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 that help destroy the remaining tumour. Oncolytic viruses are thought not only to cause direct destruction of the tumour cells, but also to stimulate host anti-tumour immune system responses. Oncolytic viruses also have the ability to affect the tumor micro-environment in multiple ways.
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. A number of viruses including adenovirus, reovirus, measles, herpes simplex, Newcastle disease virus, and vaccinia have been clinically tested as oncolytic agents. Most current oncolytic viruses are engineered for tumour selectivity, though naturally occurring oncolytic viruses such as reovirus and senecavirus, have undergone clinical trials.
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strain enterovirus RIGVIR, which was approved in Latvia in 2004 for the treatment of skin melanoma; the approval was withdrawn in 2019.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. In 2015, talimogene laherparepvec (aka 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.
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.
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. Efforts to treat cancer through immunisation or virotherapy (deliberate infection with a virus), began in the mid-20th century. 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, adenovirus, coxsackie virus, ECHO enterovirus RIGVIR, and others. 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, the response destroyed the virus thus preventing it from destroying the cancer. Early efforts also found that only certain cancers could be treated through virotherapy. Even when a response was seen, these responses were neither complete nor durable. The field of virotherapy was nearly abandoned for a time, as the technology required to modify viruses did not 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. 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.
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. In a wide range of in vivo cancer models, the HSV1716 virus has induced tumour regression and increased survival times.
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. Other safety trials have used HSV1716 to treat patients with melanoma and squamous-cell carcinoma of head and neck. Since then other studies have shown that the outer coating of HSV1716 variants can be targeted to specific types of cancer cells, 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, 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.
Other oncolytic viruses based on HSV have also been developed and are in clinical trials. One that has been approved by the FDA for advanced melanoma is Amgen's talimogene laherparepvec.
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. 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. Despite the promises of early in vivo lab work, these viruses do not specifically infect cancer cells, but they still kill cancer cells preferentially. While overall survival rates are not known, short-term response rates are approximately doubled for H101 plus chemotherapy when compared to chemotherapy alone. It appears to work best when injected directly into a tumour, and when any resulting fever is not suppressed. Systemic therapy (such as through infusion through an intravenous line) is desirable for treating metastatic disease. It is now marketed under the brand name Oncorine.
Mechanisms of action Immunotherapy With advances in cancer immunotherapy such as immune checkpoint inhibitors, increased attention has been given to using oncolytic viruses to increase antitumor immunity. 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. It has been shown that immunosuppression by chemotherapy and inhibition of the complement system can enhance oncolytic virus therapy.
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.
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.
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.
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. 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. 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. 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. 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.
Viruses selectively infect tumor cells because of their defective anti-viral response. 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.
Oncolytic behaviour of wild-type viruses The following table summarizes some key wild-type viruses with reported oncolytic properties +Some naturally occurring viruses investigated for oncolytic activity Virus Virus family Natural host Clinical investigation Reovirus (e.g., Reolysin/pelareorep formulation) Reoviridae Humans (respiratory/enteral, often asymptomatic) Multiple clinical trials (phase I–III), primarily in combination therapies Senecavirus A (Seneca Valley Virus, e.g., NTX-010/SVV-001) Picornaviridae Swine (originally detected in pigs; incidental in humans) Phase I/II clinical trials (e.g., neuroendocrine tumors, small cell lung cancer, pediatric solids) Echovirus 7 (RIGVIR/ECHO-7 Rigvir) Picornaviridae Humans The potential use of echovirus as an oncolytic virus to treat cancer was discovered by Latvian scientist Aina Muceniece in the 1960s and 1970s. A 2015 retrospective study of 79 patients reported that Rigvir treatment after surgical excision was associated with prolonged survival in stage IB–IIC melanoma compared to observation alone Former registration/approval in Latvia was given in 2004 and was withdrawn in 2019 due to low viral titer, and invalid testing methods; limited use in some countries; evidence considered insufficient for broader approval. Newcastle disease virus Paramyxoviridae Birds (avian) Multiple clinical trials (phase I/II), including intravenous delivery Sendai virus (Murine respirovirus) Paramyxoviridae Rodents (mice/rats) Preclinical studies; limited historical/experimental human use. Clinical studies of UV inactivated variant for prostate cancer and melanoma Vesicular stomatitis virus Rhabdoviridae Livestock/insects Preclinical; some attenuated variants in trials mainly genetically modified Coxsackievirus A21 (Cavatak) Picornaviridae Humans Clinical trials (phase I/II) for treating melanoma, non-muscle-invasive bladder cancer, and various other solid tumors.
Vaccinia virus