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. 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, although there are naturally occurring examples such as reovirus and the senecavirus, resulting in 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strain enterovirus RIGVIR, which was approved in Latvia in 2004 for the treatment of skin melanoma; the approval was withdrawn in 2019.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 (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.
On December 16, 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 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.
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.