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Oncolytic virus
Oncolytic virus
Oncolytic virus
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An oncolytic virus is a virus that preferentially infects and kills cancer cells. As the infected cancer cells are destroyed by oncolysis, they release new infectious virus particles or virions to help destroy the remaining tumour.[1][2] Oncolytic viruses are thought not only to cause direct destruction of the tumour cells, but also to stimulate host anti-tumour immune system responses.[3][4] Oncolytic viruses also have the ability to affect the tumor micro-environment in multiple ways.[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 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 national regulatory agency was genetically unmodified ECHO-7 strain enterovirus RIGVIR, which was approved in Latvia in 2004 for the treatment of skin melanoma;[11] the approval was withdrawn in 2019. An oncolytic adenovirus, a genetically modified adenovirus named H101, was approved in China in 2005 for the treatment of head and neck cancer.[12] In 2015, talimogene laherparepvec (OncoVex, T-VEC), an oncolytic herpes virus which is a modified herpes simplex virus, became the first oncolytic virus to be approved for use in the United States and the European Union, for the treatment of advanced inoperable melanoma.[13]

On 16 December 2022, the Food and Drug Administration approved nadofaragene firadenovec-vncg (Adstiladrin, Ferring Pharmaceuticals) for adult patients with high-risk Bacillus Calmette-Guérin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors.[14]

History

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A connection between cancer regression and viruses has long been theorised, and case reports of regression noted in cervical cancer, Burkitt lymphoma, and Hodgkin lymphoma, after immunisation or infection with an unrelated virus appeared at the beginning of the 20th century.[15] Efforts to treat cancer through immunisation or virotherapy (deliberate infection with a virus), began in the mid-20th century.[15][16] As the technology to create a custom virus did not exist, all early efforts focused on finding natural oncolytic viruses. During the 1960s, promising research involved using poliovirus,[17] adenovirus,[15] Coxsackie virus,[18] ECHO enterovirus RIGVIR,[19] and others.[16] The early complications were occasional cases of uncontrolled infection (resulting in significant morbidity and mortality); an immune response would also frequently develop. While not directly harmful to the patient,[15] the response destroyed the virus thus preventing it from destroying the cancer.[17] Early efforts also found that only certain cancers could be treated through virotherapy.[18] Even when a response was seen, these responses were neither complete nor durable.[15] The field of virotherapy was nearly abandoned for a time, as the technology required to modify viruses didn't exist whereas chemotherapy and radiotherapy technology enjoyed early success. However, now that these technologies have been thoroughly developed and cancer remains a major cause of mortality, there is still a need for novel cancer therapies, garnering this once-sidelined therapy renewed interest.[15][20] In one case report published in 2024, a scientist Beata Halassy treated her own stage 3 breast cancer using an Edmonston-Zagreb measles vaccine strain (MeV) and then a vesicular stomatitis virus Indiana strain (VSV), both prepared in her own laboratory, in combination with trastuzumab. While the treatment was successful and self-experimentation has a long history in science, the decision to publish the case report attracted controversy due to the unapproved nature of the viral agents and treatment protocol used.[21][22]

Herpes simplex virus

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Main article: Oncolytic herpes 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.[23][24] In a wide range of in vivo cancer models, the HSV1716 virus has induced tumour regression and increased survival times.[25][26][27]

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.[28][29][30] Other safety trials have used HSV1716 to treat patients with melanoma and squamous-cell carcinoma of head and neck.[31][32] Since then other studies have shown that the outer coating of HSV1716 variants can be targeted to specific types of cancer cells,[33] 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,[34] 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.[35]

Other oncolytic viruses based on HSV have also been developed and are in clinical trials.[36] One that has been approved by the FDA for advanced melanoma is Amgen's talimogene laherparepvec.[37]

Oncorine (H101)

[edit]

The first oncolytic virus to be approved by a regulatory agency was a genetically modified adenovirus named H101 by Shanghai Sunway Biotech. It gained regulatory approval in 2005 from China's State Food and Drug Administration (SFDA) for the treatment of head and neck cancer.[12][38] Sunway's H101 and the very similar Onyx-15 (dl1520) 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.[38] Despite the promises of early in vivo lab work, these viruses do not specifically infect cancer cells, but they still kill cancer cells preferentially.[38] While overall survival rates are not known, short-term response rates are approximately doubled for H101 plus chemotherapy when compared to chemotherapy alone.[38] It appears to work best when injected directly into a tumour, and when any resulting fever is not suppressed.[38] Systemic therapy (such as through infusion through an intravenous line) is desirable for treating metastatic disease.[39] It is now marketed under the brand name Oncorine.[40]

Mechanisms of action

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Immunotherapy

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With advances in cancer immunotherapy such as immune checkpoint inhibitors, increased attention has been given to using oncolytic viruses to increase antitumor immunity.[41] There are two main considerations of the interaction between oncolytic viruses and the immune system.[citation needed]

Immunity as an obstacle

[edit]

A major obstacle to the success of oncolytic viruses is the patient immune system which naturally attempts to deactivate any virus. This can be a particular problem for intravenous injection, where the virus must first survive interactions with the blood complement and neutralising antibodies.[42] It has been shown that immunosuppression by chemotherapy and inhibition of the complement system can enhance oncolytic virus therapy.[43][44][45]

Pre-existing immunity can be partly avoided by using viruses that are not common human pathogens. However, this does not avoid subsequent antibody generation. Yet, some studies have shown that pre-immunity to oncolytic viruses doesn't cause a significant reduction in efficacy.[46]

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.[47]

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.[48]

Immunity as an ally

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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.[49][50] One important mechanism is the release of substances by tumor lysis, such as tumor-associated antigens and danger associated-molecular patterns (DAMPs), which can elicit an antitumor immune response.[51] This essentially produces a personalised cancer vaccine.

Many cases of spontaneous remission of cancer have been recorded. Though the cause is not fully understood, they are thought likely to be a result of a sudden immune response or infection.[52] 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.[53] 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.[54][55]

Viruses selectively infect tumor cells because of their defective anti-viral response.[41] Imlygic, an attenuated herpes simplex virus, has been genetically engineered to replicate preferentially within tumor cells and to generate antigens that elicit an immune response.[41]

Oncolytic behaviour of wild-type viruses

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Vaccinia virus

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Vaccinia virus (VACV) is arguably the most successful live biotherapeutic agent because of its critical role in the eradication of smallpox, one of the most deadly diseases in human history. Long before the smallpox eradication campaign was launched, VACV was exploited as a therapeutic agent for the treatment of cancer. In 1922, Levaditi and Nicolau reported that VACV was able to inhibit the growth of various tumors in mice and rats. This was the first demonstration of viral oncolysis in the laboratory. This virus was subsequently shown to selectively infect and destroy tumor cells with great potency, while sparing normal cells, both in cell cultures and in animal models. Since vaccinia virus has long been recognized as an ideal backbone for vaccines due to its potent antigen presentation capability, this combines well with its natural oncolytic activities as an oncolytic virus for cancer immunotherapy.[56]

Vesicular stomatitis virus

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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.[57] 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.[58][59][60][61] 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.[58]

Recent research has shown that this virus has the potential to cure brain tumours, thanks to its oncolytic properties.[62]

Poliovirus

[edit]
Main article: PVSRIPO

Poliovirus is a natural invasive neurotropic virus, 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)[63] 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.[64]

Reovirus

[edit]

Reoviruses generally infect mammalian respiratory and bowel systems (the name deriving from an acronym, respiratory enteric orphan virus). Most people have been exposed to reovirus by adulthood; however, the infection does not typically produce symptoms. The reovirus' oncolytic potential was established after they were discovered to reproduce well in various cancer cell lines, lysing these cells.[65]

Reolysin is a formulation of reovirus intended to treat various cancers currently undergoing clinical trials.[66]

Senecavirus

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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.[citation needed]

RIGVIR

[edit]

