Miguel Angel Perales, MD: “What we do today with CAR-T cell therapy against cancer sounds like science fiction” | Health and wellness

The therapeutic revolution that has taken place in the fight against cancer is achieving victories that were unimaginable until recently. Dr. Miguel Angel Perales, chief 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 outlook and does not like to use the word cure lightly. In his case, everyday life calls for optimism. “The difference between what I do and what my other oncology colleagues do with solid tumors is that I offer treatments that can cure patients,” he confidently decides. He refers to CAR-T therapies, a cell therapy that has shaken up the traditional approach to treating blood cancer. This technology, which is already used to treat some blood cancers and lymphomas, consists of extracting T lymphocytes from the patient – a type of immune cell responsible for defending the body – modifying them in the laboratory with genetic engineering and returning them to the body. patient so they can fight the tumor better. “In lymphoma (treated) with CAR-T, the cure rate is 45%,” the doctor explains. Before CAR-T, the percentage of people cured was half.

Perales (Brussels, 56) 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 whose mother is English, has been in the United States for 25 years, seeing patients and researching the ins and outs of cancer. The leap achieved in this time is enormous, as this scientist, an expert in cell therapy, admits: “What we do today, day after day in the clinic, with CAR-T therapy may seem like science fiction. When I explain to a patient that we’re going to collect their cells, we’re going to put a vector in there, and all of a sudden, all of those cells are going to attack the cancer, which sounds like science fiction.

I ask. What does CAR-T therapy mean for leukemia?

Answer. It was a complete change in treatment. We have patients alive today because of this. For more than 20 years I have been performing allogeneic (stem cell) transplants, 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 the options for autologous transplantation are very poor , for example, in lymphoma. CAR-T therapy was first approved in these patients after relapse, and now we have long-term results that suggest they are still alive more than five years later. What has changed since 2017, when CAR-T was first approved, is that we are now trialling the second line: these are patients who relapse early, within the first year or who do not respond to even the first line of treatment. In this group, we know that the classical outcomes of chemotherapy or even autologous transplantation are very poor, and our trial was a comparison between taking the patient directly to CAR-T or doing classical CAR-T. chemotherapy Followed by an autologous transplant. And what we’ve seen is that CAR-T works better, it’s more effective, fewer patients will relapse, and more patients survive compared to classical therapy.

s. CAR-T started with patients who were desperate, had no treatment alternative, and now say they are progressing to early stages. What is the hypothesis? The earlier it is taken, the better the results or is it too aggressive to be used 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, we’d better give it to the first line, because if not, it may not reach the patient in the second line or third line. From an immunological point of view, the more treatment there is, the worse the T cells we will use to make CAR-T will become. So a patient who receives CAR-T before will have a healthier immune system than someone who receives it in the third, fourth, or fifth line.

s. Can CAR-Ts completely replace traditional bone marrow transplantation?

R. In my current practice, 80% or 90% of the patients I give CAR-T for diffuse large B-cell lymphoma are in second-line (before definitive transplant). And what we’ve seen in the United States is that the highest level of self-cultivation was in 2015, and since then it has been declining. And it will go down more and more because CAR-T treatment is better. Sometimes there is a patient who relapses later and we do a transplant, and if they relapse after the transplant, we do CAR-T after that. But the majority of patients I treat at my center are second-line CAR-T patients.

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

s. Are CAR-Ts then intended to be first-line treatment, even before chemotherapy?

R. Before chemotherapy, no. But I think what we’ll see is that for patients with very aggressive lymphoma, who we know upfront that they’re going to do poorly with chemotherapy, they’ll start with a few cycles of chemotherapy. chemotherapy The CAR-T will then be delivered to the front line. But we must point out that this is better than doing the usual thing.

s. However, CAR-Ts are not free of side effects. What is the impact of this collateral damage?

R. We’ve learned a lot: When we started, eight of the first 10 patients went to the ICU. But they were also patients who were waiting several months to access CAR-T, and they were very advanced patients, with multiple lines of treatment… Today, we’ve learned a lot about selecting patients, and we’re treating them very early and managing it. We are treating 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 we are now treating them more aggressively. As for neurotoxicity, almost all patients recover completely. The mortality rate due to treatment after allogeneic transplantation can be 10% to 20%; In CAR-T, the percentage is less than 1%. To 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.

s. One limitation of CAR-T is its price: treatments marketed by the pharmaceutical industry run about 300,000 euros per patient. Even the academic CAR-T developed by Hospital Clínic, which is cheaper, is still expensive (about 90 thousand euros). What can he do?

R. I don’t have an answer for that. What I can say is that in the United States we analyzed whether the CAR-T procedure or autologous transplantation was cheaper and showed that it was cheaper to do the CAR-T procedure. The reason was that 55% of the patients who were in the control group ended up receiving CAR-T: instead of receiving CAR-T immediately upon relapse, they went to chemotherapy And then, if chemotherapy If the treatment doesn’t work, they go to CAR-T, or if the chemotherapy works, they go to a transplant and if it doesn’t work, they go to CAR-T. In other words, it’s CAR-T now or CAR-T later. But the cost is much greater because you have to pay for everything you gave before. I can’t say how we’re going to lower the price. Academic CAR-T is an interesting and unique model in Spain. But in the United States this cannot be done.

s. What is the industry’s responsibility in this type of medicine? Because, here there is the peculiarity of using the patient’s own cells to carry out these treatments.

R. It is a difficult treatment to produce. It’s a treatment that’s done on every patient and you have to take into account all the costs of removing the cells, sending them, producing them… The margin there is much lower than it is on some pills.

s. One proposed proposal is payment by results, depending on the response to that drug.

R. It’s a very interesting idea, and it’s a very valuable model that could be implemented here. In the United States, no. But from a health economics point of view, it’s a very interesting model. What is done in the United States in pediatric acute lymphocytic leukemia is they only pay if they are in remission by day 28.

s. Although promising, it is not infallible. Some patients relapse. Why is this happening?

R. There are many reasons. The CAR-T will recognize CD19, which is on the cell surface and found in all normal B cells, and your CD19 is the same as mine. In other words, if you 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 they will relapse, if that CD19 is no longer there, the CAR-T is no longer useful. Another reason may be that the T cells become immunologically tired and stop working. Sometimes the T cells don’t survive, stop working, or the lymphoma becomes invisible to CAR-T.

“I think stem cell transplantation will disappear and we will have more specific cell therapies.”

s. Will CAR-Ts also revolutionize solid tumors?

R. We have seen promising results in some cases, such as mesothelioma, where the 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 differences in tumors because they grow over a longer period. Also, the tumor microenvironment is more difficult for the immune system, as there is greater suppression of immune cells. I think there will be something, but it will take some time.

s. If twenty years ago they thought CAR-T cars were science fiction, what other science fiction could we see today becoming reality in the future?

R. Where we don’t have CAR-T is acute myeloid leukemia, which is a disease in which we mostly do allogeneic transplants. There we need CAR-T, there are tests and I think we can get it within five years. Little by little, I believe that allogeneic transplantation will disappear and we will have more specific cell therapies, fewer complications, fewer side effects, and a lower risk of death due to treatment. I think in 5 or 10 years we will have CAR-T for solid tumors. The Covid vaccine platform will also dramatically change cancer vaccine options.

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