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CAR-T Meeting 2023 | CAR-T therapy in acute and chronic leukemias: where are we now and where are we heading?

John Gribben, MD, DSc, FRCP, FRCPath, FMed Sci, Barts Cancer Institute, London, UK, shares some insights into clinical indications for CAR-T therapy in acute and chronic leukemias, highlighting recent updates and challenges in this space. Prof. Gribben first discusses the role of CAR-T therapy in acute lymphoblastic leukemia (ALL), drawing focus on the two approved products in this malignancy: tisagenlecleucel (tisa-cel) and brexucabtagene autoleucel (brexu-cel). Prof. Gribben then goes on to explain mechanisms of resistance to CAR-T therapy in ALL and ongoing academic research in this space. Following this, Prof. Gribben discusses updates and challenges with the use of CAR-T therapy in T-cell malignancies and acute myeloid leukemia (AML), and concludes by highlighting challenges with developing efficacious CAR-T products for patients with chronic lymphocytic leukemia (CLL), which may be overcome by combining CAR-T cells with Bruton’s tyrosine kinase (BTK) inhibitors. This interview took place at the EBMT-EHA 5th European CAR T-cell Meeting held in Rotterdam, The Netherlands.

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Transcript (edited for clarity)

So at the EHA-EBMT joint CAR-T meeting in Rotterdam, we had a session on the role of CAR-T in acute and chronic leukemias that I was involved in chairing. We’ve got two products which are licensed and approved in CAR-T for acute leukemia, both in acute lymphoblastic leukemia, one tisagenlecleucel, which is approved for pediatric and young adults with ALL up to the age of 25...

So at the EHA-EBMT joint CAR-T meeting in Rotterdam, we had a session on the role of CAR-T in acute and chronic leukemias that I was involved in chairing. We’ve got two products which are licensed and approved in CAR-T for acute leukemia, both in acute lymphoblastic leukemia, one tisagenlecleucel, which is approved for pediatric and young adults with ALL up to the age of 25. And then brexucabtagene autoleucel, which is then approved for adult patients with ALL. We had a session yesterday talking about the role of CAR-T in ALL and the successes and some of the mechanisms of failure. A major mechanism that we’ve identified of the reason why a CAR-T fails in ALL is that it targets CD19 and what we see emerging over time are CD19 negative leukemic cells so the cells lose expression of CD19 and then the CARs no longer work.

So we had a whole session yesterday thinking about what might be the ways in which we can look to try to prevent that occurring. One thing that’s very clear from many of the studies in acute lymphoblastic leukemia is CAR-T is being used as what we call a bridge to an allogeneic stem cell transplant. That is we use the CAR-T to take a refractory patient into a minimal disease state and then follow it and consolidate it with an allogeneic stem cell transplant. And I think a learning for many people who are looking to read the literature in this field is to try to understand just how many of these patients are going on to receive an allogeneic stem cell transplant, so that when you look at the progression free and overall survivals, you realize it’s not just the CAR-T which is doing this, but the CAR-T followed by the allogeneic stem cell transplant.

Now some of the other ways that were discussed, there’s a lot of academic work and a lot of studies in development looking at what we call dual CARs, targeting, for instance, CD19 and CD22. And the idea here is that by targeting more than one antigen, we can try to prevent the emergence of the cells which just lack one particular antigen. And there’s a whole variety of strategies which were discussed in terms of various ways in which this could be done. We’d also seen in the previous session, of course, a whole talk from investigators from UPenn looking at trying to understand the basic scientific mechanisms whereby the cells become resistant. So I think that was also very interesting to have heard that before we heard the session on acute leukemia. In the other sessions in leukemia we’re all talking about disease indications where CAR-T is being explored but for which there’s not yet any licensed product.