RIGVIR is a drug that was approved by the State Agency of Medicines of the Republic of Latvia in 2004.[67] It was also approved in Georgia[68] and Armenia.[69] It is wild type ECHO-7, a member of echovirus group.[70] The potential use of echovirus as an oncolytic virus to treat cancer was discovered by Latvian scientist Aina Muceniece in the 1960s and 1970s.[70] The data used to register the drug in Latvia is not sufficient to obtain approval to use it in the US, Europe, or Japan.[70][71] As of 2017 there was no good evidence that RIGVIR is an effective cancer treatment.[72][73] On 19 March 2019, the manufacturer of ECHO-7, SIA LATIMA, announced the drug's removal from sale in Latvia, quoting financial and strategic reasons and insufficient profitability.[74] However, several days later an investigative TV show revealed that State Agency of Medicines had run laboratory tests on the vials, and found that the amount of ECHO-7 virus is of a much smaller amount than claimed by the manufacturer. According to agency's lab director, "It's like buying what you think is lemon juice, but finding that what you have is lemon-flavored water". In March 2019, the distribution of ECHO-7 in Latvia has been stopped.[75] Based on the request of some patients, medical institutions and physicians were allowed to continue use despite the suspension of the registration certificate.[76]

Semliki Forest virus

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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.[77] The modified virus was also found to efficiently kill human glioblastoma tumour cell lines.[77]

Other

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The maraba virus, first identified in Brazilian sandflies, is being tested clinically.[78]

Coxsackievirus A21 is being developed by Viralytics under trade name Cavatak.[79] Coxsackievirus A21 belongs to Enterovirus C species.[80]

Influenza A is one of the earliest viruses anecdotally reported to induce cancer regression.[81] This has prompted preclinical development of genetically engineered oncolytic influenza A viruses.[82] Murine Respirovirus, which is frequently called Sendai virus in scientific literature, has shown some oncolytic properties that are described in the section Murine respirovirus as an oncolytic agent.[citation needed]

Engineering oncolytic viruses

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Directed evolution

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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.[83]

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.[83]

Attenuation

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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.[84] 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.[citation needed]

The enzymes thymidine kinase and ribonucleotide reductase in cells are responsible for DNA synthesis and are only expressed in cells which are actively replicating.[85] These enzymes also exist in the genomes of certain viruses (E.g. HSV, vaccinia) and allow viral replication in quiescent(non-replicating) cells,[86] so if they are inactivated by mutation the virus will only be able to replicate in proliferating cells, such as cancer cells.

Tumour targeting

[edit]

There are two main approaches for generating tumour selectivity: transductional and non-transductional targeting.[87]

  • 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.[87]
  • 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.[87]
    • 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.[87]
    • 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.[citation needed]

Double targeting with both transductional and non-transductional targeting methods is more effective than any one form of targeting alone.[88]

Further information: Oncolytic adenovirus

Reporter genes

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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.[89][90] 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.[91] 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.[89]

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.[citation needed]

Modifications to improve oncolytic activity

[edit]

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

Suicide genes

[edit]

Viruses can be used as vectors for delivery of suicide genes, encoding enzymes that can metabolise a separately administered non-toxic pro-drug into a potent cytotoxin, which can diffuse to and kill neighbouring cells. One herpes simplex virus, encoding a thymidine kinase suicide gene, has progressed to phase III clinical trials. The herpes simplex virus thymidine kinase phosphorylates the pro-drug, ganciclovir, which is then incorporated into DNA, blocking DNA synthesis.[92] 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.[93]

Suppression of angiogenesis

[edit]

Angiogenesis (blood vessel formation) is an essential part of the formation of large tumour masses. Angiogenesis can be inhibited by the expression of several genes, which can be delivered to cancer cells in viral vectors, resulting in suppression of angiogenesis, and oxygen starvation in the tumour. The infection of cells with viruses containing the genes for angiostatin and endostatin synthesis inhibited tumour growth in mice. Enhanced antitumour activities have been demonstrated in a recombinant vaccinia virus encoding anti-angiogenic therapeutic antibody and with an HSV1716 variant expressing an inhibitor of angiogenesis.[94][95]

Radioiodine

[edit]
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.[89] This approach has been used successfully preclinically with adenovirus, measles virus and vaccinia virus.[96][97][98]

Approved therapeutic agents

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Investigational therapeutic agents

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EnteroMix, a Russian vaccine based on four non-pathogenic viruses, undergoing a phase I clinical trial. [105]

Oncolytic viruses in conjunction with existing cancer therapies

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It is in conjunction with conventional cancer therapies that oncolytic viruses have often shown the most promise, since combined therapies operate synergistically with no apparent negative effects.[106]

Clinical trials

Onyx-015 (dl1520) 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.[107]

Vaccinia virus GL-ONC1 was studied in a trial combined with chemo- and radiotherapy as Standard of Care for patients newly diagnosed with head & neck cancer.[108]

Herpes simplex virus, adenovirus, reovirus and murine leukemia virus are also undergoing clinical trials as a part of combination therapies.[109]

Pre-clinical research

Chen et al. (2001)[110] 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.[citation needed]

SEPREHVIR (HSV-1716) has also shown synergy in pre-clinical research when used in combination with several cancer chemotherapies.[111][112]

The anti-angiogenesis drug bevacizumab (anti-VEGF antibody) has been shown to reduce the inflammatory response to oncolytic HSV and improve virotherapy in mice.[113] A modified oncolytic vaccinia virus encoding a single-chain anti-VEGF antibody (mimicking bevacizumab) was shown to have significantly enhanced antitumor activities than parental virus in animal models.[114]

In fiction

[edit]

In science fiction, the concept of an oncolytic virus was first introduced to the public in Jack Williamson's novel Dragon's Island, published in 1951, although Williamson's imaginary virus was based on a bacteriophage rather than a mammalian virus.[115] Dragon's Island is also known for being the source of the term "genetic engineering".[116]

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.[117]

See also

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References

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Further reading

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Oncolytic virus

View on Grokipedia
from Grokipedia
An oncolytic virus is a naturally occurring or genetically modified virus that selectively replicates in and lyses cancer cells while sparing healthy tissues, thereby inducing tumor destruction and stimulating antitumor immune responses. Oncolytic viruses exploit inherent vulnerabilities in cancer cells, such as defective antiviral signaling pathways (e.g., impaired interferon responses) and overexpressed receptors, allowing preferential infection and replication within tumors. This process triggers direct oncolysis—cell lysis—releasing tumor antigens and danger signals that activate innate and adaptive immunity, including natural killer cells, T cells, and dendritic cells, to target both local and distant metastases. Additionally, engineered OVs can express immunostimulatory transgenes, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), to enhance immune infiltration into immunosuppressive tumor microenvironments. The concept of oncolytic virotherapy dates back to the early , with anecdotal reports of tumor regressions following viral infections in cancer patients, but systematic research began in the – using wild-type viruses like or adenoviruses in clinical trials. Advances in genetic engineering during the 1990s enabled the creation of tumor-selective OVs, such as the first modified (HSV-1) in 1991 for brain tumors, shifting the field toward safer, more targeted agents. By the , regulatory approvals marked a turning point: Rigvir (an type 7 ; approved in in 2004 for ; suspended in 2019 due to quality control issues), followed by H101 (an adenovirus; approved in in 2005 for head and neck cancers). To date, four oncolytic viruses have received regulatory approval worldwide, though availability varies by region: Rigvir (2004, ; suspended in 2019 due to quality control issues), H101 (2005, ), talimogene laherparepvec (T-VEC, an HSV-1 variant; FDA-approved in 2015 for advanced and EMA-approved in 2016), and Delytact (G47Δ, an HSV-1; approved in Japan in 2021 for malignant ). No additional approvals have been granted worldwide as of November 2025. T-VEC remains the only FDA-approved oncolytic virus, administered intratumorally to express GM-CSF for immune enhancement. By 2022, over 300 clinical trials investigating oncolytic viruses had been registered globally, predominantly in phase I/II, exploring OVs in combination with immunotherapies (e.g., PD-1 inhibitors), , and for various solid tumors, including , , and , with promising response rates in immunogenic malignancies.

