However, during those years the progress of Cell and Molecular Biology revealed that among the intricate biological mechanisms there were opportunities to regulate the functions of the immune system and "convince" it to attack cancer. The very complexity of this system made it difficult to know what interventions would be beneficial. The intuition was that a malignant tumor, in order to become malignant, must harbor mutations or genetic changes that distinguish them from normal cells and that, under certain conditions, can be recognized by the immune system.

In its defense, the body relies on cells that have "licence to kill" other cells that may pose a threat. These, called cytotoxic lymphocytes, are needed to control infections. The task of the immunotherapy specialist has a lot to do with knowing how to use these defenses - in constant evolution - redirecting them on the cancer to treat or prevent it.

The "new immunotherapy" emerged in the last years of the 20th century from successful experiments on tumor-bearing mice. We had come to the conclusion that the immune cells that can recognize and kill cancer cells carry receptors in their membrane that act as "brakes or accelerators" of their functions. Thus, to combat cancer, it seemed logical to block these "brakes and step on the accelerators"..., and so it was done. To achieve this, antibodies developed at laboratory were used to target these receptors and, voilà, the tumors in mice were eradicated with unusual efficacy. These pharmacological agents are now known as immunostimulatory monoclonal antibodies (which stimulate the immune response).

The efficacy of blocking two of the receptors that act as "brakes", PD-1 and CTLA-4, was quickly echoed by the biotechnology industry. In recent years we have witnessed large-scale experimentation with this new pharmacological class in patients. The result is very good, although only a small percentage of patients (between 10 and 30%) still benefit from the treatment. challenge Our important task now is to know how to identify the patients who will benefit from the treatment on laboratory before starting the treatment.

These drugs, which are already in the marketing phase, have two main problems. On the one hand, they can trigger autoimmune reactions, controllable in most cases if diagnosed in time, and, on the other hand, a very high economic cost, which some have called "socioeconomic toxicity".

Cancer immunotherapy, in the face of these partial successes, has triggered a "gold rush" in the pharmaceutical industry. First, with the development of a growing issue immunomodulatory agents against multiple targets and, second, with the combination of treatments seeking synergistic effects. It would have been unimaginable in the year 2000 that advances in immunotherapy are today the main determinants of the stock market price of multinational companies with enormous capitalization.

Excellent physicians and researchers with expertise in immunotherapy work on the staffs of pharmaceutical companies, and this is one of the explanations for the speed and magnitude of the progress we are experiencing.

It is quite possible that in cancer immunotherapy the best is yet to come. The main hopes for improving our results are centered on two objectives. We can now know the sequence of the information Genetics of the patient and his or her tumor and, by comparing them, predict their antigens. Thus, the first goal is that we will soon be able to synthesize and test individualized vaccines to vigorously "start" the engine of the immune response. Once achieved, these vaccines should be combined synergistically with other agents designed to block the "brakes and step on the accelerators" of immune system cells. The motto seems to be: combine and conquer!

At laboratory we can grow lymphocytes with killing capacity and introduce into them genetic instructions to recognize the tumor and attack it. These strategies are revolutionizing the treatment of certain leukemias. Hence, the second goal is to resolve the question of whether this technology will be successful in other tumors, but the field is advancing rapidly.

In Spain there are a number of good immunotherapy researchers trained in prestigious foreign centers. We also have excellent oncology specialists who have played leading roles in clinical trials where the efficacy of new immunotherapy treatments has been evaluated in patients, including some recently approved for use in patients. There are also some teams from research that have successfully combined the research of laboratory with the clinical research in what we call research translational.

Perhaps this research field in cancer has not been sufficiently prioritized in time in Spain from an economic and political point of view, despite the emerging evidence of its clinical efficacy. I am saddened by the comparison with the countries around us. In this respect, the Americans, Germans, Italians, Dutch, French and English "beat us by a long shot". In Spain there is no lack of talent or "quarry", there is a lack of awareness. Proposing an analogy, with the right support we could be as good in immunotherapy as we are in soccer with our national team.

When I talk to my students about cancer immunotherapy, I usually end by saying that the important thing is surely "what we do not know". And what is even more important is "what we don't know that we don't know". In immunotherapy there is still a long way to go until we cure or alleviate all patients. Following the rules of the scientific method, the only way to achieve this that I know of is called research.