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Expanded Use of CAR T Therapy in Hematologic Malignancies

Panelists: David Maloney, MD, PhD, Fred Hutchinson Cancer Research Center; Caron Jacobson, MD, Harvard Medical School; Frederick Locke, MD, Moffitt Cancer Center; Max Topp, MD, University Hospital of Wuerzburg; Jason Westin, MD, The University of Texas MD Anderson Cancer Center
Published: Thursday, Feb 27, 2020



Transcript: 

David Maloney, MD, PhD: One of the complicating factors, let’s assume lisocabtagene maraleucel gets approved. We’re going to have 3 different products. We’ll probably have 3 different REMS [Risk Evaluation and Mitigation Strategy] programs. Up until now, we’ve had multiple different criteria for even calling toxicity. The management is different. We need some consensus. Is there any hope for the future here for consensus?

Max Topp, MD: Well, we’ve got the paper that at least has made the effort of actually coming to a consensus on the grading system. That is really a step in the right direction.

David Maloney, MD, PhD: I don’t believe there’s a consensus on therapy?

Max Topp, MD: No.

Caron Jacobson, MD: There may be one. I think there may be a CARTOX [CAR T-Cell Therapy-Associated Toxicity Working Group] 2.0 that comes to a journal near you.

Frederick Locke, MD: Not only CARTOX 2.0, but several professional societies, including ASTCT [American Society for Transplantation and Cellular Therapy], are working on consensus guidelines. And then SITC [Society for Immunotherapy of Cancer] is also working on consensus guidelines regarding how to treat toxicities with immune effector cell therapies. I think going through those processes, even here at this ASH [American Society of Hematology] meeting and having those meetings, it’s clear that there are going to be areas where the management differs at different centers, and maybe even by the product or the patient—pediatric versus adult, ALL [acute lymphoblastic leukemia] versus lymphoma—but there are some basic tenets that will be out there for people in centers who are new to CAR [chimeric antigen receptor] T-cell therapy to look to.

Caron Jacobson, MD: And then you said they’ll have 3 REMS programs with the presumed FDA approval of lisocabtagene maraleucel. We’re going to have 4, right? Because we’re going to see BCMA [B-cell maturation antigen] CARs.

David Maloney, MD, PhD: But I think the point is, we’re seeing more similarities. We’re seeing a convergence of therapy. At our center anyway, our policy is to try to actually keep people out of the ICU [intensive care unit], to treat them before they get so sick that they end up in the ICU. And that wasn’t always the plan. In some of the earlier clinical trials, we treated people and we were afraid to intervene. So I think we need more data about early intervention. I know there’s an early plan on steroid use that has already been reported a little bit with the axicabtagene ciloleucel, and there are ongoing cohorts that are going to even look at that in an earlier fashion. I think that’s very exciting.

But there are other diseases. Caron, you just mentioned that. What about myeloma? What did you see at this meeting about myeloma?

Caron Jacobson, MD: We’ve seen things that had been published preceding this meeting about myeloma. We’ve seen very high, very good PR [partial response] rates, and CR [complete response] rates, and even MRD [minimal residual disease]-negative CR rates. The durability, historically, with the current products seems to be an issue. The median durability of response or median progression-free survival is around 9 to 11 months, which is a problem for myeloma. And I think that your group presented some data about a way to maybe overcome those relapses?

David Maloney, MD, PhD: The CARs that are in the clinic right now, the bb2121 is a murine construct, so one of the complicating factors is: do the cells persist? Do they get immunologically rejected? We actually have experience with our human CAR against BCMA. We have a couple of trials with that. But at this meeting, one of the more interesting trials was a combination with a gamma secretase inhibitor. It turns out that gamma secretase cleaves BCMA off of the cell surface and is prevalent in serum. And so, you can actually have loss of the BCMA antigen from the surface due to gamma secretase. And if you can block that, the expression of BCMA goes to about 100%.

In an early phase trial, we’re seeing very encouraging results, with high response rates and very few relapses so far. It’s really early, so we can’t claim too much about it, but I know this was a very well received abstract at the meeting, and we are very excited about it. And I know that approach has even been considered in some of the other BCMA-directed treatment options.

Frederick Locke, MD: Yes, I thought the data were really impressive. It’s very early. But to the point of the lack of durability to some of the BCMA CARs and the products that we expect will be FDA approved, I think that also becomes an issue when, if they become approved, at what price will they be? Because you have to look at quality-adjusted life years. If you’re not potentially curing the same degree of patients as we see with lymphoma, then the value of that therapy, overall, may be less. We also know that many of these patients are older to begin with, so I think that’s something we have to keep our eye on as well.