Michael Hudecek talked about acute myeloid leukemia where the challenge that we have is the targets which are expressed on the leukemic cells are also often expressed on normal hematopoietic cells so that when the CAR-T eradicates the leukemia, it also eradicates the host’s hematopoiesis. And he talked a little bit about different strategies which are being used and explored, CRISPR-ing out some of those antigens on the normal cells, trying to prevent those hematopoietic cells from being eradicated. Or again, using the approach to get the patient into remission and then to have an allogeneic stem cell transplant to be able to replace the hematopoiesis afterwards. Michael also talked about a whole variety of different antigens which they’re trying to identify to find that elusive perfect antigen, which is expressed on the leukemic cell but not on the normal hematopoiesis. We then heard a talk from Max Mamonkin from Baylor in Texas where he was targeting T-cell leukemias and lymphomas.

Now we’ve seen a variety of different approaches where people try to do that. The issue there of course is if you’re targeting a T-cell antigen, you’re talking about something which is also on the surface of the CAR-T cell. And the issue is do you then have what we call fratricide, that is can the CAR then attack itself? And Max talked about different mechanisms whereby they’re trying to explore ways in which they can develop a CAR-T cell which will attack the T-cell malignancy but not lead to attack of the CAR product itself. And he talked about a variety of different ways in which in clinical trials they’re trying to do that and how also, as they’ve done some of the clinical trials and they’ve identified some of the mechanisms of failure, they’ve been able to adapt their program and going forward. So we’re now starting to see some really interesting concepts appearing in that space. And I’m quite aware of a number of other academic trials going on around the world looking to try to tackle that malignancy.

And then I gave a talk looking at CLL and commented on the fact that the very first successful studies published from Carl June’s group at UPenn on CAR-T were actually in CLL in 2011. And here we are 12 years later, and despite the success of those studies, we’ve still got no approved product. Now one of the major mechanisms why it’s been difficult to do this in CLL is that CLL is very immunosuppressive. So we know from a lot of work from my lab and many other labs that CLL itself suppresses the T-cells, so that when you obtain the T-cells to make the CAR, those defective T-cells will end up being defective CARs. That has led to a whole variety of ways in which the CAR-Ts have been slightly less successful in CLL than we’d like to see. So again, people have been exploring and I presented some preclinical work from my lab and I presented some preclinical work from UPenn and from Seattle in which people have been able to identify that the use of this agent ibrutinib, which of course we use to treat CLL, has an unexpected benefit in CLL in that it improves the function of the T-cells.

And in both pre-clinical models and now in clinical trials, when we use ibrutinib or now potentially other BTK inhibitors, at the time we’re looking to collect the T-cells to make the CARs, that appears to enhance the function of the CAR cells. And a large study, which is being performed using the liso-cel product, which is approved for non-Hodgkin’s lymphoma, but which has been explored in CLL. The latest iteration of that is using ibrutinib in combination with the liso-cel product. And our expectation is the licensing indication will probably be to use a BTK inhibitor plus using the CAR T-cells. Now of course, BTK inhibitors have revolutionized the treatment of CLL and of course we know very well about what it does to the CLL. And I think many people think that the ibrutinib works just by removing the CLL cells and therefore the T-cells recover. But it’s very clear that it has an effect on the T-cells to enhance its activity.

And a benefit seems to be that you enhance the activity of the CAR product without increasing the toxicity. And a large problem has been that many agents that we use to try to improve the way that a CAR-T cell work also work to increase not just the efficacy but also increase the toxicity. And ibrutinib certainly doesn’t seem to do that. And we’re doing a lot of work trying to understand the mechanism whereby this happens. Now what’s this going to mean in the future? So of course a patient may well have had ibrutinib in the past and the sorts of patients who are going to be eligible for CAR-T are people who failed that therapy. But it does appear as if you would be able to give ibrutinib even to a patient whose CLL is resistant to ibrutinib but still see an immunomodulatory effect. But that of course is being explored in trials and we are very hopeful that the company will be filing for licensing approval in CLL in the near future so that we have a product in our hands to be able to offer to our patients.


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