Definition and Fundamentals

Core Principles of Oncolytic Activity

Oncolytic viruses are genetically modified or naturally selective viruses that preferentially replicate in tumor cells, leading to their destruction through while sparing normal cells. This selective arises from inherent differences between malignant and healthy tissues, allowing the viruses to serve as targeted therapeutic agents in . The fundamental process of oncolysis begins with viral entry into the , followed by genome uncoating and replication using the host's cellular machinery. As viral progeny accumulate, they disrupt cellular integrity, resulting in membrane rupture and release of new infectious particles into the . This propagation amplifies the lytic effect locally, propagating the antitumor activity without systemic dissemination in healthy tissues. Cancer cells' selective vulnerability to oncolytic viruses stems from common molecular defects, such as impaired interferon (IFN) signaling pathways that normally mount an antiviral response in healthy cells. These defects, including mutations in genes like IFNAR1 or STAT1, reduce the tumor cell's ability to activate protective mechanisms like RNA interference or apoptosis upon viral infection, enabling unchecked replication. Consequently, viruses exploit these weaknesses to achieve tumor-specific amplification. The term "oncolytic" originates from the Greek "onkos," meaning mass or tumor, combined with "lytic," denoting dissolution or breakdown. Oncolytic viruses are classified based on their genetic material into DNA viruses, primarily double-stranded DNA types, and RNA viruses, mainly single-stranded RNA variants, which influences their replication strategies and engineering potential.

Selective Targeting of Cancer Cells

Oncolytic viruses exhibit selective targeting of cancer cells through exploitation of tumor-specific molecular vulnerabilities that are rare or absent in normal tissues. Many cancers harbor mutations in the RAS signaling pathway, which inactivate protein kinase R (PKR), a key antiviral defense mechanism; this allows viruses like reovirus to replicate preferentially in RAS-transformed cells while being restricted in healthy cells with intact PKR activity. Similarly, dysfunction in the tumor suppressor protein, common in over 50% of human cancers, enables adenoviruses such as ONYX-015—lacking the E1B-55K gene—to replicate in p53-deficient cells but not in normal p53-proficient ones, as p53 normally promotes viral clearance. Overexpression of (EGFR) in tumors like facilitates entry and replication of viruses such as virus, which hijacks EGFR-RAS signaling to upregulate essential for viral DNA synthesis. Receptor-mediated entry further enhances selectivity, as cancer cells often upregulate surface receptors that serve as viral attachment points. For instance, coxsackievirus A21 binds to and , both overexpressed on various cells, allowing efficient infection while sparing normal cells with lower receptor density. type 1 (HSV-1) variants target herpesvirus entry mediator (HVEM), which is elevated in melanomas and hepatocellular , promoting tumor-specific . Adenoviruses exploit coxsackievirus and adenovirus receptor (CAR) or CD46, which are dysregulated in transformed cells, to achieve preferential entry. Cancer cells' evasion of apoptosis provides another layer of selectivity, as oncolytic viruses rely on delayed to complete their replication cycle. Tumors with defective apoptotic pathways, such as those involving mutations or upregulated anti-apoptotic proteins like , permit viruses like Newcastle disease virus (NDV) to propagate without premature host cell suicide, contrasting with normal cells that rapidly undergo post-infection. HSV-1 mutants, such as R3616, further capitalize on high RAS activity in cancers, which inhibits PKR and delays via γ34.5 gene deletion effects. Tumor microenvironment factors, including hypoxia and , also favor viral propagation in malignant tissues. Hypoxic regions, prevalent in solid tumors due to poor vascularization, activate hypoxia-inducible factors (HIFs) that enhance viral gene expression; for example, adenovirus CNHK500 incorporates a hypoxia-responsive promoter (5HRE) to drive selective replication in low-oxygen environments while remaining quiescent in normoxic normal tissues. The acidic extracellular in tumors (typically 6.5–6.8), resulting from accumulation via the Warburg effect, can facilitate viral entry and infectivity for certain oncolytic viruses compared to the neutral (7.4) of healthy tissues. The of oncolytic viruses—defined as the ratio of antitumor efficacy to toxicity in normal tissues—underpins their clinical viability, often exceeding that of traditional chemotherapeutics due to inherent tumor selectivity. This index is amplified by the viruses' reliance on cancer-specific defects, ensuring robust replication and in tumors with minimal off-target effects, as demonstrated in preclinical models where viral titers in tumors were orders of magnitude higher than in adjacent normal cells.

Historical Development

Early Observations and Preclinical Studies

The earliest observations of oncolytic activity date back to the early , when clinicians noted spontaneous tumor regressions in cancer patients coincident with viral infections. In 1912, Italian physician Nicola De Pace reported marked regression of cervical carcinomas in three patients following administration of live vaccine, attributing the effect to the virus's destructive action on malignant tissue while sparing normal cells. Similar anecdotal cases emerged through the 1940s and 1950s, including remissions of and Hodgkin's during outbreaks of , , and , prompting speculation that viruses could selectively target hyperproliferative cancer cells. These serendipitous findings, documented in case reports from institutions like Memorial Hospital in New York, laid the groundwork for intentional viral experimentation but were limited by inconsistent outcomes and lack of mechanistic understanding. Preclinical studies in the mid-20th century shifted focus to controlled animal models to validate these observations. In 1940, surgeon George T. Pack observed partial remission in a human with malignant following administration of after a , which supported the clinical anecdotes. More systematically, Alice E. Moore at the Sloan-Kettering Institute pioneered oncolytic testing in starting in 1949, demonstrating that the Russian Far East encephalitis virus completely regressed transplantable mouse sarcoma 180 tumors , with no apparent damage to healthy tissues in surviving animals. Moore's work, extended through the to viruses like vesicular stomatitis and Columbia SK, highlighted dose-dependent efficacy and tumor-specific in immunocompromised mouse models, establishing viruses as viable anticancer agents. These experiments, often using subcutaneous or intraperitoneal tumor implants, reported regression rates up to 100% in select cases, though systemic toxicity remained a challenge. By the 1950s and into the 1970s, preclinical research expanded to diverse animal species and tumor types, refining the concept of spontaneous oncolysis. Studies with naturally occurring viruses, such as adenoviruses in Syrian hamsters and reoviruses in mice, confirmed selective replication in neoplastic tissues. Key figures like Chester Southam collaborated with Moore to test over 20 viral strains in rodent models, observing that oncolytic effects correlated with tumor vascularity and host immune status. Initial hypotheses posited that cancer cells' rapid division and defective antiviral responses—particularly impaired production—enabled preferential viral entry and propagation, as evidenced by assays showing 10- to 100-fold higher viral yields in malignant versus normal cells. These ideas, formalized in reviews by the 1970s, emphasized metabolic vulnerabilities in transformed cells as the basis for selectivity, paving the way for targeted virotherapy without genetic modification.

Key Milestones in Clinical Translation

The clinical translation of oncolytic viruses began with exploratory human trials using wild-type viruses in the mid-20th century, gaining momentum in the through the as researchers tested their safety and preliminary efficacy in cancer patients. During the , several wild-type viruses, including adenoviruses, were administered directly to patients with various solid tumors, marking some of the earliest deliberate attempts at oncolytic virotherapy following earlier spontaneous observations. These trials, often small-scale and focused on viruses like type 7 adenovirus for conditions such as , demonstrated tolerable safety profiles but inconsistent antitumor responses, prompting a shift toward more controlled studies. By the , preclinical engineering efforts for (HSV) variants, such as deletions in neurovirulence genes, transitioned to Phase I trials; for instance, the first-in-human study of engineered HSV1716 began in the late for patients with recurrent malignant , establishing feasibility and paving the way for subsequent generations of modified viruses. A significant milestone in the 2000s was the regulatory approval of the first oncolytic viruses, beginning with non-engineered agents and progressing to recombinant ones. In 2004, approved Rigvir, a wild-type type 7 , for the treatment of ; it was later withdrawn in 2019 due to lack of confirmatory data. In November 2005, China's State approved H101 (Oncorine), a genetically modified E1B-deleted adenovirus, for the treatment of head and neck in combination with . This approval, based on Phase III trials showing improved response rates compared to chemotherapy alone, represented the world's first licensed recombinant oncolytic viral therapy and spurred global interest in adenovirus-based approaches. H101's success underscored the advantages of tumor-selective replication while minimizing damage to normal tissues, influencing subsequent efforts. The 2010s saw further advancements with approvals in major markets, solidifying oncolytic viruses as a viable cancer modality. In October 2015, the U.S. (FDA) approved (T-VEC, Imlygic), an engineered HSV-1 expressing , for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with advanced recurrent after initial surgery. This approval stemmed from the Phase III OPTiM trial, which reported a 16.3% durable response rate versus 2.1% with alone, marking the first oncolytic virus approved by the FDA. Building on this, in June 2021, Japan's Ministry of Health, Labour and Welfare granted conditional approval to G47Δ (teserpaturev, Delytact), a triple-mutated HSV-1, for unresectable malignant in patients with residual or recurrent tumors post-surgery and radiotherapy. Supported by a Phase II trial demonstrating an 84.2% one-year survival rate, this approval expanded oncolytic options for brain cancers. In the , clinical translation has accelerated with expanded emphasizing combination therapies and regional approvals, reflecting maturing evidence of efficacy. The approval of G47Δ in further catalyzed investigations into HSV variants, with ongoing Phase III studies exploring their integration with immunotherapies; for example, the IGNYTE-3 , initiated in 2024 and continuing into 2025, evaluates RP1 (vusolimogene oderparepvec), an oncolytic HSV-1 armed with immune-modulating transgenes, in combination with nivolumab for advanced , aiming to enhance response durability in immunotherapy-resistant patients. These efforts, alongside Phase III investigations of other HSV-based agents in solid tumors, highlight a focus on synergistic combinations with checkpoint inhibitors and to broaden therapeutic impact across cancer types.

