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Evaluating CAR T Therapy in Acute Lymphoblastic Leukemia

Insights From: Max S. Topp, MD, University Hospital of Wuerzburg
Published: Tuesday, Feb 26, 2019



Transcript: 

Max S. Topp, MD: CAR [chimeric antigen receptor] T-cell therapy has become available within Europe now for patients up to the age of 25 and is commercially available in a few selected centers in Central Europe. So it’s being offered to patients in that context. And I think it will also be established as a very valuable option for patients with relapsed/refractory ALL [acute lymphoblastic leukemia] in the age group until about 18, 19, or 20.

The clinical value for patients beyond that age group, anyone beyond 25, is under investigation. The first clinical trial that was published by Jae Park ,MD, in the New England Journal of Medicine to me was quite disappointing because the long-term survival rates for these patients was quite low. And the toxicity of this drug is horrendous because about a third of patients go into ICU [intensive care unit]. There are treatment-related deaths with CAR T-cell therapy, cytokine release syndrome, and neurotoxicity.

So, it was very interesting, although very small data by Jae’s paper. But they took some responders to get a transplant—a sequence of CAR T plus transplant—and compared them to the patients who just got CAR T, and it was even. Small numbers, all the caveats, but … it was a negative trial. So that was quite an eye opener. Yet, that was the first trial that was published with the second generation of CAR T. You learn something from that. You learn how to manage it. There might be smarter ways of managing the toxicity. Maybe better patient selection in that situation. So there are things that are just happening at the moment here, and we have clinical trials in that context.

I think we can improve with CAR T therapy and have better results. But in the long term, I do see the CAR T therapies being only used for patients in relapsed/refractory ALL. I don’t see that CAR T therapy will ever be able to be used for frontline therapy. Whereas blinatumomab, as well as inotuzumab, are both off-the-shelf products, also from their toxicity profiles, that will be included in frontline therapy. So it’s a moving field. What we’re talking about now is very hypothetical. If CAR T therapy will be available as the third line of therapy for relapsed/refractory disease, what is the role of that? Now it actually isn’t there yet; in 5 years we will have the art of the frontline therapy for inotuzumab and blinatumomab, and I’m very sure that those will be integrated in frontline therapy. So it’s a moving field.

I think allotransplantation has its merits. There’s a substantial body of evidence that it can cure patients. Blinatumomab has some evidence that it can, as a single agent, potentially also deliver a cure, only in relapsed/refractory situation, as well as in the MRD [minimal residual disease] situation. But I can see blinatumomab eventually reducing the rate of allotransplants in ALL through using it further in the frontline therapy and being more effective in certain subgroups of patients.

Whereas with CAR T therapy and transplantation, that sequence, I’m very uncertain if that will be the future. It’s economically also a question, because both therapies are quite expensive. It’s to be seen if the health authorities, the agencies, will actually approve a drug or that sequence of those 2 therapies with the trial data that we can present in this situation. It’s an open question. I’m not certain where the journey will take us here. Also there was the hope that CAR T therapy can replace transplant. But looking at the first data that we’ve been seeing, it’s not clear if that’s going to happen.

We are just talking about the simple concepts that we have currently for CAR T cells, the second-generation CAR T cells. There is a whole wave of innovation coming down the road where the T cells are becoming engineered to be switched on and off, to be able to be removed by safety switches, by dual CAR T therapy targeting CD19 or CD22, or both, or other antigens in there. So what I said before was based on the current trial data in the phase II setting with simple versions of CAR T therapy, which is already complicated enough. But the field is moving on to the next generation of CAR T technology.

It will be very interesting to see what that looks like, and it may change how we think about that. It’s a very interesting topic. And not to forget, we are also talking about CAR T therapy being not an off-the-shelf product, but there are initiatives of using off-the-shelf CAR T therapy with third-party T cells, so universal CAR T. And that’s something that as the first trials have gone on the way, it has to be seen how that will have an impact in the field in that context. So there’s a lot of movement there going on, and it will be interesting to have this conversation in 5 years to see how positions might change.

