"I had never seen a lymphoma disappear in a refractory patient like CAR-T therapy does"

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Oncohematologist Miguel Ángel Perales says that CAR-T therapy has transformed his daily work with patients: "I have never seen a lymphoma disappear in a refractory patient like CAR-T therapy does." He recalls a specific case, a young man who had already received several lines of treatment and had a tumor "the size of a peach" in his neck; 28 days after the infusion, the improvement was obvious, "it was impressive". It also expresses concern for patients who are unable to access therapy. He could say it just as clearly in any of the five languages he speaks: he learned our language from his Spanish father; Raised in Belgium, where he obtained his degree in Medicine, at the Free University of Brussels, he speaks French, Dutch and German. The rest of his career has been spent in the United States, where he serves as director of the Adult Bone Marrow Transplant Program at Memorial Sloan Kettering Cancer Center in New York.

He points out his reservations about certain aspects of the current regulatory system that may hinder innovation in this type of treatment. "I don't have the solution," he says, "but you have to point out the problem in order to address it." It is, in fact, one of his initiatives as president of the American Society for Cell Transplantation and Therapy (ASTCT).

Based on your experience with CAR-T cells, what are they contributing to the treatment of haematological cancer? The situation here in the United States is different from Spain, at least as far as what we can use is concerned. We have been administering CAR-T therapy at our center since it was approved in 2017, although we had already participated in trials before, so our experience goes back about ten years. In the U.S., we use it very frequently in acute lymphoblastic leukemia (ALL) in children and, more recently, since a new approval, in adults. In diffuse large B-cell lymphoma (DLBCL) it is approved in second-line treatment for patients who relapse early (first 12 months) or in those refractory to first-line. Also in those who relapse and cannot receive autologous transplantation, which was previously the standard approach. In addition, CAR-T therapy is indicated in mantle cell and follicular lymphoma. In multiple myeloma, it is indicated in different lines. In Europe, after the approval of the European Medicines Agency (EMA), each country has a different rate of incorporation, so this may be the case of Spain, where the CAR-T for mantle lymphoma, which we have been administering to many patients for three years, still does not have funding. The same is true of the second-line DLBCL, which has not yet arrived in Spain. In my practice I do allogeneic transplantation and cellular immunotherapy, and 90% of patients with lymphoma who receive CAR-T cells are in the second line of therapy. It is very difficult to tell a patient that they are going to receive one treatment knowing that there is another one that provides more survival. So the superiority is clear... And not just in the clinic. We did a study on the cost-efficiency of axi-cel [axicabtagene ciloleucelen] in the second line for DLCL. We compared with data from patients receiving the following lines, up to seven or eight in some cases, and found that more than 55% of patients in the control group end up receiving CAR-T therapy. So the difference is 'CAR-T now or later'; But if you get it later, overall survival goes down and you need to give other treatments. In short, putting CAR-T earlier is cheaper. Our study was supported by one company, but another independent group of researchers at City of Hope carried out similar work with results very similar to ours, which they published in Blood. We now want to repeat the study with updated survival data.
What is estimated survival for second-line DLCL? In the tests, it is around 50%. The patient has received fewer treatments, and since CAR-T cells are made from autologous lymphocytes, they are expected to be in better condition than cells that have already seen 20 lines of treatment. In fact, in the second line, a little more efficacy and survival are observed. But for me it's insufficient, I'd like to be closer to 100%. Much remains to be done. Among these necessary advances is the determination of prognostic factors: How to identify early who will need a CAR-T? There's a lot of discussion about that today. On the one hand, there are biological risk factors, such as having a double hit, but there is also the role that PET imaging plays after chemotherapy cycles. Lately, circulating tumor DNA (ctDNA) has gained strength as a prognostic factor, which some studies suggest may be better than PET. The problem with ctDNA is that there is no consensus on how it is best measured, and while it is included in trials, the FDA does not consider it a valid test to grant an approval. Another aspect of improvement is the development of allogeneic CAR-T, are they close to