Antonio Pérez-Martínez, head of the Pediatric Hemato-Oncology Service at Hospital Universitario La Paz.
The advanced therapies they are the only hope for patients who are in a very advanced stage of their disease. However, what is defined as medicine of the 21st century is still in an initial phase and does not always work. With the aim of solving these inefficiencies, from the Hospital La Paz of the Community of Madrid they have Pioneeringly produced and infused in Spain with its own dual CAR-T bispecific therapy -19 / 22- to minors with acute B lymphoblastic leukemia who had relapsed in their disease following the administration of a commercial CAR-T, so there was no other therapeutic alternative for them.
Something that affects more than half of children with acute lymphoblastic leukemia and 60 percent of patients who have diffuse B-cell lymphoma. Some data that the team of Antonio Pérez-Martínez, head of the Pediatric Hemato-Oncology Service of the Hospital Universitario La Paz, have refused to accept, and in search of get full cure are developing a pioneering treatment that might represent a paradigm shift within advanced therapies produced in the National Health System (SNS).
What are you looking to solve with this dual CAR-T?
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“We have shown that a public Hospital has academic and production capacity” |
One of the escape mechanisms to CAR-T is that the leukemic cell stops expressing the target by which it is recognized. We administer the CAR-T only once, but it lasts and remains. Leukemic cells are constantly monitoring CAR-T because they want to learn to live with it in order to survive. It is as if they hide, which causes that almost 50 percent of patients relapse due to the regulation of the C 19 molecule. There are also other patients who relapse even expressing the molecule and the escape mechanisms are different.
In short, we do an approach to the first CAR-T through several targets, so we are subjecting the cell to various pressures. So, although one regulates the other, it continues to act and thus we can rescue or address several lines. This is very important because for a successful approach you need multiple targets. Dual CAR-T is a response to this possible immune escape mechanism.
Does it only apply to patients who have previously received a commercial CAR-T?
Indeed. As of today we are in a clinical trial and it has not yet been authorized for use. In fact, the vector (lentiviral material from which CAR-T is created) is not ours, but the laboratory that has given it to us. Currently, most advanced therapies are sent to the pharmaceutical industry to be manufactured and that comes at a cost. However, we have now shown that we have academic capacity and that a public hospital only needs one vector, to be able to produce a CAR-T, since the other ingredients are in the hospital. It is a very important paradigm shift because it makes you much more autonomous, you can estimate the times and lower costs.
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“Producing your own CAR-T makes you more autonomous, controlling time and reducing costs” |
How long does it take to produce it?
It takes between one and two weeks, depending on the weight of the patient. The estimate of the weight we want to infuse is 3 million per kilo separated into three doses. We make 1 million the first day, if there is no CRS, 1 million the next and 1 million the next. So it is not the same that the patient weighs 10 kilos, which is a total intake of 30 million cells, that weighs 50. It is what the pediatric age has, that we have children with leukemia of six months and 17 years.
What requirements must you meet to be able to produce it?
It has to meet regulatory, microbiological, genetic, and potency criteria. This product is not yet approved, however, we have recently passed an inspection by the Spanish Medicines Agency for another advanced therapy product and it put its focus on the two dual CAR-T products that we had made. They stayed with us for three days and when they left we received a patient who had relapsed in another autonomous community to a commercial CAR-T. So, we once more requested compassionate use from the Agency and its authorization to be able to produce it in house.
How many patients have treated with this CAR-T?
This would be the third.
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“We must universalize the CAR-T and get out of that spiral of violence in which we are now in which only some centers can do this type of therapy” |
Do you have preliminary data on its effectiveness?
We have safety and effectiveness data. Regarding safety, absolutely nothing has happened and regarding effectiveness we have two patients who have been treated. One has responded and is still doing well following more than a year. However, the other patient, despite partially responding, progressed and died from the disease. The most important thing in these very preliminary phases is to do no harm, and to show that you have the possibility of being able to do it with acceptable costs for the system. The message is that we can do the development in house. Furthermore, it can be done even in centers that currently have a designation by the Ministry as additional centers. Far from restricting academic development, what we try to do is promote it.
Once the safety and efficacy are confirmed, might this production be done en masse by Spanish hospitals?
Unlike the other CAR-T, this will allow an in-house development, that is, you buy the ingredients and produce the cake for yourself. This lowers costs, makes it more efficient and allows an academic development that makes the care in hospitals more excellent. On the other hand, in the medium term, the idea is to universalize the CAR-T and get out of that spiral of violence in which we are now in which only some centers can do this type of therapy.
“We must allow clinical trials in centers that are not designated by the Ministry to administer CAR-T” |
Is there inequity in the SNS to access CAR-T therapies?
In the end, the feeling that we hematologists have is that they do not arrive because a patient who is in a third level hospital in a town or in a small city and has to go to the big city is not the same as a patient who is in Móstoles and that you can immediately come. We must generate equity in the system, we have already shown that this is something that can be managed by centers that have experience in complex transplants, which is more complicated than a CAR-T. We must allow clinical trials in centers that are not designated by the Ministry because if we put one in one place and eight in another, those eight will continue to grow and one will drown. So in the end it is not only an inequity for the patient, but also an inequity for the professionals and for the development of public hospitals.
One of the basic pillars for this treatment to be universalized in the designation of reference centers?
Without a doubt, it is a fundamental pillar. At this point, following three years of experience, the strategy should be reconsidered. If we compare ourselves with the large European countries, we are far below the centers of France, Italy, Germany and the United Kingdom. The strategy might be understood at first, but today the argument of no patients is not real. There are those patients, but they are not arriving. In addition, it is a therapeutic strategy that transcends hematology, that is, it is a platform where many diseases have a place and it is the medicine of the 21st century. The SNS have to attend to this need in a scientific, social way, with criteria of this type and not with other types of criteria, which are fundamentally political.
Are there units prepared from the centers that meet the criteria that they should have to be a designated center?
In the large hospitals in the Community of Madrid, all of them have more than enough capacity to be able to undertake this treatment. At first I can understand that certain limitations are put, but not at this time. In addition, they are not limitations due to the quality of the centers but mainly due to spending control. The fear that transcends this is that if instead of the 11 centers we put 21 there will be more patients and the answer is yes, obviously, if you put more centers there will be more patients because there will be more referral centers where they go to be able to go.
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