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 Cancer Center in New York, is, as is often the case with oncologists, conservative in his 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 in oncology do with solid tumors is that I give treatments that can cure patients,” he states confidently. He is referring to CAR-T treatments, a cellular therapy that has shaken up the traditional approach to hematologic cancer. This technique, which is already used to treat various leukemias and lymphomas, consists of extracting T lymphocytes from the patient — a type of immune cell that is 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 [treated] with CAR-T, the cure rate is 45%,” the doctor says. Before the CAR-T, the percentage of people cured was half that.
Perales 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 is 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 with CAR-T therapy, day by day in the clinic, may seem like science fiction. When I explain to the patient that we are going to collect their 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 says.
Question. What has CAR-T therapy meant in the treatment of hematological cancer?
Answer. There has been a total change in how we treat it. We have patients who are alive today because of this. I have been doing allogeneic [stem cell] transplants, which use cells from a donor, for more than 20 years, and autologous transplants, with cells from the patients themselves. With allogeneic treatment we have been able to cure patients, but in those where the autologous transplant was made, the options are very bad in, say, lymphoma. CAR-T treatment was first approved in these patients after relapse, and now we have long-term results in that the patients 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 typical results with chemotherapy or even with autologous transplant are very bad, and the trial we did was a comparison between taking the patient directly to CAR-T or doing the classic chemo treatment followed by autologous transplant. 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 traditional treatment.
Q. CAR-T began with patients whose prognoses were hopeless, with no therapeutic alternative, and now you say that the treatment is given in earlier stages. What is your hypothesis? Surely, the sooner it is administered, the better the results will be, or is it too aggressive to use early?
A. In oncology there are two philosophies. Some say: “I’ll save the best treatment for later, in case the first one doesn’t work.” 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 the patient receives, 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 first will have a healthier immune system than the one who receives it in the third, fourth, or fifth line.
Q. Can CAR-Ts end up completely replacing traditional bone marrow transplantation?
A. In my current practice, 80% or 90% of patients receive CAR-T to diffuse large cell lymphoma in the second line [before an eventual transplant]. 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 them a transplant, and if they relapse after the transplant, we give them a CAR-T afterward. 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. Is the aim for CAR-Ts to end up being the first-line treatment, even before chemotherapy?
A. Before chemo, no. But I think what we are going to see is that, patients who have a very aggressive lymphoma, who we know in advance are going to do poorly with chemo, 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 usual thing.
Q. CAR-Ts, in any case, are not free of side effects. What impact does this collateral damage have?
A. We have learned a lot: when we started, eight of the first ten patients went to the ICU. But they were also patients who had been waiting several months to get CAR-T. They were very advanced patients, who had received several lines of treatment. Today, we have learned a lot about patient selection, we are treating them much earlier, and we handle complications better. There are two very specific complications that come from CAR-T, which are cytokine syndrome and neurotoxicity, which can appear between 24 and 48 hours. Now we treat them more aggressively and, in cases of neurotoxicity, almost all the patients recover completely. Mortality due to treatment after allogeneic transplant can be between 10% and 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 ($316,273) per patient. Even the academic CAR-T developed by the Hospital Clínic, which is cheaper, is still expensive (about €90,000 or $94,882). What can be done about that?
A. 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 chemo didn’t work, they went to CAR-T. If chemo did work, they went to transplant and if that didn’t work, they went 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 beforehand. 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 industry’s responsibility with this type of drug? Because, in Spain there is the peculiarity that, to carry out these therapies, the patient’s own cells are used.
A. It is a therapy that is difficult to produce. It is a [bespoke] treatment that is done for each patient, and you have to take into account all the expense of removing the cells, sending them, and producing them. There is much less margin than in some pills.
Q. One of the proposals is payment by results, depending on the response of that drug.
A. It is a very interesting idea. It is a model that has a lot of value and that could be done [in Spain]. 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. Despite being promising, the CAR-Ts are not infallible. Some patients relapse. Why does this happen?
A. There are several 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 (the biological part of the CAR-T), it works for both of us. Lymphoma cells will sometimes lose CD19, and if it no longer exists, the CAR-T is no longer useful, and some cells will relapse. Another reason may be that the T cells become immunologically tired and no longer function. Sometimes, the T cells become worn out, 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-T also revolutionize solid tumors?
A. We have seen promising results in some cases, such as mesothelioma, where work has also been done in combination with checkpoint inhibitors [a type of immunotherapy]. But in solid tumors, the biology is somewhat different. There are more variations in the tumors because they grow over a longer term. What is more, the tumor microenvironment is more difficult for the immune system because there is more suppression of immune cells. I think there will be something, but it will take time.
Q. If we thought that CAR-Ts were science fiction 20 years ago, what other science fiction today can we see become reality in the future?
A. 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. We need a CAR-T for that. Tests are being done, 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 five or ten years we will have CAR-T for solid tumors. And the Covid vaccine platform is going to greatly change the options for cancer vaccines.
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