Miguel Ángel Perales, oncologist: “What we are doing today with CAR-T cell therapy against cancer seems like science fiction”

The therapeutic revolution that has been established in the fight against cancer is delivering victories that were unthinkable until recently. Dr. Miguel Ángel Perales, head of the Adult Bone Marrow Transplant Service at Memorial Sloan Kettering Hospital in New York, is, as is often the case with oncologists, conservative in expectations and does not like to use the word cure lightly. , but, in his case, everyday life invites optimism. “The difference between what I do and what other colleagues do in oncology with solid tumors is that I give treatments that can cure patients,” he confidently resolves. He is referring to CAR-T treatments, a cellular therapy that has shaken up the traditional approach to hematological cancer. This technique, which is already used to treat some leukemias and lymphomas, consists of extracting T lymphocytes from the patient – a type of immune cells that are responsible for the body’s defense -, modifying them in the laboratory with genetic engineering and returning them to the patient so that they can better fight the tumor. “In lymphoma [tratado] With CAR-T, the cure rate is 45%,” exemplifies the doctor. Before the CAR-T, the percentage of people cured was half.

pear trees (Brussels, 56 years old) has ended up in Barcelona in the middle of a European tour full of professional and personal commitments, from his daughter’s birthday in Paris to a conference at a hematology congress in Romania. The doctor, whose father is Spanish and mother English, has been in the United States for 25 years, seeing patients and researching the ins and outs of cancer. The leap that has been made in this time is gigantic, admits this scientist, an expert in cell therapy: “What we are doing today, day by day in the clinic, with CAR-T therapy may seem like science fiction. When I explain to the patient that we are going to collect his cells, we are going to put a vector inside and, suddenly, all those cells are going to attack the cancer, it is something that seems like science fiction,” he reflects.

Ask. What has CAR-T therapy meant in the treatment of hematological cancer?

Answer. It has been a total change in treatment. We have patients who are alive today because of this. I have been doing transplants for more than 20 years. [de células madre] allogeneic, which are cells from a donor, and also autologous, with cells from the patient himself, and with this type of treatment we have been able to cure patients, but in those where autologous transplant does not work, the options are very bad, for example, in lymphoma. CAR-T treatment was first approved in these patients after relapse and now we have long-term results that they are still alive more than five years later. What has changed since 2017, when CAR-T was first approved, is that we have now done a second-line trial: these are patients who relapse early, within the first year or who do not even respond to the first line of treatment . In this group, we know that the classic results with chemotherapy or even with autologous transplant are very poor, and the trial we did was a comparison between taking the patient directly to CAR-T or doing the classic treatment of chemo followed by transplant autologous. And what we saw is that CAR-T works better, it is more effective, fewer patients are going to relapse and there are more patients alive than with the classic treatment.

Q. CAR-T began with patients who were hopeless, with no therapeutic alternative, and now it says that they advance to earlier stages. What is the hypothesis? The sooner it is administered, the better the results will be or is it too aggressive to use early?

R. In oncology there are two philosophies. Some say: “I save the best treatment for later, in case the first one doesn’t work for me.” And my philosophy is the opposite: if we have something that works well, it is better to give it to the first line, because if not, it may not reach the patient in the second line or the third line. From an immunological point of view, the more treatment is given, the worse the T cells that we are going to use to make the CAR-T will be. So the patient who receives the CAR-T before will have a healthier immune system than the one who receives it in the third, fourth or fifth line.

Q. Could CAR-Ts end up completely displacing traditional bone marrow transplantation?

R. In my current practice, 80% or 90% of the patients where I give CAR-T for diffuse large cell lymphoma, it is in the second line [antes de un eventual trasplante]. And what we have seen in the United States is that the highest level of autologous transplantation was in 2015 and, since then, it has been decreasing. And it’s going to go down more and more because the CAR-T treatment is better. Occasionally there is a patient who relapses later and we give him a transplant, and if he relapses after the transplant, we give him a CAR-T afterwards. But the majority of the patients that I am treating at my center are with CAR-T in the second line.

“We have cancer patients who are alive today thanks to CAR-T therapy.”

Q. Do CAR-Ts aim, then, to end up being the first-line treatment, even before chemotherapy?

R. Before chemo, no. But I think what we are going to see is that, in patients who have a very aggressive lymphoma, who we know in advance that they are going to do poorly with chemo, they will start with a couple of cycles of chemo and then CAR-T will be given on the front line. But it must be shown that this is better than doing the typical thing.