the clinic? There are many, I would say too many, studies focused on CD19; The advantage is that this target can be applied to various diseases. CARs that use NK cells have so far not been very successful. Some have been built with banks of NK cells derived from induced pluripotency cells [iPSCs], obtained by genetic reprogramming of the skin. Biologically, this is a very interesting process, but the clinical results have not been very promising. Other CAR-NK products from MD Anderson, which published a small series of patients treated at NEJM, have also been studied, but there has been no follow-up or further information. There are several companies interested in its development; some use the TALEN editing system and others use CRISPR. I'm a doctor, what matters to me is the clinical outcome. The technology in the lab can be spectacular, but at the end of the day I want to see the result in my patient. And what do the studies suggest? With allogeneic CAR-T therapy, preliminary results are being seen in lymphoma that seem promising, and progress is being made in multiple myeloma versus BCMA, although also with preliminary data for the time being. Everything points to the fact that obtaining allogeneic CAR-T therapy will actually have an impact on logistics, by shortening the time it takes to obtain the product: in the US, axi-cel is ready for lymphoma in about two and a half weeks (17 days), other products take even longer. If they were allogeneic cells, we would not have to wait so long, apart from the fact that, as I mentioned, the cells used would not have undergone previous therapies. But for allogeneic CAR-T therapy to be approved, it must be shown in trials that it is better than autologous therapy or, at least, similar, because it has the advantage of logistics. The problem is that autologous CAR-T is approved second-line lymphoma, so it is very difficult to find patients who receive them third-line or next. The FDA has told companies developing new CAR-T, allogeneic or not, to conduct studies in the third line or higher, similar to pivotal ones (Zuma, Juliet, or Transform). But there are no longer patients who fit into those types of studies. It's a regulatory issue that could be seen as an impediment to innovation. If the efficiency were at 80-90% we wouldn't even think about it, we would invest in something else, but since we are at 50%, we know that there is room for improvement. And for this, it is necessary to have a biologically better CAR-T and overcome regulatory obstacles. As president of the American Society for Transplantation and Cell Therapy, is this an issue that concerns you? It's one of my initiatives. We are in working discussions with the different actors involved, including the [FDA] agency, to see how to overcome this issue. I don't have the solution, it's a complex issue. As I see it, regulatory impediments to innovation They will get companies to stop innovating. They invest a lot of money in product development, and if they then see that they don't make it to market, there will be a time when they stop doing it.
On the other hand, I also wanted to mention that autologous CAR-T is being worked on to shorten the production time. To the point that if they manage to shorten it to a week, the allogeneic modality would lose one of its great advantages. And another interesting model is that of academic CAR-T, something very specific to Spain, which I have had the opportunity to follow closely, because for the ARI 0001 trial at the Hospital Clínic I was on the data safety oversight committee [DSMB], an independent group of experts in charge of controlling the safety of the study and protecting the patient. In the U.S., this model is less developed, probably for economic reasons and because of our health system, which is very different from the Spanish public system. Earlier, he commented that more than the biological process, at the end of the day he cares about the patients, the clinical outcome. What have these treatments contributed to patients' quality of life? There are studies in phase III trials that show that the recovery of quality of life is faster with CAR-T cells than with autologous transplantation. It has been published, for both Zuma and Transform, that most patients, regardless of acute toxicity (cytokine release syndrome and neurotoxicity, whose management is much better today than in 2017), recover very quickly. In the long run they do better. In addition, it is to be expected that CAR-T therapy will reach new indications: the results in lupus, for example, are very interesting, with the advantage that CAR-T can be a single treatment, rather than a chronic one. It's also important to bring it closer to more people. We have talked about the US and Europe, but the truth is that the majority of the world's population does not have access. In South America, for example, they are starting now. Access will be more or less complicated in our countries, but in many others there is nothing.

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