Mechanisms of Action

Direct Viral Replication and Lysis

Oncolytic viruses exert their primary antitumor effect through direct infection and replication within cancer cells, culminating in cell lysis and release of progeny virions to propagate the cycle. This process exploits the unique molecular defects in tumor cells, such as dysregulated signaling pathways and impaired antiviral responses, allowing selective viral propagation that spares normal cells. The cytopathic effect arises from the virus hijacking host cellular machinery for its own reproduction, leading to eventual membrane rupture and cell death. The viral life cycle in tumor cells begins with attachment, where the virus binds to specific surface receptors overexpressed on cancer cells, such as the coxsackie-adenovirus receptor (CAR) for adenoviruses or the low-density lipoprotein receptor for vesicular stomatitis (VSV). Entry follows via or direct fusion, delivering the viral particle into the cell. uncoating then occurs, releasing the into the appropriate cellular compartment—nucleus for DNA viruses or for RNA viruses—where it becomes accessible for transcription and translation. Replication ensues, with the viral directing the synthesis of viral proteins and using hijacked host ribosomes and polymerases. Assembly of new virions takes place concurrently, packaging the replicated genomes into capsids and, for enveloped viruses, acquiring membranes from host organelles. Finally, is triggered, often through viral-induced disruption of cytoskeletal elements and integrity, releasing 100-1000 progeny virions per infected cell, depending on the and tumor type. Viral enzymes play a crucial role in subverting host cell machinery to prioritize virion production over normal cellular functions. For instance, in adenoviruses, early proteins like E1A act as transcriptional activators to drive and disrupt controls, while E1B inhibits to prolong the replication window; additionally, viral proteases cleave host proteins to redirect resources toward assembly. In RNA viruses such as VSV, the large (L) protein functions as an to rapidly transcribe and replicate the , and matrix proteins contribute to suppressing host transcription, favoring viral dominance; some oncolytics encode proteases that degrade host factors inhibiting replication. These enzymatic activities ensure efficient takeover, with efficiency often reaching near-complete cell destruction in permissive tumor environments within 24-72 hours post-infection. Replication kinetics differ markedly between DNA and RNA oncolytic viruses, influencing their therapeutic profiles. DNA viruses, exemplified by adenovirus, replicate in the nucleus and exhibit slower kinetics, typically completing a cycle in 24-48 hours due to dependence on host DNA polymerase and phased gene expression; this allows for larger genomes and genetic modifications but may limit spread in rapidly proliferating tumors. In contrast, RNA viruses like VSV replicate entirely in the cytoplasm using self-encoded polymerases, enabling faster cycles of 6-12 hours and higher burst rates, which promote rapid amplification but increase risks of off-target effects if selectivity is compromised.

Indirect Immunostimulatory Effects

Oncolytic viruses exert indirect immunostimulatory effects by transforming the from an immunosuppressive "cold" state to an inflamed "hot" state, primarily through the induction of immunogenic cell death (ICD) in infected cancer cells. This process is triggered following direct and , which releases damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 () and from dying tumor cells. These DAMPs act as danger signals that promote the maturation and activation of antigen-presenting cells, including dendritic cells, thereby enhancing immune recognition of tumor antigens. Studies have shown that binds to (TLR4) on dendritic cells, facilitating their recruitment and upregulation of costimulatory molecules, while exposure on the cell surface serves as an "eat-me" signal to promote of tumor debris. In addition to DAMPs, oncolytic viruses release pathogen-associated molecular patterns (PAMPs), such as double-stranded (dsRNA), which activate innate immune pathways. These PAMPs are recognized by receptors including TLRs (e.g., TLR3) and retinoic acid-inducible I (RIG-I), triggering signaling cascades that culminate in the production of type I s (IFNs), such as IFN-α and IFN-β. Type I IFNs amplify innate responses by stimulating activity and secretion (e.g., TNF-α and IL-12), while also priming the tumor site for subsequent adaptive immunity. This innate activation is crucial for breaking tumor-induced tolerance and has been demonstrated in preclinical models where RIG-I agonists derived from viral PAMPs enhanced antiviral and antitumor interferon responses. The immunostimulatory cascade extends to adaptive immunity, where dendritic cells cross-present tumor antigens derived from lysed cells to CD8+ T cells, leading to their priming, proliferation, and infiltration into the tumor. This results in a robust cytotoxic T-cell response that targets both infected and uninfected cancer cells. Furthermore, systemic immune activation can produce abscopal effects, wherein regression occurs in distant, non-injected tumors due to circulating antitumor T cells and cytokines. Clinical evidence from (T-VEC), an engineered , supports this, with observed responses in non-injected lesions correlating with increased T-cell infiltration. The to oncolytic viruses has a dual nature: while it initially serves as a barrier through antiviral mechanisms like neutralizing antibodies and type I IFN-mediated clearance, which can limit viral spread, this same response can be harnessed to favor antitumor immunity. Engineered modifications, such as deletion of viral genes that antagonize IFN signaling or insertion of immunomodulatory transgenes (e.g., GM-CSF), help modulate this balance, reducing premature viral elimination while amplifying antitumor effects. Preclinical and early indicate that such strategies enhance T-cell persistence and overcome immunosuppressive checkpoints in the .

Naturally Occurring Oncolytic Viruses

Vaccinia Virus

Vaccinia virus (VACV) is a large, enveloped, double-stranded belonging to the genus in the family , characterized by a of approximately 190 kilobase pairs encoding around 200 genes. It exhibits a broad host range, capable of infecting a variety of mammalian species, and replicates entirely in the host cell , producing multiple virion forms including intracellular mature virus, cell-associated enveloped virus, and extracellular enveloped virus that facilitate systemic spread. Historically, wild-type VACV strains, such as the Lister and Western Reserve strains, were instrumental as the primary against , enabling the World Health Organization's global eradication campaign that declared the disease eliminated in 1980. As a naturally occurring oncolytic agent, wild-type VACV demonstrates preferential replication and in cancer cells, particularly within hypoxic and angiogenic tumor environments, where defective responses and altered signaling pathways impair antiviral defenses. This selectivity is enhanced by the virus's dependency on (EGFR) activation, which is often upregulated in malignant cells and promotes VACV entry and replication. Additionally, VACV's production of extracellular enveloped virions enables efficient vascular dissemination, allowing the virus to exploit the leaky, disorganized vasculature of tumors for targeted delivery and accumulation following intravenous administration. Preclinical studies in the established the antitumor potential of wild-type VACV, demonstrating significant tumor regression in models of metastatic , including clearance of liver metastases in colorectal xenografts after systemic injection. These experiments highlighted VACV's ability to selectively colonize and destroy tumor nodules while sparing normal tissues, with high viral titers recovered from metastatic sites compared to healthy organs. For instance, intravenous delivery in immunocompetent led to durable remissions in established hepatic tumors, underscoring the virus's innate without genetic modification.

