Marta Alonso (1974), Sara Labiano (1987) and Virginia Laspidea (1995). Three proper names and three different generations (X, millennial and millennial-centennial, respectively), but united by the same DNA: finding solutions to fight childhood cancer in its most aggressive forms. They work a few meters away in the laboratories of the Applied Medical Research Center (CIMA) of the University of Navarra (Pamplona), determined to change a painful reality: cancer continues to be the leading cause of death from disease in children under 15 years of age in Spain and pediatric solid tumors represent one of the most hostile areas of medicine, especially brain tumors and sarcomas, which lead the mortality rates.
The objective is to gain years, months or even minutes of life from lethal diagnoses that have a very low survival rate and lack effective treatment. For this reason, cancer research - whose World Day was celebrated last Thursday - is key, an area traditionally underfunded in the pediatric field due to the lower volume of patients compared to adults. In this context, the support of private entities is essential. The three researchers have the financial support of the CRIS Foundation Against Cancer, whose excellence programs are focused on retaining talent, providing infrastructure to laboratories and promoting the definitive leap towards research autonomy.
A characteristic of pediatric solid tumors such as diffuse midline glioma - an extremely aggressive brain cancer located in the brain stem that mainly affects children between 5 and 10 years old, with a survival rate that does not exceed 10% two years after diagnosis - is the so-called immune desert. This is one of the greatest challenges that these scientists face: the environment of this glioma in the brain barely has the presence of T lymphocytes, the immune system cells that detect and destroy tumor threats. Added to this is its critical location: the brain stem controls vital functions such as breathing, swallowing or heart rate, which completely rules out the surgical option.
Since it was not possible to operate, these tumors were no longer biopsied and by not doing so, there was no longer any live tumor tissue to be able to study them, "neither at the level of diagnosis nor to be able to generate models." "There was a time when a doctor from the Dana-Farber Cancer Institute (Boston) carried out a clinical trial to biopsy them again and also know the name and surname of the tumor, because they were diagnosed by imaging. Since they began to be biopsied again, around 2010, we began to have more knowledge of their molecular composition and cell lines were generated that already opened the field a little," explains Alonso, principal investigator of the Advanced Therapies Group for Pediatric Solid Tumors at the TOP.
Through the CRIS Excellence Program, endowed with 1.25 million euros distributed over five years, Alonso leads the Virus Project against Childhood Gliomas, an area to which he has been dedicated for 20 years, since he left after completing his thesis at the MD Anderson Cancer Center in Houston. Its Viroimmunotherapy laboratory is directed by Spanish researchers Juan Fuello and Candelaria Gómez Manzano, key figures worldwide in the fight against brain tumors: they genetically modified an adenovirus (the virus that causes the common cold) and reprogrammed it to become an oncolytic virus, that is, it only kills tumor cells by destroying them from within (it can infect healthy ones, but it does not kill them). It also awakens the immune system since the lymphocytes recognize the tumor remains after destruction. "There I came into contact with this world and I decided that when I had my laboratory I wanted to dedicate myself to pediatric brain tumors," says Alonso.
When he returned to Pamplona and had his laboratory in 2011, he transferred that research to pediatric models, conducting a pioneering trial between 2019 and 2021 that demonstrated safety and was published in the New England Journal of Medicine. "Especially because of the location, it was the first time in the world that a virus was placed in the brainstem and I think that is why it had quite an impact," he adds.
One more step in oncolytic viruses
With the project financed by CRIS Contra el Cancer they have taken another step. "In the laboratory what we have done is evolve the virus as if it were a Pokémon, let's say. We are evolving them," he points out graphically. In that sense, the researcher indicates that the virus lacked power and had room to push the immune response. They also want to produce molecules that make the cells around the tumor that are used by it (as there are almost no lymphocytes in the area) stop helping that tumor.
The project also includes a line of research to evaluate the neurocognitive impact and toxicity of the therapies used, such as radiotherapy, on the brains of mice to protect the child's developing brain. Also a regulatory part to "try to close the circle with the laboratory until we can reach the clinical trial."
This is where Alonso's work connects with that of Sara Labiano, principal investigator of the Radio-Immunotherapy Strategies Group for pediatric tumors at CIMA and a biologist by training. "In the microenvironment of these tumors there are practically no T lymphocytes, the vast majority are myeloid cells." These cells act as "tumor friends" and the researcher combines oncolytic virus with a CD40 agonist - a protein that is expressed in myeloid cells and in cells that present tumor antigens - to activate the immune system so that these myeloid cells stop helping the tumor and exert their antitumor effect. "We are combining it with radiotherapy, which is the first line of treatment for diffuse midline gliomas."
