Rotavirus vaccine restored tumor susceptibility to immunotherapy

Rotavirus vaccine restored tumor susceptibility to immunotherapy
in vitro treatment of cancer cells with live or attenuated rotavirus enhances transcription of interferon pathway genes 1 Shekarian et al. / Science Translational Medicine, 2019

Commercial vaccines for rotavirus, a pathogen that causes acute diarrhea, can make standard anti-cancer immunotherapy more effective. The researchers have demonstrated that attenuated virus vaccines have anti-cancer activity – like real oncolytic viruses. Administration of the vaccine to mice activates the transcription factor NF-κB, which controls the genes of the immune response and, in combination with immunotherapy, allows for 100% survival.

Some viruses may have an antitumor effect. This is due to the fact that they are more likely to attack cancer cells than normal cells, and in the fight against the virus, they attract the attention of the immune system. In a long fight against a tumor, immune cells may lose interest or become tired, and the viral “shake” here helps attack the cancer with renewed vigor. This idea formed the basis of the study of Tala Shekarian (Tala Shekarian) from the University of Lyon and her French colleagues, who decided to use attenuated viruses paired with immunotherapy.

Immunotherapy itself is aimed at “unblocking” immune cells that are under the negative influence of tumor signaling substances. It restores their work, but in some cases, immune cells are still not able to defeat cancer. The low effectiveness of immunotherapy has been demonstrated for small-sized cancer cells, for cases with low T cell infiltration and an abundance of myeloid cells in the tumor area. In order to further stimulate immune cells in this case, their “interest” can be warmed up by injection of oncolytic viruses or toll-like receptor agonists. Once in cancer cells, they cause a response that is noticeable to the immune system. As a result, infected cancer cells die of the virus on their own, or they are helped in this by immune cells attracted by distress signals.

The development of new drugs with oncolytic viruses takes quite a lot of time and money, so the researchers tested the already tested commercial vaccines from attenuated viruses for their usefulness in combination with immunotherapy. To begin with, they tested 14 vaccines, four of which – from typhoid, from tuberculosis and two rotavirus vaccines – turned out to be promising. In experiments on cancer cell lines, they all caused activation toll-like receptorsand rotavirus vaccines also activated NF-κB transcription factor, an important regulator of the immune response genes.

The scientists tested the direct anticancer activity of the most promising rotavirus vaccines in a mouse model of neuroblastoma resistant to immunotherapy with CTLA-4, PD-1, and PD-L1 inhibitors. They demonstrated that injection of rotavirus generally inhibits tumor development and delays the death of mice. Moreover, in one embodiment, four out of ten mice recovered. Combination therapy with CTLA-4 inhibitors and rotavirus vaccine showed even more encouraging results: in this case, all 20 experimental mice recovered, while control mice died by the thirtieth day of the study. In the case of several tumours, a similar effect was achieved, despite the fact that the vaccine was injected into only one of them.

Rotavirus therapy results for two mouse neuroblastoma models
Shekarian et al., Science Translational Medicine 2019

The mechanism by which a vaccine enhances the effects of immunotherapy, researchers studied in vitro. They showed that in cancer cells during cultivation, along with a weakened or ordinary rotavirus, transcription of the genes of the interferon 1 pathway, a signaling substance that regulates apoptosis, suppresses tumor growth and enhances the immune response, is enhanced. First, the infected cell learns about the virus using the RIG-1 receptor, which activates the interferon-1 pathway and stimulates the antiviral response to which the immune cells flock.

It is important that such a “side effect” was found in an already tested vaccine. This is a finished product that has undergone clinical trials, and to adapt it to a new role requires significantly less effort and time than to develop a new one.

Viruses can not only help treat tumors, but also provoke their appearance.