Vesicular Stomatitis Virus

Vesicular stomatitis virus (VSV) is a member of the family, characterized as a non-segmented, negative-sense single-stranded with a compact 11 kb genome encoding five structural proteins: (N), (P), matrix protein (M), (G), and large polymerase (L). It primarily infects such as , , and pigs, causing mild flu-like vesicular lesions, but exhibits natural in humans due to the absence of a significant and low seroprevalence, resulting in minimal pathogenicity beyond occasional lab-acquired infections. This inherent safety profile, combined with its rapid cytoplasmic replication cycle—typically completing within 6-8 hours—and broad via G protein binding to receptors or phospholipids, positions wild-type VSV as a promising naturally occurring oncolytic agent. The oncolytic selectivity of VSV stems from its exquisite sensitivity to type I (IFN) signaling, a key antiviral defense pathway often defective in cancer cells. In normal cells, VSV infection triggers robust IFN production and signaling through pathways involving and IRF proteins, leading to rapid viral clearance and minimal replication. In contrast, many tumor cells harbor mutations or epigenetic silencing in IFN-related genes (e.g., reduced expression of IFN receptors or downstream effectors like PKR), impairing this response and permitting unchecked VSV replication, cytopathic effects, and eventual cell lysis. This mechanism exploits a common vulnerability in cancers, as first demonstrated in diverse human tumor cell lines where VSV selectively induced while sparing IFN-competent normal cells. Preclinical studies in the 2000s highlighted VSV's efficacy against tumors and metastatic . In orthotopic models of in , intravenous administration of wild-type VSV resulted in selective and destruction of multifocal tumor masses, including invasive satellite lesions, with limited spread to surrounding normal tissue due to intact IFN responses in healthy neurons. Similarly, in immune-competent rat models of orthotopic , intratumoral injection of VSV led to robust within tumors, significant inhibition of tumor growth, and prolonged survival without evident in normal liver cells. These findings underscored VSV's potential for treating aggressive, disseminated cancers, with viral titers reaching up to 10^8 plaque-forming units per gram of tumor tissue in responsive models. Early clinical insights from Phase I trials of VSV-based therapies have affirmed its safety profile and capacity for tumor localization upon intratumoral administration. In studies involving patients with and other solid tumors, intratumoral injections were well-tolerated, with primarily mild flu-like symptoms and no dose-limiting , alongside evidence of viral persistence and replication confined to injected lesions as monitored by and . These observations validate the preclinical selectivity and support further exploration of VSV in oncolytic applications.

Reovirus

Reovirus, a member of the Reoviridae family, is a non-enveloped with a double-stranded consisting of 10 segments, organized into two concentric icosahedral capsids approximately 85 nm in diameter. It is ubiquitous in the environment and commonly detected in human respiratory and gastrointestinal tracts, yet it remains non-pathogenic in immunocompetent individuals, typically causing mild or infections without severe . This natural safety profile has positioned reovirus as a promising candidate for oncolytic virotherapy, where its selective replication in transformed cells exploits cancer-specific vulnerabilities. The oncolytic mechanism of reovirus hinges on the activation of the RAS signaling pathway, a frequent alteration in human cancers. In normal cells, reovirus replication is inhibited by the double-stranded RNA-activated protein kinase (PKR), which phosphorylates eIF2α to block viral protein synthesis. However, RAS transformation dysregulates this antiviral response, allowing efficient viral replication; specifically, activated RAS enhances endosomal acidification, promoting proteolytic uncoating of the viral outer capsid by lysosomal cathepsins and facilitating subsequent viral disassembly, genome release, and progeny production. This pathway-specific selectivity enables reovirus to target tumors with RAS mutations or upstream activations, such as those in EGFR signaling, without harming healthy tissues. Preclinical evidence from the and established reovirus's efficacy against RAS-driven tumors in models. In a seminal 1998 study, reovirus type 3 Dearing strain selectively replicated in and cleared v-ras-transformed 3T3 cell tumors implanted subcutaneously in mice, demonstrating tumor regression without systemic toxicity. For , a 2001 xenograft model using human U-118MG cells in athymic mice showed that intratumoral reovirus injection led to complete tumor clearance in 50% of treated animals, correlating with RAS pathway activation and within tumors. Similarly, in models during the early , reovirus treatment of androgen-independent xenografts in nude mice resulted in significant tumor growth inhibition and extended survival, attributed to RAS-mediated viral oncolysis. Translational progress includes early-phase clinical trials assessing reovirus safety and activity in specific cancers. A phase I trial in children with relapsed or extracranial solid tumors administered intravenous reolysin (a clinical-grade reovirus formulation) at escalating doses, confirming tolerability with no maximum tolerated dose reached and evidence of viral clearance from blood within days, supporting further pediatric evaluation. In head and neck cancers, a phase I/II trial combining reolysin with and in patients with recurrent or metastatic reported an objective response rate of 28% and stable in 50%, with detected in tumor biopsies, indicating preliminary antitumor efficacy.

Other Wild-Type Examples

Senecavirus A, a porcine also known as Seneca Valley virus (SVV-001), shows oncolytic potential through its receptor ANTXR1 (TEM8), which is upregulated in various cancers including sarcomas. Preclinical models have highlighted its activity against sarcomas and skin cancers, where it induces tumor cell lysis and systemic antitumor immunity without significant toxicity to normal tissues. It was the first evaluated in human clinical trials for oncolytic use, primarily targeting neuroendocrine tumors but with broader preclinical promise. As of 2025, a phase I/II trial is evaluating SVV-001 in combination with nivolumab and for high-grade neuroendocrine tumors. RIGVIR, an adapted wild-type type 7 (ECHO-7), was approved in in 2004 for the treatment of and local skin/subcutaneous metastases, marking one of the earliest regional authorizations for a naturally oncolytic virus; however, its marketing authorization was suspended in in 2019 due to discrepancies in confirmatory data. Its selectivity for melanoma cells arises from preferential replication in tumors expressing intercellular adhesion molecule-1 (), leading to direct and improved survival in retrospective studies of surgically treated patients. Semliki Forest virus (SFV), an , demonstrates rapid oncolysis in preclinical models of due to its high replication rate and induction of in tumor cells bearing GD2 antigens. While effective in lysing cell lines and enhancing immune responses , human clinical data remain limited, with most studies confined to animal models and early vector evaluations. Among naturally occurring oncolytic viruses, viruses predominate due to their rapid replication, error-prone genomes that facilitate tumor adaptation, and inherent immunostimulatory properties that amplify antitumor effects. Regional approvals, such as RIGVIR's in , underscore the potential for localized deployment of unmodified strains, though global adoption has been slower pending further validation.

Engineered Oncolytic Viruses

Attenuation and Safety Modifications

Attenuation of oncolytic viruses involves genetic modifications to diminish their in healthy tissues, thereby enhancing for therapeutic applications while retaining the capacity for selective replication and within tumor cells. Common strategies include the deletion or of viral genes critical for efficient replication in normal host cells, which exploits inherent differences in cellular machinery between malignant and non-malignant tissues. These modifications reduce the risk of uncontrolled viral spread, a primary concern with wild-type viruses that can cause severe infections in immunocompetent individuals. A prominent example is the deletion of the ICP34.5 gene (also known as γ34.5) in , which encodes a neurovirulence factor that promotes synthesis shutdown evasion in normal cells. This deletion attenuates the virus by impairing its replication in neurons and other healthy cells, thereby blocking neurovirulence, but allows propagation in transformed cells with disrupted signaling pathways. Similarly, in adenoviruses, deletion of the E1B-55kDa gene product, as in the dl1520 (also called ONYX-015) construct, impairs late viral mRNA nuclear export in normal cells, allowing selective replication in tumor cells with altered processing pathways. Although originally attributed to deficiencies, the mechanism is p53-independent. This modification results in reduced viral yield in healthy cells compared to tumor cells, as demonstrated in preclinical models. Safety profiling of attenuated oncolytic viruses typically employs multi-step growth curve assays to quantify replication kinetics, revealing significantly slower viral propagation in normal cells versus robust expansion in tumor cells over multiple cycles. For instance, ICP34.5-deleted HSV-1 shows orders-of-magnitude lower titers in primary human fibroblasts than in cell lines after successive infections. These assays, often complemented by animal models assessing biodistribution and toxicity, confirm the attenuation's effectiveness in limiting off-target effects. Regulatory oversight, particularly from the U.S. (FDA), mandates comprehensive preclinical data on to ensure minimal pathogenicity, including shedding studies that monitor viral excretion and environmental transmission risks to verify in patients. FDA guidelines emphasize demonstrating reduced replication in non-target tissues through and assays, alongside genetic stability assessments, to mitigate potential adverse events before advancing to clinical trials. Such requirements have facilitated the safe development of attenuated viruses like dl1520, which underwent rigorous evaluation for off-target replication prior to human testing.

