Oncologists have in their hands a treatment that is curing patients who a few years ago were doomed to die. Immunotherapy has achieved spectacular results in people with melanoma whose life horizon was three years. However, the most promising cancer therapy, on which science has placed much of its hopes, is surrounded by unknowns that trip up researchers and clinicians. Why in some cases does it work so well and in others the effect is zero?
A group of leaders in research into this advanced therapy met last week in Madrid to put a collective brain to work: socialize what is already known and share what is not yet known. María Casanova-Acebes is leader of the cancer immunity group at the National Cancer Research Center (CNIO) and one of the organizers of the international meeting. Attend elDiario.es between conferences.
As a researcher, she has discovered a very interesting thing: that tumor cells distort the circadian rhythm of the immune system so that it cannot recognize and attack them. Is it like saying that cancer causes jet lag in the system so that he is clueless?
Say jet lag That’s a lot to say. We have a synchrony in our rhythms that are timed by the light that our body receives and makes us capable of fighting infections, wounds or cancer. But if we alter these rhythms, either because we change our diet or sleep patterns, that sends different signals to the body that makes the immune system become very stupid when it comes to recognizing things. And a series of changes are generated in cells that can generate a tumor. We are studying how these alterations that are occurring in our lifestyle habits generate disturbances in the immune system and the initiation of tumor processes.
We have seen that the molecular clock of macrophages is particularly inhibited and that is enough to generate a pro-tumor response: instead of helping in the fight against cancer, they give it trophic mechanisms to grow. We like to say that it is a mechanism of subversion of the immune system. The tumor cells tell the macrophage: you are going to work for my benefit, instead of eliminating me, and they block their circadian physiology. We are studying what signals are sent to the macrophage and how we can reverse it.
Taking these biorhythms into account, is there any time that is better than another to administer immunotherapy, which uses precisely this immune system to fight tumor cells?
There are five studies in different tumors, such as melanoma, lung or bladder, that suggest that if immunotherapy is administered before four in the afternoon there is greater survival and less toxicity. These therapies generate colitis, skin inflammation or joint pain, so if you give the drug in the morning, in addition to being more effective, you are minimizing the adverse effects.
We are trying to understand how this immunotherapy affects macrophages by inducing cell death at different times of the day in animals. When we generate immunogenic death in tumors in the morning it is better to recruit T cells. Not only promoting the activity of the immune system, but blocking or activating things in the tumor cells. In cancer it is difficult to go with a single therapy. When you put pressure on the tumor with chemotherapy, for example, you look for ways to move forward. The objective is to design a more effective drug, which requires less quantity and is also less toxic.
We are studying how these alterations that are occurring in our lifestyle habits generate disturbances in the immune system and the initiation of tumor processes.
Are you only testing it on mice at the moment?
We have two projects that have the idea of validating our observations in mice in humans. One is based on monitoring a group of flight crew members. We have three cohorts to analyze what changes occur in the immune system in people subjected to jet lag, with disturbances lasting more than seven hours. We compare it to short-range flight workers. We have seen that, in terms of risk of illness and sick leave, people who travel shorter have more inflammatory pathologies. In general, more illnesses reported. It is interesting because we believe that the disruptions can be different: in the jet lag chronic there is a part that can be adapted.
We do the other project at the Valdecilla hospital (Santander) with a cohort of 400 patients. We are going to analyze those who have received immunotherapy before four in the afternoon and after that time. We want to look specifically at neutrophils, a type of cell, in metastatic tumors. It is the cell that most anticipates the immune response.
The challenges posed by this elite of therapies, immunotherapy, seem great. Are we far from it having reached its full potential?
Immunotherapy has just been put on the scene. We are at the tip of the iceberg, in the 10% that is seen when 90% is under water. We are now studying how to predict patient responses because we have not had time. There is a global effort to understand not only responsive cases but also non-responsive cases. We are in that 10% that we are going to continue exploring because we know quite little.
For those who do work, is it a lifeline for people who were practically hopeless a few years ago?
It is being seen that immunotherapy has completely cured patients with melanoma. This type of cancer is the one that is giving the best results. People with a prognosis of 3 to 5 years to live are cured. It is a radical change. We also see positive results in some types of lung cancer and pay attention to the first observations in breast or head and neck. The latter was on the list of those in which nothing worked, along with the ovary and pancreas.
Whether it works better or worse depends only on the type of tumor?
It’s not just one thing. It was previously thought that the type of antigens or mutations was what predicted how immunotherapy treatments would work. Then an article flatly denied that. Now 10 or 12 combinations are used that have to test positive to administer this immunotherapy. Clinicians think about it carefully, they seek advice from basic researchers to make these decisions because it is a treatment with side effects and has a very high cost.
However, sometimes even though these parameters are met, the treatment does not respond and you wonder, what is happening? You then begin to investigate what is so special about that person that it didn’t work.
Can the immune system be recruited to go to work against tumor cells?
It can be recruited in many ways, it is not just that many cells reach you but the activated cells that have to enter the tumor. It is complicated because sometimes there are physical impediments, and once they arrive, they have to have the appropriate signals so that they recognize the tumor cells and kill them. We have been trying to understand these impediments for five years and how to manipulate them so that they are not obstacles.
Can combining immunotherapy with radiotherapy, for example, help?
Both radiotherapy and chemo generate a series of signals that the immune system likes: a little inflammation, a series of damage patterns… Then the system says “let’s repair it.” It is possible to call the immune system, but sometimes the tumor cell evades this second recognition.
#María #Casanova #cancer #researcher #Immunotherapy #cured #patients #life #expectancy #years
