In the case of glioblastomal cells, it has been shown that in mice, the injection of IL-12 enhanced HSV not only has oncolytic effects, but it also has antiangiogenic effects, thus decreasing the blood flow to the tumor.[39]

Viral agents administered intravenously have the potential to be effective against metastatic cancers, which are especially difficult to treat conventionally, although none have been so far.[40] However, blood-borne viruses can be deactivated by antibodies and cleared from the blood quickly e.g. by Kupffer cells (extremely active phagocytic cells in the liver, which are responsible for adenovirus clearance).

Oncolytic immunotherapy

If the viral agent is designed to stimulate the immune system (eg against a cancer) it can be termed an oncolytic immunotherapy. One such is Talimogene laherparepvec approved by the FDA in 2015. Others in clinical trials include JX-594.

Oncolytic behaviour of wild-type viruses

Vesicular stomatitis virus

Vesicular stomatitis virus (VSV) is a rhabdovirus, consisting of 5 genes encoded by a negative sense, single-stranded RNA genome. In nature, VSV infects insects as well as livestock, where it causes a relatively localized and non-fatal illness. The low pathogenicity of this virus is due in large part to its sensitivity to interferons, a class of proteins that are released into the tissues and bloodstream during infection. These molecules activate genetic anti-viral defence programs that protect cells from infection and prevent spread of the virus. However in 2000, Stojdl, Lichty et al.[41] 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.[42][43][44][45] 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.[42]

Recent research has shown that this virus has the potential to cure brain tumours, thanks to its oncolytic properties.[46]

Poliovirus

Main article: PVSRIPO

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)[47] 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.[48]

Reovirus

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.[49]

Reolysin is a formulation of reovirus that is currently in clinical trials for the treatment of various cancers.[50]

Senecavirus

Senecavirus, also known as Seneca Valley Virus, is a naturally occurring wild-type oncolytic picornavirus discovered in 2001 as a tissue culture contaminate at Genetic Therapy, Inc. The initial isolate, SVV-001, is being developed as an anti-cancer therapeutic by Neotropix, Inc. under the name NTX-010 for cancers with neuroendocrine features including small cell lung cancer and a variety of pediatric solid tumours.

RIGVIR

Main article: RIGVIR

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.[20] 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.[15] 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.[51]

Other

The maraba virus, first identified in Brazilian sandflies, is being tested clinically.[52][53]

Engineering oncolytic viruses

Directed evolution

An innovative approach of drug development termed “directed evolution” involves the creation of new viral variants or serotypes specifically directed against tumour cells via rounds of directed selection using large populations of randomly generated recombinant precursor viruses. The increased biodiversity produced by the initial homologous recombination step provides a large random pool of viral candidates which can then be passed through a series of selection steps designed to lead towards a pre-specified outcome (e.g. higher tumor specific activity) without requiring any previous knowledge of the resultant viral mechanisms that are responsible for that outcome. The pool of resultant oncolytic viruses can then be further screened in pre-clinical models to select an oncolytic virus with the desired therapeutic characteristics.[54]

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.[54]

Attenuation

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.[55] 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.[56] These enzymes also exist in the genomes of certain viruses (E.g. HSV, vaccinia) and allow viral replication in quiescent(non-replicating) cells,[57] so if they are inactivated by mutation the virus will only be able to replicate in proliferating cells, such as cancer cells.

Tumour targeting

Further information: Oncolytic adenovirus

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

Transductional targeting involves modifying the viral coat proteins to target tumour cells while reducing entry to non-tumour cells. This approach to tumour selectivity has mainly focused on adenoviruses and HSV-1, although it is entirely viable with other viruses.