Tumor-Specific Targeting Strategies

Tumor-specific targeting strategies in oncolytic viruses aim to enhance selectivity by confining , entry, or propagation predominantly to malignant cells, thereby minimizing damage to healthy tissues. These approaches leverage genetic and to exploit tumor-associated molecular alterations, such as aberrant or receptor overexpression, building on the inherent selectivity of some viruses while improving precision. Key methods include transcriptional control, modification of viral entry mechanisms, arming with homing transgenes, and techniques. Transcriptional targeting restricts viral to tumor cells by placing essential viral under the control of tumor-specific promoters. These promoters, such as the human (hTERT) promoter or the promoter, are active in cancer cells due to their reliance on dysregulated pathways like maintenance and anti-apoptotic signaling, but remain quiescent in normal cells. For instance, in adenoviral vectors, the E1A —crucial for viral replication—has been driven by the E2F-1 promoter to target (Rb) pathway-defective tumors, demonstrating selective replication in cells. Similarly, (PSA) promoters have been used in adenoviruses to limit replication in models. This strategy has been pivotal in engineering viruses like CG0070, where the E1A is controlled by the E2F-1 promoter, enhancing safety in clinical settings. Retargeting viral entry, also known as transductional targeting, involves modifying the viral capsid or envelope proteins to redirect attachment and infection toward tumor-specific receptors while ablating binding to normal cell receptors. This is achieved through genetic alterations, such as incorporating ligands or single-chain antibodies into viral surface proteins. A prominent example is the retargeting of (HSV) glycoprotein D to the receptor (uPAR), which is overexpressed on various tumor cells, allowing selective entry into malignant tissues like gliomas. In adenoviruses, fiber knob domain modifications have been used to target or other tumor-associated receptors, reducing off-target effects in non-cancerous cells. variants have also been engineered to exploit , a receptor upregulated in many cancers, for enhanced . These modifications improve the by ensuring viruses primarily infect and lyse tumor cells. Arming oncolytic viruses with s that promote tumor homing further refines specificity by enabling the virus or its progeny to navigate toward or within the . This involves inserting genes that encode factors inhibiting or recruiting immune cells to tumor sites, such as interleukin-12 (IL-12), which suppresses (VEGF) and enhances localized immune responses. For example, the adenovirus VG161, armed with IL-12, has shown targeted accumulation in models by disrupting tumor vasculature and promoting T-cell infiltration. Similarly, HSV-based G47Δ-mIL12 incorporates murine IL-12 to drive selective immune-mediated homing and clearance of tumor cells in . These insertions are designed to amplify the virus's natural without broadly disseminating to healthy tissues. Directed evolution selects for oncolytic virus variants with improved tumor through iterative passaging in tumor cell cultures under selective pressure, mimicking natural to favor replication in malignant environments. This process generates mutants with enhanced entry efficiency or replication kinetics specific to tumor defects, such as deletions in non-essential genes that confer tumor selectivity. For instance, HSV-1 strain HF10, derived through serial passaging, lacks UL43 and UL49.5 genes, resulting in robust replication and spread in tumor xenografts while sparing normal cells. In adenoviruses like ONYX-015, directed approaches have refined E1B deletions for p53-deficient tumor targeting. This method has yielded high-impact variants used in preclinical models, emphasizing empirical optimization over rational design alone.

Enhancements for Therapeutic Efficacy

To enhance the therapeutic efficacy of beyond direct cell lysis, engineers insert genetic payloads that induce additional antitumor mechanisms, such as localized toxicity, vascular disruption, or imaging-guided monitoring, while leveraging prior tumor-specific targeting to ensure selective delivery. These modifications amplify immune responses and tumor destruction without compromising viral replication. One key approach involves incorporating suicide genes, which convert non-toxic prodrugs into cytotoxic agents within infected tumor cells. The (HSV-TK) gene is a prominent example, where the viral phosphorylates (GCV) into a monophosphate form that is further activated by cellular kinases into a triphosphate analog, incorporating into DNA and causing chain termination and . This system exhibits a potent , as the toxic metabolites diffuse to neighboring uninfected tumor cells, enabling broader killing even if viral infection is incomplete. Preclinical studies with HSV-TK-armed adenoviruses in models demonstrated significant tumor regression when combined with GCV, with up to 80% reduction in tumor volume compared to virus alone. A phase II trial of Ad5-yCD/mutTKSR39rep-ADP combined with intensity-modulated (IMRT) for intermediate-risk showed safety and a 42% relative reduction in positive biopsies at 2 years compared to IMRT alone. Anti-angiogenic payloads further boost efficacy by disrupting tumor vasculature, starving hypoxic regions and potentiating viral spread. Oncolytic viruses engineered to express endostatin, a fragment of XVIII that inhibits (VEGF) signaling and endothelial cell migration, have shown marked antitumor activity in preclinical models. For instance, an oncolytic (HSV-Endo) delivering endostatin suppressed and reduced tumor burden by 70% in human colon cancer xenografts. Similarly, thrombospondin-1, which binds on endothelial cells to block proliferation and induce , has been incorporated into oncolytic adenoviruses, leading to normalized tumor vessels and enhanced in head and neck models. A vaccinia virus variant expressing an endostatin-angiostatin achieved complete tumor eradication in 50% of treated xenografts, outperforming unarmed controls. Reporter genes enable non-invasive monitoring of viral biodistribution and replication kinetics, optimizing dosing and assessing treatment response in real time. (GFP) facilitates to visualize viral spread in superficial or explanted tumors, as demonstrated in oncolytic adenovirus models where GFP expression correlated with infection sites in murine xenografts. reporters, such as , support bioluminescence imaging (BLI) for deeper tissue penetration, quantifying viral persistence with high sensitivity; in reovirus studies, luciferase-armed variants revealed peak replication at 48 hours post-infection in models. These tools have accelerated preclinical optimization, with BLI detecting as few as 10 infected cells and guiding clinical translation by confirming tumor-selective localization. For radioenhancement, the sodium iodide symporter (NIS) gene is inserted to mediate uptake of radioiodides like iodine-131 (¹³¹I), concentrating radiation within tumors for synergistic virotherapy. NIS, a transmembrane glycoprotein, actively transports iodide into infected cells via the sodium gradient, enabling SPECT/PET imaging and targeted radiotherapy. In oncolytic measles virus (MV-NIS), expression in glioblastoma xenografts resulted in 50-fold higher ¹³¹I accumulation compared to non-transduced cells, enhancing cell killing through beta-particle emission and the crossfire effect on adjacent stroma. This radiosensitization extended median survival in murine models from 25 to 45 days, with dosimetry confirming therapeutic doses without systemic toxicity. Similar efficacy was observed in herpes simplex virus-NIS constructs for hepatocellular carcinoma, where ¹³¹I uptake amplified oncolysis by 2-3 fold. Recent advances include the use of to engineer more precise modifications in oncolytic viruses, such as enhanced immune-modulating payloads or tumor-specific insertions, and innovative platforms like to temporally control OV release and activity, demonstrating improved efficacy in preclinical solid tumor models as of 2025.