The project, financed with 400,000 euros distributed over five years by the CRIS Emerging Leader Program - which has allowed it to have its own laboratory at CIMA - is carried out in mice that are not administered systemically, but locally. "We believe that this route of administration is key." And due to the location of these tumors, it is very difficult for treatments to reach them if they are administered systemically (in a vein throughout the body). Labiano points out that there are trials administering this CD40 systemically that have not improved survival, while one carried out a year ago in adults with breast cancer in which it was administered intratumorally is having positive responses. This researcher's mouse models already manage to maintain 20% long-term survivors (group in which they are measuring the possible impact of radiotherapy that Alonso mentioned).
Also in sarcomas
Virginia Laspidea, a researcher in Alonso's group, researches solid tumors but in the field of sarcomas (tumors that occur in bones and soft tissues), specifically rhabdomyosarcoma and Ewing sarcoma. Although these types show a favorable prognosis of 70% if detected early, the figure plummets below 20% if the tumor metastasizes to the lung or there are recurrences (relapses) after treatment. In the case of Laspidea, her project has a CRIS Out-Back scholarship, which finances international stays and ensures her return to Spain, which allowed her to spend two years at the UCL Cancer Institute in London with Karin Straathof before returning to CIMA.
His research focuses on deciphering how the immune system responds to irradiating sarcomas - especially rhabdomyosarcomas - with protons. Once that response has been analyzed, it combines proton radiotherapy with oncolytic viruses and CAR-T cells. The effectiveness of these is usually limited in sarcomas by the physical barriers of the tissue itself. "To try to improve this, we first irradiate the tumor because it is known that radiotherapy triggers the activation of your immune system and this will help the function of the CAR-T cells," details Laspidea. Preliminary trials already show that the combination with protons improves the effect of using CAR-T alone.
Collaboration before competition
Not only are there links and feedback between their research, but the three have a relationship that is far from the competitiveness that usually occurs in science and research. In fact, Alonso is a mentor to both. Laspidea did his thesis with Alonso and returned to his laboratory after his postdoc in London. "Almost my entire career I have been working with Marta on pediatric tumors. Working in her laboratory has guided me to where I am now," she emphasizes. "Virginia came very young to do an internship, then she stayed to do her master's thesis and the thesis, they have been together for many years," says Alonso.
"As I come from Marta's laboratory and she has been so generous with me by giving me her models, all the techniques and progress we make at a technical and knowledge level are shared between the two laboratories. Also now with Virginia, we are not afraid of stepping on each other," Labiano confesses. Alonso admits that this exchange also responds to a personal harmony and a trust of years because "this is a very competitive world and, at times, a little ugly."
In the case of Labiano and Alonso, their relationship began with a curious episode that stayed with them both. The day the first defended her thesis and was going home, she met Alonso in the parking lot. "I practically didn't talk to Marta, although everyone went to tell her about their problems and they have her as an unofficial advisor, but that day she congratulated me for having defended my thesis and asked me where I was going as a postdoc. When I told her that I was going to Lausanne she told me: 'Don't go to Switzerland, go to the US'. I thought: 'Why is this woman getting involved in my life?'", she confesses, making Alonso and Laspidea laugh. "At the same time I thought it would be great to work with her because of the way she said it. When I wanted to return from Switzerland I saw that she had a postdoc position and I wrote to her. The funny thing is that in the interview she remembered that moment," he recalls.
"I'm very nosy, that's true. From my point of view he was kind, but I understand that not knowing us well he could have been a little aggressive. He wrote a very good thesis and I had seen her at immunology meetings. I thought, although I didn't tell her that way, that such a valuable aunt should not go to Switzerland, not because there are no top places like the one Sara was in, but thinking that in other places she could have more projection. But she looked at me as if to say: 'Excuse me?', and I thought: 'What a great aunt.' serious', and that conversation stuck with me.
For the three researchers, especially the youngest ones, having female references mitigates psychological barriers such as imposter syndrome, a phenomenon with greater statistical roots among women (scientists or not). "A male mentor believes it more, so to speak. Also seeing a little how they act has to serve as an example for us," reflects Labiano, who believes that a female boss "knows a little about where you are going to have to go through, the difficulties they have also gone through, because the panorama is not changing that much either." In that sense, Labiano points out that among the emerging researchers (those who are starting their research group) at the center he does not see differences, but "there comes a point that I don't know why, it is something invisible that happens", the differences begin. Partly due to networking and socialization outside the laboratories and symposia dominated by male dynamics, the researchers consider.
