Viruses, the most feared infectious agents, can also become allies against cancer, according to new research. This was demonstrated by a group of scientists exploring current research opportunities that combine traditional therapies and genetic engineering.
HSV1. Image Courtesy of Thomas Splettstoesser
Oncolytic viruses, literally “cancer-killing viruses,” have been around for more than a century, thanks to the first described case in 1904, when a patient suffering from myeloid leukemia went into remission after a suspected flu infection. Oncolytic viruses have the advantage of preferentially multiplying in tumor cells and leading to their regression by lysing the cells and stimulating the tumor immune response.
Oncolytic viruses Properties
Cancer cells have very specific properties. They produce large amounts of nucleotides for rapid reproduction, form a network of blood vessels for oxygenation, and have the ability to divert the immune response by not responding to certain cytokines (interferon type 1). Moreover, they confuse the immune system by producing proteins on their surface that can inhibit cytotoxic cells. This last point, incidentally, is a cornerstone of research into immunotherapies used to treat some cancers.
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It is these different properties that will be exploited in the use of oncolytic viruses. To be a suitable candidate, the virus used must have little or no toxicity to normal tissue, be immunogenic, and preferentially target cancer cells.
Thanks to genetic engineering, it is now possible to delete viral genes (knock-out) or add transgenes (knock-in). These techniques make it possible to develop transgenic viruses that will preferentially multiply in malignant cells. Deleting the gene for thymine kinase, which forces the virus to infect cells with a high nucleotide production capacity, and adding a gene encoding cytokines that stimulate anti-tumor immune activity are just a few examples.
Combination therapies
Although using oncolytic viruses for the treatment of cancer has been explored for several years, their use is still limited because of many unknowns. For instance, the antiviral pathways of tumor cells are still unknown, and there are physical barriers that limit the penetration of viruses into tumor cells. In addition, they can be destroyed by antibodies circulating in the body. However, a recent analysis showed that they can be valuable allies when combined with other conventional treatments (radiotherapy, chemotherapy) or more innovative treatments such as immunotherapy with checkpoint inhibition (a promising strategy, but one that only works in 10 to 20% of cases). Genetic manipulation applied to oncolytic viruses makes them complementary armament vectors thanks to their ability to induce cell lysis and immune stimulation.
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Currently, only a few oncolytic viruses are licensed worldwide. Amongst them is a modified form of the Herpes simplex virus (HSV-1) which has been approved for the treatment of inoperable metastatic melanoma. Another approved oncolytic virus is the Myxoma virus, which causes myxomatosis in rabbits. It was chosen because it has a long genome that can contain stable modifications and because it is harmless to humans.
References
Rahman MM, McFadden G. Oncolytic Viruses: Newest Frontier for Cancer Immunotherapy. Cancers. 2021; 13(21):5452. https://doi.org/10.3390/cancers13215452
