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CAR T: Dominant Therapy for B-Cell ALL

Panelists: Mark R. Litzow, MD, The Mayo Clinic; Jae Park, MD, Memorial Sloan Kettering Cancer Center; Bijal Shah, MD H. Lee Moffitt Cancer Center & Research Institute; Anthony Stein Gehr Family Center for Leukemia Research
Published: Friday, Feb 22, 2019



Transcript:

Mark R. Litzow, MD:
Jae, we’ve got to talk a little bit about CAR T-cell therapy. We sort of alluded to it, but it’s really emerging as a dominant form of therapy in B-cell ALL. Can you give us your perspective on short-term, long-term outcomes—kind of where you see it fitting in?

Jae Park, MD: For right now, in CD19-targeted CAR T-cell therapy…, [in] which we have the most advanced data now…, there are several clinical trials that [are] ongoing. But we also have approved product for patients in children up to the age of 25, pediatric patients and young adults up to the age of 25 in the relapsed, the…positive B[-cell] ALL. Now we have a new product, tisagenlecleucel, for those [in the] otheratient population. And then there [are] ongoing adult and several completed and ongoing [adult] clinical [trials] targeting same antigen, CD19, in CAR T cells. There are many different variations in the construct in itself and which costimulatory domain they’re using. Most of these T cells are derived from the patient themselves, whether they have prior transplant or not.

In the data that we’re getting…are very consistent results of a high complete response [CR] rate and most of which are MRD-negative, very deep response…. which is [upward] in close to 80%. Seventy [percent] to 80% is now [the] expected CR rate after CAR T-cells, regardless of disease burden that you’re starting, which is highly encouraging. Having said that, not all of these patients are remaining at 80%—so, meaning that there are some relapses that do happen, and these are mostly early relapses that we do see. Usually the first 6 to 8 months is where the majority of the relapses do happen.

The pattern of relapses also differ, too, meaning the CD19-positive relapse or that relapses with CD19 undetectable were lost. These are different based on different constructs. So the construct that’s associated with a longer persistence, 4-1BB containing ones, such as the tisagenlecleucel… Those patients tend to relapse more with the antigen loss or antigen undetectability by flow, CD19 negative.…About 60% of their relapses will be CD19 negative versus [the] majority of the relapses [that] will be CD19-positive with the 19-28-zeta CAR T-cells that [are] also being investigated in clinical trials.

[Although] the relapse pattern may be different, the relapse rate is usually about the same. So 40[%] to 50% of these patients will relapse after achieving very high response. So it was encouraging as the very high response for these patients. Again, keep in mind that these are tried, and they’re used in the third-line setting after they have failed kind of all the therapies that we have previously discussed. Despite the fact that we’re able to get a high response rate[, which] is where we got all the excitement, and it’s how the therapy got approved, I think there is clearly room for improvement. It’s hard to improve the initial efficacy being above 80%. I wouldn’t think it’s not impossible. We are still striving for that, but really the better way that we can improve is [by] reducing the relapse rate, whether there is antigen retention or not, and then the toxicity, which is really the major obstacle for adult ALL patients.

The CAR T-cell therapy [is] investigated in the DLBCL [diffuse large B-cell lymphoma] and other diseases, too, and the patient population again and again [in which] we see the most CRS [cytokine release syndrome] and the neurotoxicity is really adult ALL. We’re trying to understand why that may be the case—why this patient population compared [with] pediatric ALL and the CLL and the Hodgkin lymphoma patients? So there are ways to kind of improve upon the current efficacy. So, right now, even though it’s in the relapsed setting in the third line, the second line or third line, we’re really hoping to move this therapy earlier.

