Cancer remains a medical and social burden worldwide despite several technological advances in the past decades. Conventional cancer treatments such as surgery, chemo-, or radiotherapy are restricted to local therapy or by dose-limiting toxicities and may induce drug resistance during treatment. In recent years, the field of immunotherapy has launched a paradigm shift in cancer therapy and for the first time could demonstrate a potential for long-term survival of patients suffering from advanced solid tumors. However, because of varying response rates, only a small minority of patients have hitherto benefitted from these immunotherapies.

The immune system can be considered a powerful “drug” that has been naturally trained by evolution to efficiently protect us from numerous diseases. Cancer that developed in the presence of an intact immune system usually has evolved mechanisms to escape an anti-tumor immune response. Viruses, however, represent a very strong danger signal and can activate the immune system even in the immunosuppressive tumor environment. Numerous case histories reported “spontaneous” tumor regressions after immunization with live viruses or after natural virus infection. This led to the investigation and development of oncolytic viruses as cancer therapeutics. However, virology was at its infancy when the oncolytic capabilities of viruses were observed in the mid-20th century. Over recent decades, technologies were developed to investigate and modify viruses. With advances in molecular biology and immunology, virotherapy has now received tremendous renewed interest based on its enormous potential.