Richard Vile at CNIO (Centro Nacional de Investigaciones Oncológicas) / A. Tabernero. CNIO
Vile, a paediatric immunologist and oncologist, has led clinical trials against very aggressive types of brain tumour.
“It’s frustrating that it takes so long to bring good scientific results to patients in clinical trials”, he says
Vile seeks to turn the immune system's response to a viral infection into a response against cancer. In his own words: “to turn an antiviral response into an anti-tumour response”.
Richard Vile is researching oncolytic viruses, which are viruses that specifically attack tumour cells. He wants to use them as a decoy to activate our immune system, and thus contribute to immunotherapy against cancer. One strategy is for oncolytic viruses to infect the tumour so that our defence cells, seeking to eliminate the viruses, end up eliminating the tumour: the equivalent of disguising tumours as viruses.
For Vile, Professor of Paediatric Immunology and Oncology at the Mayo Clinic Cancer Center in Rochester, Minnesota, USA, it is important for ideas like this to be tested quickly in clinical trials. He has led several trials, specifically against a very aggressive type of paediatric brain tumour that is currently without treatment. “It’s very frustrating that it takes so long to bring good scientific results to patients in clinical trials, although I am not arguingfor a relaxation of the regulatory process at all,” he says.
Vile recently visited CNIO at the invitation of Luis Álvarez Vallina, head of the Clinical Research in Cancer Immunotherapy Unit H12O-CNIO.
When were oncolytic viruses discovered?
The concept of oncolytic viruses emerged in the mid-twentieth century. But long before that, there were cases of patients with Burkitt lymphoma where the tumour disappeared after infections with chickenpox, flu, or other viruses. The first prototypes of oncolytic viruses were developed to replicate selectively in the tumour, and it was initially thought that, since they attacked tumour cells rather than healthy ones, they would provide an antitumour strategy. But as soon as clinical trials began, it was observed that the viruses did not replicate that much in tumour cells, and their antitumour effect was not very powerful.
Your group demonstrated that the important thing is the response of the patient’s immune system.
That’s right, we demonstrated in animal models that the antitumour effect of oncolytic viruses disappears if we experimentally eliminate the animal’s immune system. This suggests that the oncolytic effect comes from the reaction of the immune system to the infection, rather than from the infection itself. It is a key difference.
Since then my research has focused more on the virus as an alarm system, alerting the immune system, rather than as a direct weapon against the tumour.
How does the alarm system work?
Normally our immune system responds quickly and effectively to viral infections. So if we get the virus to infect and destroy a certain number of cancer cells, it may alert the immune system to the presence of more infected tumour cells, both locally and in other tumour sites, when there is metastasis.
So harnessing the antivirus response, and make it an anti-tumour response, that I think is the challenge now. It’s a strategy that offers great potential. Using the virus as a burglar alarm, rather than as the weapon itself.
Is this a controversial idea in the research community?
When the field exploded, in the late 1990s, people wanted to believe that the virus was strong enough to be the single agent that would work, and was somewhat unpopular to talk about the immune system because it was seen as the enemy of the virus, it stopped the virus from replicating.
With the data we have now we it’s fair to say that infection stimulates a defence response, and that this response is what fights cancer. But some researchers still think that the important thing is the replication of the virus.
How can the antiviral response be turned into an antitumour response?
When we introduce a virus into a patient’s tumour we see a very powerful antiviral response, because the immune system has great power and multiple tools to detect and fight viral infections, which is what it has evolved for. Our approach is to try to direct this antiviral response towards the tumour.
Specifically, we have modified viruses to express tumour antigens [tumour proteins], so that when the virus infects the patient, a double response is stimulated, against the virus and against the tumour, because the virus also expresses antigens from the latter. So the antiviral response becomes by definition also an antitumour response.
You are also trying to combine current immunotherapy, specifically CAR-T cells, with oncolytic viruses. Why?
Yes, we can also use that strong antiviral response as an adjuvant to CAR-T cells [patient’s own T cells modified in the laboratory to get them to detect and kill tumour cells]. One of the reasons T cells have not worked well in solid tumours is because the tumour has the ability to suppress the immune system, so the T cells reach the tumour but cannot work well. By introducing a virus into the tumour, it’s like lighting a fire in it: CAR-T cells can better detect the tumour and act against it.
How do you see this area in a decade’s time?
I truly belileve that in 10 years’ time viruses will be part of effective anti-tumour therapies. Theses viruses will be engineered so that they will be carried to tumours by CAR-T cells, and once inside the tumour, they will produce molecules that will activate those same CAR-T cells. When we combine both strategies, oncolytic viruses and CAR-T, we will have a really powerful resource against cancer.
What phase of this research are you at now?
Clinical trials. We have administered some viruses to patients, we are now starting to infuse CAR-T cells, and the next step,we hope, will be a test combining virus with CAR-T cells.
What tumours are you working on?
We are quite focused on a particularly difficult type of paediatric brain tumour. It is very poorly immunogenic tumour. One of the advantages of working on it is that, if our idea works with this tumour, what we learn can be applied to many other non-immunogenic tumours.
You are in contact with patients. What is it like seeing announcements made about advances in cancer research that will take quite a while to reach clinical practice?
Every day we see announcements of ‘the next big thing’ in the media, followed by the statement that such advancements will take five to ten years to reach patients. But some of the people who are reading about them have children who will die long before that. There is a huge disconnect between the media enthusiasm when reporting on research findings… and the reality of the patients. Communicating an advance in the scientific literature is not the same as talking about something ready to be tested in the clinic.