Non-transductional targeting involves altering the genome of the virus so it can only replicate in cancer cells, most frequently as part of the attenuation of the virus. Transcription targeting can also be used, where critical parts of the viral genome are placed under the control of a tumour-specific promoter. A suitable promoter should be active in the tumour but inactive in the majority of normal tissue, particularly the liver, which is the organ that is most exposed to blood born viruses. Many such promoters have been identified and studied for the treatment of a range of cancers. 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.[58]

Reporter genes

Viral luciferase expression in a mouse tumour

Both in the laboratory and in the clinic it is useful to have a simple means of identifying cells infected by the experimental virus. This can be done by equipping the virus with 'reporter genes' not normally present in viral genomes, which encode easily identifiable protein markers. One example of such proteins is GFP (Green fluorescent protein) which, when present in infected cells, will cause a fluorescent green light to be emitted when stimulated by blue light.[59][60] 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.[61] 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.[59]

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

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

Modifications to improve oncolytic activity

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

Suicide genes

Viruses can be used as vectors for delivery of suicide genes, encoding enzymes that can metabolise a separately administered non-toxic pro-drug into a potent cytotoxin, which can diffuse to and kill neighbouring cells. One herpes simplex virus, encoding a thymidine kinase suicide gene, has progressed to phase III clinical trials. The herpes simplex virus thymidine kinase phosphorylates the pro-drug, ganciclovir, which is then incorporated into DNA, blocking DNA synthesis.[62] 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.[63]

Suppression of angiogenesis

Angiogenesis (blood vessel formation) is an essential part of the formation of large tumour masses. Angiogenesis can be inhibited by the expression of several genes, which can be delivered to cancer cells in viral vectors, resulting in suppression of angiogenesis, and oxygen starvation in the tumour. The infection of cells with viruses containing the genes for angiostatin and endostatin synthesis inhibited tumour growth in mice. Enhanced antitumour activities have been demonstrated in a recombinant vaccinia virus encoding anti-angiogenic therapeutic antibody and with an HSV1716 variant expressing an inhibitor of angiogenesis.[64][65]

Radioiodine

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.[59] This approach has been used successfully preclinically with adenovirus, measles virus and vaccinia virus.[66][67][68]

Interactions with host immunity

Immunity as an obstacle

A major obstacle to the success of oncolytic viruses is the patient immune system which naturally attempts to inactivate any virus. This can be a particular problem for intravenous injection, where the virus must first survive interactions with the blood complement and neutralising antibodies.[69] It has been shown that immunosuppression by chemotherapy and inhibition of the complement system can enhance oncolytic virus therapy.[70][71][72]

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.[73]

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.[74]

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.[75]

Immunity as an ally

Although it poses a hurdle by inactivating viruses, the patient's immune system can also act as an ally against tumors; infection attracts the attention of the immune system to the tumour and may help to generate useful and long-lasting antitumor immunity.[76][77] 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.[78] 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.[79] 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.[80]

Approved therapeutic agents

Clinical research

As of July, 2014 at least nine virus groups are in clinical trials.[85] These include "Adenoviridae, Picornaviridae, Herpesviridae, Paramyxoviridae, Parvoviridae, Reoviridae, Poxviridae, Retroviridae and Rhabdoviridae."

Approved somewhere

Started phase III

Started phase II

Started phase I

Oncolytic viruses in conjunction with existing cancer therapies

It is in conjunction with conventional cancer therapies that oncolytic viruses have often showed the most promise, since combined therapies operate synergistically with no apparent negative effects.[111]

Clinincal trials

Onyx-015 underwent trials in conjunction with chemotherapy before it was abandoned in the early 2000s. The combined treatment gave a greater response than either treatment alone, but the results were not entirely conclusive.[112]

Pre-clinical research

Chen et al. (2001)[113] 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.[114][115]

The anti-angiogenesis drug Bevacizumab (anti-VEGF antibody) has been shown to reduce the inflammatory response to oncolytic HSV and improve virotherapy in mice.[116]

In fiction

In science fiction, the concept of an oncolytic virus was first introduced to the public in Jack Williamson's novel Dragon's Island, published in 1951, although Williamson's imaginary virus was based on a bacteriophage rather than a mammalian virus.[117] Dragon's Island is also known for being the source of the term "genetic engineering".[118]

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.

See also

Further reading

External links

References

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