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

Oncohematologist Miguel Ángel Perales affirms that CAR-T therapy has transformed his daily work with patients: “I have never seen a lymphoma disappear in a refractory patient as CAR-T therapy achieves”. He remembers 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”. He also expresses concern for patients who cannot 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 developed in the United States, where he serves as director of the Adult Bone Marrow Transplant Program at the Memorial Sloan Kettering Cancer Center in New York.

He notes 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 we have to point out the problem to address it.”. It is, in fact, one of his initiatives as president of the American Society of Transplantation and Cell Therapy (Astct).

According to your experience with CAR-T cells, what are they contributing to the treatment of hematological cancer? The situation here, in the United States, is different from that of Spain, at least in regards to what we can use. At our center we have been administering CAR-T therapy since it was approved in 2017, although we had already participated in trials before, so our experience goes back about ten years.. In the US we use it very frequently in acute lymphoblastic leukemia (ALL) in children and, more recently, with a new approval, in adults.. In diffuse large B cell lymphoma (DLBCL), it is approved as a second line of treatment for patients who relapse early (first 12 months) or in those refractory to the first line.. Also in those who relapse and cannot receive an autologous transplant, 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 on 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 financing. The same thing happens in the LBDCG in the second line, which has not yet arrived in Spain. In my practice I do allogeneic transplant and cellular immunotherapy, and 90% of lymphoma patients who receive CAR-T cells are in second line therapy. It is very difficult to tell a patient that they are going to receive a treatment knowing that there is another that provides more survival. So the superiority is clear…And not only in the clinic. We did a study on the cost-efficiency of axi-cel [axicabtagene ciloleucelen] in second line for DLBCL. We compare with the data of patients who received the following lines, up to seven or eight in some cases, and we 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 receive it later, the overall survival decreases and you need to administer other treatments. In short, putting CAR-T before is more economical. Our study was supported by a company, but another independent group of researchers from the 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 survival is estimated for DLBCL in second line? In trials 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, somewhat more efficiency and survival are observed in the second line. But for me it is insufficient, I would like to be closer to 100%. There is still much to be done. Among these necessary advances is the determination of prognostic factors: How to identify early who will need a CAR-T? There is a lot of current discussion about this.. 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) is gaining strength as a prognostic factor, and some studies suggest that it may be better than PET.. The problem with ctDNA is that there is no consensus on how it is best measured, and although it is included in trials, the FDA does not consider it a valid test to grant approval. Another aspect of improvement is the development of allogeneic CAR-T Are they close to the clinic? There are many studies, I would say too many, focused on CD19; The advantage is that this target can be applied in 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 it is a very interesting process, but the clinical results have not been very promising.. Other CAR-NK products from MD Anderson have also been studied, which published a small series of patients treated in NEJM, but there has been no follow-up or more information. What about allogeneic CARs with T lymphocytes? There are several companies interested in their development ; some use the TALEN editing system and others, CRISPR. I am a doctor, what matters to me is the clinical result. The technology in the laboratory 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 compared to BCMA, although also with preliminary data at the moment. Everything indicates that in reality obtaining allogeneic CAR-T therapy will impact logistics, by shortening the times 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 suffered from the previous therapies.. But for allogeneic CAR-T therapy to be approved, it must demonstrate 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-Ts are approved in the second line in lymphoma, so it is very difficult to find patients who receive them in the third or subsequent line.. The FDA has told companies that are developing new CAR-Ts, allogeneic or not, that they must carry out studies in the third line or more, similar to the pivotal ones (Zuma, Juliet or Transform). But there are no longer patients who fit into these types of studies.. It is a regulatory problem that could be seen as an impediment to innovation. If the efficiency were at 80-90% we wouldn't even consider 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 of Transplantation and Cellular Therapy, is this an issue that concerns you? It is among my initiatives. We are holding working discussions with the different agents involved, including the agency [FDA], to see how to overcome this issue. What is your proposal? I don't have the solution, it is a complex issue. As I see it, regulatory impediments to innovation will cause companies to stop innovating.. They invest a lot of money in developing products, and if they later see that they do not reach the market there will be a time when they will stop doing it.
On the other hand, I also wanted to mention that work is being done on autologous CAR-T to shorten 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, since for the ARI 0001 trial at the Clínic I was on the data safety supervision committee [DSMB, for its acronym in English], an independent group of experts in charge of monitoring the safety of the study and protecting the patient. In the US, this model is less developed, probably for economic reasons and because of our health system, which is very different from the Spanish public system. You have previously commented that more than the biological process, at the end of the day you care about the patients, the clinical result.. What have these treatments contributed to the quality of life of patients? There are studies in phase III trials where it is observed that the recovery of quality of life is faster with CAR-T cells than with autologous transplant. It has been published, for both Zuma and Transform, that the majority of patients, regardless of acute toxicity (cytokine release syndrome and neurotoxicity, the management of which is much better today than in 2017), recover very quickly. They are better in the long term. Furthermore, it is 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 one-time treatment, rather than a chronic one.. It is also important to bring it 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 start now. Access will be more or less complicated in our countries, but in many others there is nothing.