JUAN FUEYO And CANDELARIA GÓMEZ: “We Use The Cold VIRUS To Eliminate The Most Aggressive Brain Tumors”
This marriage of Spanish neurologists, are two of the most prominent investigators of the MD Anderson Cancer Center of the University of Texas, and their findings are revolutionizing the fight against cancer.
Candelaria and Juan Fueyo (both part of the Spanish national team of Science 2018) are investigating at the MD Anderson Cancer Center in Texas (USA), recently on the cover of all media, when it was announced that the Nobel Prize in Medicine of this Year fell into the hands of James P. Allison, the father of cancer immunotherapy, and head of the Department of Immunology at the Anderson.
The Swedish Academy has honored the striking effects of a new cancer therapy that will revolutionize medicine, and the work of Candelaria Gómez and Juan Fueyo are on that path.
In their first Phase 1 clinical trial with humans, they showed that a cold virus, to which they have made two genetic modifications, can activate the patient’s immune cells and, as in a cascading effect, these cells in addition to ending the virus, destroy Glioblastoma, the most common malignant brain tumor, aggressive and lethal. This type of cancer does not respond to chemotherapy or radiotherapy and has a life expectancy of just 14 months.
Q: What did you get in that trial with humans?
Candelaria: “In 20% of the patients, the tumor disappeared completely and they managed to live between 3 and 5 years more, with quality of life, without the side effects that produce the chemotherapy and the radiotherapy”
John: “Oncolytic virus therapy has enormous potential. So we’re getting this award thinking it’s a global award to the use of immunotherapy to treat tumors. It is one of the great milestones of the decade, it is the effort of more than ten years working in laboratories from all over the world in this direction. ”
Q: Did you started to work on the virus 10 years ago?
John: More, much more. The first time we published about a virus that replicated with the idea of attacking cancer, it was in the year 2000. The article was published in the magazine Oncogene in January of the new millennium. Then a more important investigation was published, a first trial with animals.
The results were spectacular. We had a 60% survival in mice, and he thinks that to treat brain cancer there is nothing, or very little.
Q: Why chose the cold virus?
Candelaria: We started almost by chance when we arrived in the US. UU wanted to do gene therapy and at that time there was a highly recognized Catalan virologist, Ramón Alemán, who had formed in the same institution, and worked in Adenovirus, we started to collaborate with him and so we chose Adenovirus, which is what he knew Manipulate genetically.
Q: Was cancer your goal?
Candelaria: Yes, when we finished our residency in Spain, we came to the US. UU to do research to treat brain tumors.
Q: Was the cold virus a good choice?
Candelaria: Yes. The cause of the common cold seems like a good viral structure to work with. There are quite a few groups now using oncolytic virus, but if we were to choose again, I would choose this one again, it is much less toxic than any of the ones that are proposed.
Q: What does it mean to be less toxic? Do you work with others who are more?
John: Adenovirus is genetically modified to only multiply in cancer cells. There are some viruses that do not require modification, and others that require more, as is the case with polio. But among researchers, it would be important that because something is possible, it does not mean that it is ethically respectable.
Q: I don’t understand you… what is ethically unrespectable?
John: There are research groups that are modifying potentially very dangerous viruses, such as Zika or polio. And it is very risky to use a virus whose main target cells are those of the intestine and neurons. Delta 24, the virus we are working with, has already been given to many patients and has not had toxicity.
Q: But what advantage do you then have to work with herpes, Zika, polio viruses?
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John: There are those who know what herpes virus is, and then it modifies it, and they think, “if it is so toxic, it will probably have a lot of effect on the tumor…”. The idea is benign, to cure the patient, but all of this molecular biology that is now so easy in the laboratory, requires that ethical standards be established. There aren’t any right now. Society has to be more involved, and start deciding things like this can be done with this less toxic virus, to be done with it… It’s a matter of security.
Q: Well… how does Delta24 act on the tumor?
Candelaria: It is called adenovirus because it was discovered in the adenoids, ie it has tropism by the respiratory system, adheres to the membrane of the cells, replicates and kills them. So we thought the same virus could get him to join the tumor cells, and destroy them. This was the initial hypothesis. But when we went to clinical studies, we saw that the virus infected the tumors, was replicated, at two weeks the virus could not detect it anymore, and yet there was an immune response with population of lymphocytes within the tumor. What that means… So the immune system had destroyed the virus and was now in charge of the tumor.
Q: And did the tumor begin to destroy itself?
Candelaria: That’s right. The important thing is that after infection with the virus, lymphocytes appear in the tumors, so the virus produces an alarm signal in any tissue, even in the tumor, and this is a call for lymphocytes that come to destroy the virus. And why do they still destroy the tumor? Well, we don’t know. What is the switch that turns on the immune response to the tumor? We don’t know yet.
Q: Why does it work in some cases and others don’t?
John: No group working with general immunotherapy can know in advance which patients will respond well. We need to find biomarkers that can give us a remake to this, or improve therapies in order to reach a greater number of patients. Machine learning will help us with this. For example, what happens if you activate a chemical? What if these genes were activated that weren’t activated? An algorithm predicts what the tumor will do, and you can anticipate. These new therapies are based on the properties of immunotherapy, is very specific, very flexible, and has memory.
Q: How lived the first trial with humans?
John: With the first patient we do not sleep for fear of provoking something worse, an encephalitis for example. The neurosurgeon, just injecting the virus, came running to the lab to ask, “Are you sure?” A colleague told us: everything will be fine…
Candelaria: It was a Phase 1 clinical trial to see if the new agent was toxic or not…. The dose was going up, which never became toxic, and it is not only that there were no adverse effects, it is that patients had a sense of well-being that is not given with other therapies, such as chemo, where the patient feels more and more sick. With this treatment it’s like you have a self-healing situation, that your own body will heal you, and that makes you feel very good. It is due to the awakening of your own immunity against the tumor.
With this treatment it’s like you have a self-healing situation, that your own body will heal you
Q: The next step in your research?
John: We have enough hope in a clinical study that opens now in Navarre and we will also do here. It is a third generation of virus, which expresses a T-cell activator. We have published pre-clinical studies and the results are even better. The idea is to increase the percentage of patients who respond.
Q: And I think a rehearsal with children in Navarre is taking place?
Juan: Yes, Marta Alonso, a pediatric researcher at the University Clinic of Navarra, who studied with us, has opened an essay to treat children who have incurable gliomas in the brain stem. The brain stem, for us neurologists, is untouchable. That’s where all the systems that regulate the heart, the consciousness, the mobility…. Well, in children, who have no other treatment, let’s do it. In these cases, no one dares or wants to biopsy. Marta has started this year with clinical studies, so far there is no toxicity, and we will see what the answers are….
Q: Now you have no funding problems in your research?
John: The incidence of brain tumor is 10 new cases per 100,000 inhabitants. For example Oviedo, I am from Oviedo. There are 250,000 inhabitants, they have 25 new cases per year. There’s no way a big company is interested in such small incidents. However, once the virus is “absorbed” by those investigating immunotherapy, it has acquired great popularity, and they try to consider a special case of immunotherapy. We defend that it is “virus-immunotherapy”, that the virus does not lose its prominence.
Q: Do you yourselves many lives?
John: “When we were doing guards in the ER in Barcelona, maybe one day you saved four lives. We’ve been here 20 years, and we’ve saved four. But this makes you excited. “