Millions of people owe their lives to Japanese scientist Tasuku Honjo and American James Allison, fathers of immunotherapyone of the greatest revolutions in the history of medicine. In 1992, Honjo discovered a human protein, PD-1, which acts as a brake on the body’s defenses. By inhibiting it with a drug approved in 2014, white blood cells are released and attack cancer cells with greater ferocity. Some previously incurable tumors are no longer a death sentence, but the enemy is still powerful. More than half of the cases of melanoma with metastasesfor example, are resistant to the drug. Two Spanish scientists… Anaïs Elewaut29 years old, from Malaga, and Guillem Estiville28 years old, from Barcelona – discovered, through experiments on rodents, a promising way to improve miraculous immunotherapy: certain anti-inflammatories, such as aspirin.

“We find that mice (genetically modified to develop tumors similar to those in humans) that receive immunotherapy and anti-inflammatories generally live much longer. We even have cured mice. Without anti-inflammatories, they are resistant to immunotherapy,” Estivill explains by telephone. The two Spanish scientists work at the Research Institute of Molecular Pathology in Vienna (Austria), under the direction of biologist Anna Obenauf. Their study was published Wednesday in the journal Naturea benchmark for the best science in the world.

The defenses of the human body, white blood cellsform inside bones, but some types travel to the thymus – a small gland in the chest – to mature into cytotoxic T lymphocytes, capable of destroying cells infected by viruses or bacteria. Cancer, which forms when human cells themselves multiply in an uncontrolled manner, is characterized by its ability to evade the immune system, which often does not recognize it as a threat.

The Vienna team identified a crucial actor in activating these Killer T cells previously unnoticed: monocytes, another type of white blood cell formed in the bone marrow. The new work shows that monocytes travel in the blood and can capture fragments of cancer cells and present them to T cells, which then reactivate and attack the tumor.

The study also sheds light on cancer’s strategy to hide from defenses. Tumor cells increase the production of prostaglandin E2, a lipid substance that blocks the action of monocytes. At the same time, they reduce the production of interferons, proteins that stimulate the immune system. The Vienna group says anti-inflammatory drugs that inhibit cyclooxygenase, such as aspirin, are “a promising strategy” for increasing the effectiveness of immunotherapy because they block the production of inflammatory molecules, such as prostaglandin E2. .

Estivill is optimistic, given previous results seen in humans. “We did a meta-analysis and we saw that, in immunotherapy clinical trials, patients who reported taking anti-inflammatory drugs had a better response, not only aspirin, but also all inhibitors of cyclooxygenase, like ibuprofen and many others that they take regularly to reduce pain,” he says.

The Barcelona biologist emphasizes that these anti-inflammatories provide short-term benefits to cancer patients by slowing the progression of the disease, but that over time the tumor returns. In their study, the Vienna group proposes different combinations of immunotherapy, anti-inflammatories in appropriate doses and other types of drugs that induce the production of interferons. “It works in mice. We have demonstrated this in melanoma and in pancreatic, lung and colon cancer,” emphasizes Estivill, who recognizes that human tumors are “much more heterogeneous”, so it remains to be seen if the strategy works in the same way. manner in man.

Elewaut, a biotechnologist whose parents are Belgian, explains that prostaglandin E2 levels in tumors are very high. “I think that to inhibit this process and for the immunotherapy to work better, it’s going to take a lot of aspirin and a lot of ibuprofen, and the problem is that these drugs also have a lot of side effects: stomach problems, problems cardiovascular, etc. So you have to try to combine aspirin, immunotherapy and probably other drugs,” she says. “People should not think that aspirin alone will cure cancer.”

The director of the Austrian laboratory, Anna Obenaufconfirms that “aspirin is only one of several possibilities,” but there are similar, more powerful and specific medications, such as celecoxib, used to relieve pain and inflammation in patients. arthritis. “Clinical trials with several of these drugs are underway. I suspect it will have some effect, but we have already shown in our study how to further enhance this effect with additional combination therapies,” she says. Obenauf trained more than ten years ago in the laboratory of Spanish pharmacologist Joan Massagué, director of the Sloan Kettering Institute, a center dedicated to cancer research in New York.

Biologist Marisol Soengaspresident of the Spanish Cancer Research Association, applauds the new work in which she was not involved. “The study is very rigorous and very comprehensive, because it uses very diverse cellular models and also different models of genetically modified animals,” she explains. Soengas also heads the melanoma group at the National Cancer Research Center in Madrid. According to her, all caution must still be maintained, while waiting to see the results of the combination of anti-inflammatories with the most common immunotherapies, such as those called immune checkpoint inhibitors.

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