Max Topp, MD: And I think that’s the problem with myeloma. At least with non-Hodgkin lymphoma, we usually have very clear criteria for lines of therapy. Whereas in multiple myeloma, we really have no clear pathway to define what a third-line, fourth-line, or fifth-line patient is. There are just so many ways regarding how to get to that point. And then to make an exact decision of, “OK, we’re going to take the fourth-line patient,” is I find a real challenge to actually come up with guidance on that.

Caron Jacobson, MD: Right. There are some ongoing studies that will hopefully address whether this lack of durability of response may be an issue of lines of therapy. There are some of these randomized trials that are starting to take patients and randomize them in different lines of therapy, and that will hopefully answer that question.

David Maloney, MD, PhD: Obviously consolidative CARs. What if we stop doing autotransplants? What if we use consolidative CARs? I think in the bb2121 trial, the median lines of therapy was 7 or 8. It was really a huge number, so you don’t know what that mutational burden is from all of that prior therapy. I’ve never seen anything look better in terms of inducing a complete remission.

Max Topp, MD: Although I really do see that BCMA-targeted therapy has really exciting data that have been presented at the previous ASH meetings, and this one, too, showing very similar response rates and duration of response being in a similar range. It’s not quite clear how this is going to be sequenced in this context. And also, looking at the toxicity profile that you may get with the bispecifics, this might be even more favorable. It’s an off-the-shelf product, so we just have to see how that will work.

David Maloney, MD, PhD: We’ve also seen other diseases. Do you want to mention mantle cell?

Caron Jacobson, MD: We had discussed this briefly before, but the response rate in mantle cell is even a little bit higher than it is in diffuse large B-cell lymphoma. It’s over 80%, and the CR rate is higher. It’s over 60% in mantle cell lymphoma. Of course this is an early study with limited follow-up at this point, but these responses appear to be durable and they’re durable in the highest-risk mantle cell lymphoma groups. They’re durable on TP53-mutated mantle cell lymphoma. They’re durable in blastoid and pleomorphic variants. They’re durable in patients who have complex karyotype. And so, I think that we’re at a time now where patients are progressing through BTK [Bruton tyrosine kinase] inhibitors. We know the median duration of response of those drugs is only about a year-and-a-half, and they’re saying, “What next?” And I think we’re going to be able to offer those patients something.

Transcript Edited for Clarity

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Transcript: 

David Maloney, MD, PhD: One of the complicating factors, let’s assume lisocabtagene maraleucel gets approved. We’re going to have 3 different products. We’ll probably have 3 different REMS [Risk Evaluation and Mitigation Strategy] programs. Up until now, we’ve had multiple different criteria for even calling toxicity. The management is different. We need some consensus. Is there any hope for the future here for consensus?

Max Topp, MD: Well, we’ve got the paper that at least has made the effort of actually coming to a consensus on the grading system. That is really a step in the right direction.

David Maloney, MD, PhD: I don’t believe there’s a consensus on therapy?

Max Topp, MD: No.

Caron Jacobson, MD: There may be one. I think there may be a CARTOX [CAR T-Cell Therapy-Associated Toxicity Working Group] 2.0 that comes to a journal near you.

Frederick Locke, MD: Not only CARTOX 2.0, but several professional societies, including ASTCT [American Society for Transplantation and Cellular Therapy], are working on consensus guidelines. And then SITC [Society for Immunotherapy of Cancer] is also working on consensus guidelines regarding how to treat toxicities with immune effector cell therapies. I think going through those processes, even here at this ASH [American Society of Hematology] meeting and having those meetings, it’s clear that there are going to be areas where the management differs at different centers, and maybe even by the product or the patient—pediatric versus adult, ALL [acute lymphoblastic leukemia] versus lymphoma—but there are some basic tenets that will be out there for people in centers who are new to CAR [chimeric antigen receptor] T-cell therapy to look to.

Caron Jacobson, MD: And then you said they’ll have 3 REMS programs with the presumed FDA approval of lisocabtagene maraleucel. We’re going to have 4, right? Because we’re going to see BCMA [B-cell maturation antigen] CARs.