Transcript Edited for Clarity

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Transcript: 

Max S. Topp, MD: CAR [chimeric antigen receptor] T-cell therapy has become available within Europe now for patients up to the age of 25 and is commercially available in a few selected centers in Central Europe. So it’s being offered to patients in that context. And I think it will also be established as a very valuable option for patients with relapsed/refractory ALL [acute lymphoblastic leukemia] in the age group until about 18, 19, or 20.

The clinical value for patients beyond that age group, anyone beyond 25, is under investigation. The first clinical trial that was published by Jae Park ,MD, in the New England Journal of Medicine to me was quite disappointing because the long-term survival rates for these patients was quite low. And the toxicity of this drug is horrendous because about a third of patients go into ICU [intensive care unit]. There are treatment-related deaths with CAR T-cell therapy, cytokine release syndrome, and neurotoxicity.

So, it was very interesting, although very small data by Jae’s paper. But they took some responders to get a transplant—a sequence of CAR T plus transplant—and compared them to the patients who just got CAR T, and it was even. Small numbers, all the caveats, but … it was a negative trial. So that was quite an eye opener. Yet, that was the first trial that was published with the second generation of CAR T. You learn something from that. You learn how to manage it. There might be smarter ways of managing the toxicity. Maybe better patient selection in that situation. So there are things that are just happening at the moment here, and we have clinical trials in that context.

I think we can improve with CAR T therapy and have better results. But in the long term, I do see the CAR T therapies being only used for patients in relapsed/refractory ALL. I don’t see that CAR T therapy will ever be able to be used for frontline therapy. Whereas blinatumomab, as well as inotuzumab, are both off-the-shelf products, also from their toxicity profiles, that will be included in frontline therapy. So it’s a moving field. What we’re talking about now is very hypothetical. If CAR T therapy will be available as the third line of therapy for relapsed/refractory disease, what is the role of that? Now it actually isn’t there yet; in 5 years we will have the art of the frontline therapy for inotuzumab and blinatumomab, and I’m very sure that those will be integrated in frontline therapy. So it’s a moving field.

I think allotransplantation has its merits. There’s a substantial body of evidence that it can cure patients. Blinatumomab has some evidence that it can, as a single agent, potentially also deliver a cure, only in relapsed/refractory situation, as well as in the MRD [minimal residual disease] situation. But I can see blinatumomab eventually reducing the rate of allotransplants in ALL through using it further in the frontline therapy and being more effective in certain subgroups of patients.

Whereas with CAR T therapy and transplantation, that sequence, I’m very uncertain if that will be the future. It’s economically also a question, because both therapies are quite expensive. It’s to be seen if the health authorities, the agencies, will actually approve a drug or that sequence of those 2 therapies with the trial data that we can present in this situation. It’s an open question. I’m not certain where the journey will take us here. Also there was the hope that CAR T therapy can replace transplant. But looking at the first data that we’ve been seeing, it’s not clear if that’s going to happen.

We are just talking about the simple concepts that we have currently for CAR T cells, the second-generation CAR T cells. There is a whole wave of innovation coming down the road where the T cells are becoming engineered to be switched on and off, to be able to be removed by safety switches, by dual CAR T therapy targeting CD19 or CD22, or both, or other antigens in there. So what I said before was based on the current trial data in the phase II setting with simple versions of CAR T therapy, which is already complicated enough. But the field is moving on to the next generation of CAR T technology.

It will be very interesting to see what that looks like, and it may change how we think about that. It’s a very interesting topic. And not to forget, we are also talking about CAR T therapy being not an off-the-shelf product, but there are initiatives of using off-the-shelf CAR T therapy with third-party T cells, so universal CAR T. And that’s something that as the first trials have gone on the way, it has to be seen how that will have an impact in the field in that context. So there’s a lot of movement there going on, and it will be interesting to have this conversation in 5 years to see how positions might change.

Transcript Edited for Clarity
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