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 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 to be approved by a regulatory agency was an oncolytic adenovirus, a genetically modified adenovirus named H101 by the Chinese company, Shanghai Sunway Biotech. It gained regulatory approval in 2005 from the CFDA, for the treatment of head and neck cancer.[11] 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.[12] Originally developed in the former USSR and now registered in Latvia, the oncolytic virus RIGVIR was also registered in Georgia in February 2015,[13] and in Armenia in 2016.

History

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

Herpes simplex virus

Herpes simplex virus (HSV) was one of the first viruses to be adapted to attack cancer cells selectively, because it was well understood, easy to manipulate and relatively harmless in its natural state (merely causing cold sores) so likely to pose fewer risks. The herpes simplex virus type 1 (HSV-1) mutant 1716 lacks both copies of the ICP34.5 gene, and as a result is no longer able to replicate in terminally differentiated and non-dividing cells but will infect and cause lysis very efficiently in cancer cells, and this has proved to be an effective tumour-targeting strategy.[20][21] In a wide range of in vivo cancer models, the HSV1716 virus has induced tumour regression and increased survival times.[22][23][24]

In 1996, the first approval was given in Europe for a clinical trial using the oncolytic virus HSV1716. From 1997 to 2003, strain HSV1716 was injected into tumours of patients with glioblastoma multiforme, a highly malignant brain tumour, with no evidence of toxicity or side effects, and some long-term survivors.[25][26][27] Other safety trials have used HSV1716 to treat patients with melanoma and squamous-cell carcinoma of head and neck.[28][29] Since then other studies have shown that the outer coating of HSV1716 variants can be targeted to specific types of cancer cells,[30] and can be used to deliver a variety of additional genes into cancer cells, such as genes to split a harmless prodrug inside cancer cells to release toxic chemotherapy,[31] or genes which command infected cancer cells to concentrate protein tagged with radioactive iodine, so that individual cancer cells are killed by micro-dose radiation as well as by virus-induced cell lysis.[32]

Other oncolytic viruses based on HSV have also been developed and are in clinical trials, 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.[11][33] 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.[33] Despite the promises of early in vivo lab work, these viruses do not specifically infect cancer cells, but they still kill cancer cells preferentially.[33] While overall survival rates are not known, short-term response rates are approximately doubled for H101 plus chemotherapy when compared to chemotherapy alone.[33] It appears to work best when injected directly into a tumour, and when any resulting fever is not suppressed.[33] Systemic therapy (such as through infusion through an intravenous line) is desirable for treating metastatic disease.[34] It is now marketed under the brand name Oncorine.[35]

Mechanisms of action

Direct oncolysis

Direct oncolysis, the cell killing effect produced by viral infection of cancer cells, was the original concept of oncolytic viruses.[1][36] 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]

Immunotherapy

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

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

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.[41]

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.[42]

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.[43]

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.[44][45] 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.[46] 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.[47] 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.[48]

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.[49] 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.[50][51][52][53] 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.[50]

Recent research has shown that this virus has the potential to cure brain tumours, thanks to its oncolytic properties.[54]

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)[55] 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.[56]

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.[57]

Reolysin is a formulation of reovirus that is currently in clinical trials for the treatment of various cancers.[58]

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.[18] RIGVIR virus was approved in Georgia in February 2015,[13] 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.[59] 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.[60] In July 2016 new positive results were published in APMIS journal about RIGVIR efficacy in treatment of lung cancer and histiocytic sarcoma.[61]

Semliki Forest virus

Semliki Forest virus (SFV) is a virus that naturally infects cells of the central nervous system and causes encephalitis. A genetically engineered form has been pre-clinically tested as an oncolytic virus against the severe brain tumour type glioblastoma. The SFV was genetically modified with microRNA target sequences so that it only replicated in brain tumour cells and not in normal brain cells. The modified virus reduced tumour growth and prolonged survival of mice with brain tumours.[62] The modified virus was also found to efficiently kill human glioblastoma tumour cell lines.[62]

Other

The maraba virus, first identified in Brazilian sandflies, is being tested clinically.[63][64]

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.[65]

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.[65]

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.[66] 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.[67] These enzymes also exist in the genomes of certain viruses (E.g. HSV, vaccinia) and allow viral replication in quiescent(non-replicating) cells,[68] so if they are inactivated by mutation the virus will only be able to replicate in proliferating cells, such as cancer cells.

Tumour targeting

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

Double targeting with both transductional and non-transductional targeting methods is more effective than any one form of targeting alone.[69]

Further information: Oncolytic adenovirus

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.[70][71] 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.[72] 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.[70]

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.[73] 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.[74]

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.[75][76]

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.[70] This approach has been used successfully preclinically with adenovirus, measles virus and vaccinia virus.[77][78][79]

Approved therapeutic agents

Clinical research

In 2014-2015 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.[85]

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
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
NCT02297529
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
NCT02514382
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

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.[113]

Clinical trials

Onyx-015 underwent trials in conjunction with chemotherapy before it was abandoned in the early 2000s. The combined treatment gave a greater response than either treatment alone, but the results were not entirely conclusive.[114]

Pre-clinical research

Chen et al. (2001)[115] 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.[116][117]

The anti-angiogenesis drug Bevacizumab (anti-VEGF antibody) has been shown to reduce the inflammatory response to oncolytic HSV and improve virotherapy in mice.[118]

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.[119] Dragon's Island is also known for being the source of the term "genetic engineering".[120]

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

References

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