David Maloney, MD, PhD: But I think the point is, we’re seeing more similarities. We’re seeing a convergence of therapy. At our center anyway, our policy is to try to actually keep people out of the ICU [intensive care unit], to treat them before they get so sick that they end up in the ICU. And that wasn’t always the plan. In some of the earlier clinical trials, we treated people and we were afraid to intervene. So I think we need more data about early intervention. I know there’s an early plan on steroid use that has already been reported a little bit with the axicabtagene ciloleucel, and there are ongoing cohorts that are going to even look at that in an earlier fashion. I think that’s very exciting.

But there are other diseases. Caron, you just mentioned that. What about myeloma? What did you see at this meeting about myeloma?

Caron Jacobson, MD: We’ve seen things that had been published preceding this meeting about myeloma. We’ve seen very high, very good PR [partial response] rates, and CR [complete response] rates, and even MRD [minimal residual disease]-negative CR rates. The durability, historically, with the current products seems to be an issue. The median durability of response or median progression-free survival is around 9 to 11 months, which is a problem for myeloma. And I think that your group presented some data about a way to maybe overcome those relapses?

David Maloney, MD, PhD: The CARs that are in the clinic right now, the bb2121 is a murine construct, so one of the complicating factors is: do the cells persist? Do they get immunologically rejected? We actually have experience with our human CAR against BCMA. We have a couple of trials with that. But at this meeting, one of the more interesting trials was a combination with a gamma secretase inhibitor. It turns out that gamma secretase cleaves BCMA off of the cell surface and is prevalent in serum. And so, you can actually have loss of the BCMA antigen from the surface due to gamma secretase. And if you can block that, the expression of BCMA goes to about 100%.

In an early phase trial, we’re seeing very encouraging results, with high response rates and very few relapses so far. It’s really early, so we can’t claim too much about it, but I know this was a very well received abstract at the meeting, and we are very excited about it. And I know that approach has even been considered in some of the other BCMA-directed treatment options.

Frederick Locke, MD: Yes, I thought the data were really impressive. It’s very early. But to the point of the lack of durability to some of the BCMA CARs and the products that we expect will be FDA approved, I think that also becomes an issue when, if they become approved, at what price will they be? Because you have to look at quality-adjusted life years. If you’re not potentially curing the same degree of patients as we see with lymphoma, then the value of that therapy, overall, may be less. We also know that many of these patients are older to begin with, so I think that’s something we have to keep our eye on as well.

Max Topp, MD: And I think that’s the problem with myeloma. At least with non-Hodgkin lymphoma, we usually have very clear criteria for lines of therapy. Whereas in multiple myeloma, we really have no clear pathway to define what a third-line, fourth-line, or fifth-line patient is. There are just so many ways regarding how to get to that point. And then to make an exact decision of, “OK, we’re going to take the fourth-line patient,” is I find a real challenge to actually come up with guidance on that.

Caron Jacobson, MD: Right. There are some ongoing studies that will hopefully address whether this lack of durability of response may be an issue of lines of therapy. There are some of these randomized trials that are starting to take patients and randomize them in different lines of therapy, and that will hopefully answer that question.

David Maloney, MD, PhD: Obviously consolidative CARs. What if we stop doing autotransplants? What if we use consolidative CARs? I think in the bb2121 trial, the median lines of therapy was 7 or 8. It was really a huge number, so you don’t know what that mutational burden is from all of that prior therapy. I’ve never seen anything look better in terms of inducing a complete remission.

Max Topp, MD: Although I really do see that BCMA-targeted therapy has really exciting data that have been presented at the previous ASH meetings, and this one, too, showing very similar response rates and duration of response being in a similar range. It’s not quite clear how this is going to be sequenced in this context. And also, looking at the toxicity profile that you may get with the bispecifics, this might be even more favorable. It’s an off-the-shelf product, so we just have to see how that will work.

David Maloney, MD, PhD: We’ve also seen other diseases. Do you want to mention mantle cell?

Caron Jacobson, MD: We had discussed this briefly before, but the response rate in mantle cell is even a little bit higher than it is in diffuse large B-cell lymphoma. It’s over 80%, and the CR rate is higher. It’s over 60% in mantle cell lymphoma. Of course this is an early study with limited follow-up at this point, but these responses appear to be durable and they’re durable in the highest-risk mantle cell lymphoma groups. They’re durable on TP53-mutated mantle cell lymphoma. They’re durable in blastoid and pleomorphic variants. They’re durable in patients who have complex karyotype. And so, I think that we’re at a time now where patients are progressing through BTK [Bruton tyrosine kinase] inhibitors. We know the median duration of response of those drugs is only about a year-and-a-half, and they’re saying, “What next?” And I think we’re going to be able to offer those patients something.

Transcript Edited for Clarity
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