Clinical Applications

Approved Therapies

Talimogene laherparepvec (T-VEC), marketed as Imlygic, is a genetically modified type 1 (HSV-1) engineered to selectively replicate in cells and express (GM-CSF) to enhance antitumor immunity. The U.S. (FDA) approved T-VEC in October 2015 as the first oncolytic viral therapy for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with recurrent after initial . It is administered via intratumoral injection, starting with an initial dose of up to 4 mL of 10^6 PFU/mL followed by 4 mL of 10^8 PFU/mL three weeks later, and then every two weeks until no injectable lesions remain or intolerance occurs. In the pivotal phase III OPTiM trial, T-VEC demonstrated a durable response rate of 16.3% compared to 2.1% with subcutaneous GM-CSF alone, with responses lasting at least six months; median overall survival was 23.3 months versus 18.9 months, establishing its clinical benefit in advanced . Oncorine (H101) is a recombinant adenovirus type 5 with a deletion in the E1B-55K , enabling selective replication in p53-deficient tumor cells commonly found in head and neck cancers. The China State (SFDA, now ) approved H101 in 2005 for the treatment of late-stage refractory head and neck . It is typically administered intratumorally in combination with , such as and 5-fluorouracil, at doses of 1 × 10^12 viral particles per injection for up to six cycles. A phase III randomized trial showed that H101 combined with achieved an objective response rate of 78.8% versus 39.6% with alone, with significant improvements in short-term survival and metrics, supporting its approval for enhancing tumor regression and patient outcomes in this indication. Teserpaturev (G47Δ), marketed as Delytact, is a third-generation oncolytic HSV-1 with triple (deletions in ICP6, ICP34.5, and insertion of LacZ in ICP34.5) to improve tumor selectivity, enhance antitumor immunity, and ensure safety by preventing replication in normal cells. Japan's Ministry of Health, Labour and Welfare granted conditional approval for G47Δ in June 2021 for the treatment of recurrent or residual malignant in patients over 5 years old, following surgical resection or radiation, as the first oncolytic virus approved in that country. The therapy is delivered via stereotactic intratumoral injection at a dose of 3 × 10^8 PFU/mL, up to 10 times over several months, often post-standard care like . In a phase II single-arm of 19 patients with recurrent , G47Δ achieved a one-year of 84.2%, exceeding the historical 15% rate, with a favorable safety profile showing no severe adverse events related to and only mild flu-like symptoms in most cases. RIGVIR is a naturally occurring, non-genetically modified type 7 (ECHO-7) strain adapted for oncolytic activity, selectively targeting and lysing cells while sparing healthy tissue. It received national approval in , an member state, in 2004 for the treatment of stages IB-IIC, as well as local treatment of skin and subcutaneous metastases from advanced . Administered intramuscularly or subcutaneously at doses escalating from 10^6 to 10^10 TCID50 weekly, then biweekly for maintenance, RIGVIR was used in over 500 patients in , with post-marketing data indicating prolonged overall survival in early-stage patients—such as a 4- to 6.6-fold reduction in disease progression risk for stage IIB compared to untreated cohorts—without reported serious adverse effects. However, in 2019, 's State Agency of Medicines withdrew RIGVIR's registration due to insufficient evidence from randomized controlled trials demonstrating clinical efficacy and safety.

Investigational Therapies

As of 2025, the landscape for oncolytic viruses encompasses nearly 190 registered investigations globally, with a substantial focus on rare and refractory solid tumors, including , , and pediatric malignancies. These trials predominantly evaluate engineered viruses in phases , emphasizing , antitumor , and immune in patients who have progressed on standard therapies. VG161, a recombinant oncolytic type 1 (HSV-1) armed with interleukin-12 (IL-12), IL-15/IL-15 receptor α , and a blocking peptide, is under evaluation in phase I/II trials for advanced primary refractory to prior therapies. In a phase I study of 35 patients with heavily pretreated (HCC), intratumoral VG161 administration yielded an objective response rate (ORR) of 17.14% and a control rate (DCR) of 60%, with a median overall survival of 9.4 months and no dose-limiting toxicities observed. Ongoing phase II efforts, including combinations with inhibitors like camrelizumab, report median of 6.3 months and 6-month overall survival rates of 87.5% in second-line HCC settings, highlighting VG161's potential to remodel the tumor immune microenvironment. Pexa-Vec (JX-594), an engineered vaccinia virus featuring gene deletion and (GM-CSF) insertion, demonstrated encouraging phase II results in advanced HCC, including statistically significant overall survival improvements with intratumoral dosing followed by best supportive care. However, the subsequent phase III PHOCUS trial, which tested sequential Pexa-Vec plus versus alone in 600 patients, failed to meet its primary endpoint of overall survival benefit, leading to halted development despite prior successes in immune activation and tumor necrosis. MG1MA3-CA, a replication-competent oncolytic Maraba rhabdovirus expressing the MAGE-A3 , is being assessed in phase I/II trials for incurable, advanced MAGE-A3-positive solid tumors such as and . Early phase I data from 41 patients revealed safe intravenous and intratumoral delivery, with antitumor immunity evidenced by MAGE-A3-specific + T-cell responses exceeding 1% of circulating T cells in 50% of evaluated cases, correlating with clinical benefit in select responders. Emerging candidates in 2025 include VSV-IFNβ-NIS, an armed vesicular stomatitis virus expressing interferon-β and the sodium iodide symporter, advanced to multiple phase I trials for solid tumors, with ongoing evaluations in to enhance tumor selectivity and imaging capabilities while minimizing . Similarly, parvovirus H-1PV, known for its non-pathogenic profile and oncolytic effects via arrest and immune stimulation, has progressed to phase II trials in recurrent and other adult malignancies, building on preclinical data demonstrating in medulloblastoma models through downregulation of oncogenic pathways like and NFIA. Recent phase III advancements include cretostimogene grenadenorepvec (CG0070), which showed a 75.2% complete response rate in non-muscle invasive in 2024, and CAN-2409, which met its primary endpoint of improved disease-free survival in in late 2024.

Combination with Other Cancer Treatments

Integration with Immunotherapies

Oncolytic viruses (OVs) induce immunogenic in tumor cells, releasing tumor-associated antigens and damage-associated molecular patterns that trigger innate and adaptive immune responses, thereby transforming immunosuppressive "cold" tumors into inflamed "hot" ones responsive to inhibitors (ICIs) such as PD-1/ blockers. This inflammation enhances T-cell infiltration and activation, countering the tumor microenvironment's inhibitory signals and amplifying the efficacy of ICIs. For instance, (T-VEC), an engineered , has been combined with in trials demonstrating this priming effect in patients. Key clinical trials underscore this synergy, notably the phase Ib portion of MASTERKEY-265, where T-VEC plus yielded an objective response rate (ORR) of approximately 62% in patients with unresectable stage IIIB-IV , surpassing historical monotherapy rates of around 33-40%. Long-term follow-up from this trial reported a complete response rate of 43% and a 4-year overall survival of 71.4%, with durable responses in over 90% of responders. Although the subsequent phase III MASTERKEY-265 did not meet its primary endpoint for improvement (ORR 48.6% vs. 41.3% for plus ), it confirmed the combination's tolerability and suggested benefits in subgroups with injectable lesions. Mechanistically, OVs promote tumor-infiltrating (TIL) expansion and neo release, which bolsters the antitumor activity of chimeric receptor (CAR)-T cells by improving their trafficking and persistence within solid tumors. This spillover also augments efficacy, as demonstrated in preclinical models where OV-induced neoantigens enhanced T-cell priming and systemic immunity when paired with mRNA vaccines. Such effects address CAR-T limitations in immunosuppressive environments, leading to improved tumor clearance in combination settings. As of 2025, emerging combinations integrate OVs with bispecific antibodies targeting immune checkpoints or tumor antigens, enhancing T-cell redirection and OV-mediated in cancers. Additionally, pairings with engineered therapies, such as IL-2 variants, amplify OV-stimulated immune responses while minimizing systemic toxicity, as seen in ongoing trials for solid tumors where these approaches yield higher response durability. In 2025 updates, pelareorep combined with and in first-line pancreatic ductal showed promising improvements in phase II (BRACELET-1). These advances highlight OVs' role in broadening applicability beyond checkpoint inhibition.