Q. CAR-Ts, in any case, are not free of side effects. What impact does this collateral damage have?

R. We have learned a lot: when we started, of the first 10 patients, eight went to the ICU. But they were also patients who were waiting several months to reach CAR-T, they were very advanced patients, with several lines of treatment… Today, we have learned a lot about patient selection, we are treating them much earlier and the management of We handle complications better: there are two very specific complications of CAR-T, which are cytokine syndrome and neurotoxicity, which can appear between 24 and 48 hours and now we treat it more aggressively and, of neurotoxicity, almost all The patients recover completely. Mortality due to treatment after allogeneic transplant can be 10% to 20%; in CAR-T, it is less than 1%. For me, the complications we have with CAR-T are something we can handle without a problem and the risk of losing a patient is very rare.

Q. One of the limitations of CAR-T is its price: the therapies marketed by the pharmaceutical industry are around 300,000 euros per patient. Even the academic CAR-T developed by the Hospital Clínic, which is cheaper, is still expensive (about 90,000 euros). What can be done?

R. I have no answer for that. What I can say is that in the United States we analyzed whether it was cheaper to do CAR-T or autologous transplant and we showed that it was cheaper to do CAR-T. And the reason was because 55% of the patients who were in the control group ended up receiving CAR-T: instead of receiving CAR-T immediately when they had a relapse, they went on to chemo and then, if the chemo doesn’t work, they go to CAR-T, or if chemo works, they go to transplant and if it doesn’t work, they go to CAR-T. In other words, it is CAR-T now or CAR-T later. But the cost is much more because you have to pay for everything you put in before. I can’t say how we are going to lower the price. The academic CAR-T is a very interesting model, which is unique in Spain. But in the United States it couldn’t be done.

Q. What is the responsibility of the industry in this type of drugs? Because, here there is the peculiarity that, to carry out these therapies, they use the patient’s own cells.

R. It is a therapy that is difficult to produce. It is a treatment that is done for each patient and you have to take into account all the expense of removing the cells, sending them, producing them… The margin there is much less than in some pills.

Q. One of the proposals proposed is payment by results, depending on the response of that drug.

R. It is a very interesting idea, it is a model that has a lot of value and that could be done here. In the United States, no. But from a health economics point of view, it is a very interesting model. What is done in the United States in acute lymphoblastic leukemia for children is that they only pay if they are in remission on day 28.

Q. CAR-Ts, despite being promising, are not infallible. Some patients relapse. Why does this happen?

R. There are many reasons. The CAR-T will recognize CD19, which is on the surface of the cell and is present on all normal B cells and your CD19 is the same as mine. In other words, if I make the vector, this biological part of the CAR-T, it works for both of us. Sometimes, lymphoma cells will lose CD19 and in some cells that will relapse, if that CD19 no longer exists, the CAR-T is no longer useful. Another reason may be that the T cells become immunologically tired and no longer function. Sometimes, the T cells do not persist, they stop working, or the lymphoma becomes invisible to the CAR-T.

“I think that stem cell transplantation is going to disappear and we are going to have more specific cell therapies.”

Q. Will CAR-Ts also revolutionize solid tumors?

R. We have seen promising results in some cases, such as mesothelioma, where work has also been done in combination with checkpoint inhibitors [un tipo de inmunoterapia]. But in solid tumors, the biology is somewhat different, there are more variations in the tumors because they grow over a longer term. And also, the tumor microenvironment is more difficult for the immune system, there is more suppression of immune cells. I think there will be something, but it will take time.

Q. If 20 years ago they thought that CAR-Ts were science fiction, what other science fiction today can we see become reality in the future?

R. Where we do not have CAR-T is in acute myeloid leukemia, which is a disease where, for the most part, we do allogeneic transplants. There we need a CAR-T, there are tests and I think that in five years we could have one. Little by little, I believe that allogeneic transplantation will disappear and we will have more specific cell therapies, fewer complications, fewer side effects and less risk of mortality due to the treatment. I think that in 5 or 10 years we will have CAR-T for solid tumors. And also the covid vaccine platform is going to greatly change the options for cancer vaccines.

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