Josep Dalmau: "In trying to improve the immune response against the tumor we are still attacking the brain"

BarcelonaThe neurologist Josep Dalmau is one of the world's most authoritative voices in neuro-oncology, the science that treats and studies tumors affecting the nervous system. The head of the Autoimmune Neuronal Diseases Pathogenesis group at IDIBAPS and researcher at the new CaixaResearch Institute received the Gregorio Marañón National Research Award for Medicine in 2025. Recently, the Conchita Rábago de Jiménez Díaz Foundation also honored him for his decisive contribution to the knowledge of autoimmune encephalitis, a group of brain diseases that for decades had no diagnosis or treatment.

What do autoimmune encephalitis consist of?

— We treat patients who have neurological problems due to an inflammatory process of the brain that is immune-mediated. This means that the cause of the inflammation is an immunological attack against brain cells or proteins. We all have an immune system that defends us from viruses and bacteria. It is a highly sophisticated system with biological memory, it is the guardian of the body, but which sometimes gets out of control and can attack the body itself. In this case, the nervous system. In summary, it is a whole group of encephalitides mediated by an uncontrolled immune response against nervous system receptors.

How many diseases are we talking about and what is their prevalence?

— The first one was identified in 2005, although the complete characterization arrived two years later. Since then, in the last twenty years, we have gone from knowing nothing about it to identifying about 17. Approximately there are between fifteen and twenty patients per million people, and this makes them considered rare diseases, but the figure is misleading regarding their importance. They can present as a pure psychiatric condition, epileptic seizures, or behavioral and movement disorders, and the diagnosis is differential because we can treat some of them, while there are other neurological diseases with the same symptoms, but which unfortunately have no cure. That is why they are always under suspicion.

Do they affect children and adults differently?

— Yes. It is an error to characterize all autoimmune encephalitides as a single one, as some only affect adults and others are predominantly diagnosed in children. In the case of NMDA receptor encephalitis, which is the most frequent, it occurs in both cases. When the disease is established, it is very similar in both adults and children, but the way it presents is not. In adults, especially in women – because it is more predominant than in men – it usually presents as an abrupt psychiatric condition. Many are admitted thinking they have schizophrenia until other symptoms such as epileptic seizures or loss of consciousness appear, which help to refine the diagnosis. In children, the first symptom is usually great irritability, insomnia, and agitation.

What are the next steps?

— The impact for patients is very significant because they are serious pathologies without a diagnosis that you don't know how to treat. Now we want to understand the details. For example, there are some in which patients, even with treatment, can spend months in intensive care and we don't know exactly why. In many cases, it is initiated by a tumor that contains proteins identical to those in the brain. The immune system is activated to attack the tumor, but it gets confused and ends up attacking the brain as well. Checkpoint inhibitors, a type of immunotherapy, release the brakes on the defenses to eliminate the tumor. As a side effect, extreme immunological activation can cause neurological complications. In other words, by trying to improve the response against the tumor, we also attack the brain. This is what we want to investigate now.

What role will the CaixaResearch Institute play?

— To find solutions, a connected ecosystem is needed that unites the hospital –where the patients are– with the laboratory, in this case the CaixaResearch Institute. We will investigate the mechanisms and genetic factors of certain patients, and the development of new treatments, such as CAR-T. It is a cell therapy with which we use the patient's own immune cells to correct it. It is well known in the world of oncology, it is used in leukemias and lymphomas, as well as in other immune diseases such as lupus, and now we are looking for a way to direct it to autoimmune encephalitis.

How can CAR-T be improved, being already so pioneering?

— CAR-T cells can be manipulated against different molecular targets, but these are all over the body and sometimes the response we achieve is too large. We are working on CAR-T that only activate when they reach the brain thanks to sensors that recognize the brain matrix. This way we achieve that the tumor is attacked and nothing else. We want to study all this here, and at the same time we want to develop a whole series of reagents, which we will also make between IDIBAPS and the new institute using patients' antibodies.

What will these reagents be used for?

— The advantage of having a monoclonal antibody is that it only recognizes a specific receptor. This allows us to introduce it into an animal that has developed completely normally and see exactly what happens behaviorally when we block it. Therefore, these diseases offer us a unique opportunity: to use the antibodies that patients develop themselves, convert them into reagents, and use them in animal models to understand how brain receptors work, not only in disease but also in normal conditions.