Synergy with Chemotherapy and Radiation

Oncolytic viruses (OVs) enhance the efficacy of chemotherapeutic agents by sensitizing tumor cells to drug-induced , often through disruption of and promotion of . For instance, OVs can exploit chemotherapy-induced DNA damage to amplify and tumor , while certain chemotherapeutics suppress antiviral immune responses, allowing greater OV propagation within the . This bidirectional synergy overcomes resistance mechanisms, such as arrest, where OVs interfere with repair pathways, making cells more vulnerable to agents like . A representative example is the combination of reovirus (pelareorep) with in pancreatic , where the virus sensitizes cancer cells by inducing and enhancing drug uptake via upregulated receptors, leading to improved antitumor activity. In a phase II trial, this regimen yielded a median overall survival of 10.2 months (95% CI 6.6-14.1) compared to historical controls of 6.7 months, with manageable toxicity profiles including fatigue and nausea. Similarly, oncolytic adenoviruses paired with demonstrate enhanced replication through upregulation of cellular factors like GADD34, resulting in greater tumor regression in preclinical models of . OVs also synergize with radiation therapy by leveraging the DNA damage response (DDR) to boost viral replication and oncolysis. Radiation induces double-strand breaks that activate DDR pathways, which OVs exploit to increase progeny virus production and extend tumor cell killing beyond direct lysis. In herpes simplex virus (HSV)-based therapies, viral proteins like ICP0 degrade DNA repair enzymes such as DNA-PKcs, further potentiating radiotherapy effects in radioresistant tumors like glioma. A phase I trial of oncolytic HSV-1 (G207) administered 24 hours prior to 5 Gy radiation in recurrent glioblastoma showed safety with no encephalitis cases and radiographic responses in 3 of 9 patients, achieving a median survival of 7.5 months. Early clinical data from such OV-radiation combinations demonstrate safety and potential efficacy in recurrent high-grade gliomas. Clinical evidence supports optimized timing in OV-chemotherapy and OV- combinations to maximize synergy while minimizing off-target effects. For example, pre-treatment with OVs 24-48 hours before or allows to peak during peak drug or , enhancing local tumor control. In , a phase 1b trial of oncolytic adenovirus TILT-123 combined with pegylated liposomal (a formulation) evaluates safety and preliminary efficacy in platinum-resistant cases, building on preclinical data showing increased and immune activation. Such protocols have demonstrated response rates up to 54% in phase II studies of adenovirus virotherapy with in similar settings. As of 2025, emerging trends focus on nanoparticle-based delivery systems to refine OV combinations with and , enabling timed release and reduced systemic toxicity. Nanoparticles encapsulating viral genomes or whole viruses respond to tumor-specific triggers like hypoxia or , achieving controlled dissemination and minimizing immune clearance, with preclinical models showing over 80% tumor regression and 90% lower hepatic uptake compared to free viruses. These formulations support precise scheduling of OV deployment prior to chemo-radiation cycles, potentially broadening applicability in solid tumors while lowering adverse events like fever and chills.

Challenges and Future Directions

Current Limitations and Obstacles

One of the primary limitations of oncolytic virus therapy is the host's pre-existing antiviral immunity, which often neutralizes the virus before it can effectively reach and replicate within tumors. Neutralizing antibodies against common oncolytic viruses, such as herpes simplex virus (HSV), are present in more than 50% of the population, significantly impairing initial and repeat dosing by promoting rapid viral clearance through complement activation and adaptive immune responses. This issue is particularly pronounced for viruses like adenovirus type 5, where seroprevalence can reach 50-90% in adults, limiting systemic delivery and therapeutic efficacy in seropositive patients. High levels of these antibodies have been associated with reduced overall survival, such as a median of 12.5 months in patients with high neutralizing antibody titers compared to 21.2 months in those with low titers. Delivery challenges further constrain the clinical utility of oncolytic viruses, especially in solid tumors where poor vascularization and dense impede viral penetration and spread. Intratumoral injection, the predominant administration route, often fails to achieve uniform distribution due to desmoplastic barriers, as seen in pancreatic ductal , resulting in limited exposure to metastatic or deep-seated lesions. Systemic routes like intravenous delivery exacerbate risks of off-target effects and toxicity, including liver accumulation in adenoviruses and potential environmental shedding, with HSV DNA detected in 37% of post-injection wound exudates across trials. These penetration issues contribute to inconsistent antitumor responses, compounded by immune clearance mechanisms that reduce viral . Tumor heterogeneity poses a significant barrier to broad , as genetic and microenvironmental variations lead to differential and immune activation across cancer types. In immunosuppressive tumor microenvironments, such as those with high expression, response rates drop markedly to 15% compared to 45% in low-expression settings, due to enhanced antiviral defenses that hinder oncolysis. Similarly, markers like AXL-high expression correlate with only 15% objective response rates, reflecting resistance from regulatory T cells and suppression that dampen antitumor immunity. This variability underscores the therapy's challenges in uniformly addressing diverse solid tumors, including those with "" immune profiles resistant to viral-induced . Regulatory and manufacturing obstacles also impede widespread adoption, with (GMP) production facing scalability limitations from reliance on adherent cell cultures that yield insufficient titers for large-scale clinical use. Biodistribution concerns, including uncontrolled viral dissemination, necessitate rigorous monitoring, as regulatory bodies like the FDA require isolation protocols for shedding exceeding 3 log10 copies per milliliter. These hurdles, including complex purification and storage requirements under conditions, delay progression from preclinical to commercial stages. Recent advances in oncolytic virus (OV) engineering have leveraged / technology to enable precise arming of viral genomes, facilitating multi-gene insertions that enhance therapeutic potency through approaches. For instance, in large-genome viruses such as type 1 (HSV-1), / allows for the targeted insertion of multiple transgenes, including immune-modulating cytokines and tumor-specific suicide genes, while minimizing off-target effects and improving replication specificity in cancer cells. This method has been refined with protocols like Advanced viral genome Cas9 editing (AdVICE), which supports traceless manipulation of genomes up to several megabases, enabling the creation of next-generation OVs with integrated synthetic circuits for conditional activation. Such innovations address previous limitations in viral payload capacity and safety, paving the way for more robust antitumor responses. Personalized OV therapies are gaining traction through patient-derived models and AI-optimized , allowing for tailored selection and modification based on tumor profiles. Patient-derived organoids and xenografts serve as platforms to screen OV candidates, identifying those with optimal replication and in specific tumor microenvironments, thereby improving efficacy predictions before clinical use. Complementing this, AI-driven models integrate multi-omics data to simulate viral dynamics and optimize genome edits, such as predicting immune evasion strategies or enhancing for heterogeneous tumors; for example, hybrid ecological models using time-delayed equations forecast OV-tumor interactions with high accuracy. These approaches, highlighted in recent reviews, accelerate the transition from bench to bedside by enabling rapid iteration of viral constructs matched to . Novel OV platforms inspired by bacteriophages and incorporating RNA switches are emerging to achieve tighter control over conditional replication, expanding therapeutic versatility. Bacteriophage-inspired designs draw from and lytic cycles to engineer hybrid vectors that selectively target surface markers, delivering payloads without infecting healthy tissues; recent studies demonstrate their use in disrupting tumor-promoting biofilms and eliciting antitumor immunity in solid malignancies. Meanwhile, RNA switch mechanisms, such as those responsive to oncogenic mRNAs or tumor-specific metabolites, regulate viral gene expression for replication only in malignant cells—for instance, engineered influenza A viruses with chemogenetic switches show selective activation in models, reducing systemic toxicity. These platforms represent a shift toward modular, programmable OVs that integrate synthetic regulatory elements for enhanced precision. As of , the OV pipeline reflects a surge in global clinical trials, with approximately 150 active studies worldwide—roughly double the number initiated around —driven by expanded capabilities and regulatory support. This growth underscores an increased focus on challenging indications, including liquid tumors like and , where engineered OVs such as modified adenoviruses are being tested for intravascular delivery to disseminated cells. Similarly, trials targeting metastases have proliferated, with OVs like DNX-2401 combined with checkpoint inhibitors showing promising infiltration and response rates in glioblastoma models, addressing barriers like the blood-brain barrier through intratumoral or convection-enhanced delivery. These trends signal a maturing field poised for broader integration into multimodal cancer regimens.

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