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 multiples 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strain enterovirus RIGVIR, which was approved in Latvia in 2004 for the treatment of skin melanoma; the approval was withdrawn in 2019.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 U.S. and European Union, for the treatment of advanced inoperable melanoma. 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