And I believe that this type of immunotherapy will work better in earlier lines of a setting. We still have to think about the toxicity when we start to move these things earlier. What are the patient [populations]? Can we really predict what…patient populations [are] going to get high toxicity? At least in ALL, it really correlates very well with disease burden and the T-cell dose. So these are some of the modification factors that we can make in terms of T-cell disease. And the disease burden is a little bit hard. I think we’re all trying to reduce the disease burden before the CAR T-cell infusion. Sometimes we are successful, but if they are really refractory to third lines of a setting, it is very hard to get somebody down from a 70% blast to kind of 20%. There’s 1 other reason to moving the therapy earlier before they become really refractory to all the lines of a therapy, so…adult ALL patients. If we can actually get the disease burden lower, we can safely administer this type of therapy and get better outcomes.

So I think our data [show] that in the patients that get low disease burden, they get not only low toxicity, but these [also] are the patients who actually do better long-term even without the transplanted subset of the patients. So I think for all these reasons we talked about…, there’s a lot of incentive and the strong rationale to move this therapy earlier lines of setting. I think when we do, hopefully, we can make it safer for adult ALL patients and get the product approved and available for wide patients.

Bijal D. Shah, MD: Do you think the changes in management will improve some of the toxicity profile we’re seeing?

Jae Park, MD: Yep, absolutely. I think we’re already seeing that, and I think in the CAR T-cell trials in the report that we’re going to see that we’re going to see less of grade 3 and 4 toxicity, the CRS at least, and, hopefully…, less neurotoxicity, as well, because we’re intervening a little bit earlier. As we get more data that these agents don’t interfere too much or at all with kind of T-cell activity, at least with the tocilizumab and the short doses duration of a steroid, I think all of us now feel more comfortable intervening, really. It’s not truly prophylactic yet, but…the early intervention is preventing kind of severe toxicity that will make things a little bit easier, certainly easier to manage.

Mark R. Litzow, MD: Do you think we’ll get the prophylactic where if somebody has a high disease burden, you’re pretty sure they’re going to get into big trouble?

Jae Park, MD: Yeah…, these are the next steps I think they definitely are working on. I think several groups are looking at many different approaches of a true prophylaxis, like before [patients] get even fevers, where early sign of fever is already being investigated. But, even before they get fevers, with the T-cells, can you administer some other therapy? And there are many others that people are looking at and to see whether we can [take a] prophylactic [approach].

Bijal D. Shah, MD: Exactly. I’m not sure that we need to “prophylax” CRS in the majority of cases, meaning it seems like that’s been manageable for most patients. But the neurotoxicity is the thing that we really are trying to figure out how to get a better grasp on. So does it make sense to intervene early? And, again, there [are] fascinating data that came out of [Memorial] Sloan Kettering [Cancer Center] looking at anakinra as an IL-1 receptor antibody that may mitigate the neurotoxicity. And so the question is, is there a time point where we can think about administering that? Again, maybe we use some of these [features]—disease burden, the timing of onset of CRS, something along these lines to guide some of that decision making, so that we can improve the overall toxicity profile.

Jae Park, MD: It has to be done in the clinical trial setting, of course.

Bijal D. Shah, MD: Exactly.

Jae Park, MD: Because the 1 thing that we want to make sure is that it’s not interfering with an activity. We want to ideally maintain the activity, antitumor efficacy of these CAR T-cells while minimizing toxicity—[that] is kind of where we want to head. So I think it has to be done in a controlled setting after looking at them. But, absolutely, there’s very strong rationale to looking at IL-1 along with the other cytokines, perhaps to see whether the preventative approach will be there. I think the neurotoxicity…really the big thing in adult ALL patients—that the fever here and there is tolerable.

Bijal D. Shah, MD: For most patients.

Jae Park, MD: For most patients. If we can prevent that even, even better, to get away without any fever, then it would be even ideal. But the neurotoxicity, I 100% agree, that’s kind of the 1 area that we need to improve.

Bijal D. Shah, MD: Now I’m going to be a little bit difficult.

Anthony S. Stein, MD: So, is there any difference between the toxicity profile between if you’re using a CD28 versus 4-1BB?

Jae Park, MD: Yeah, I think that’s a good question, too. I think the cellular kinetics of these 2 products [is] different, and we do know the faster cell expansion tends to get more toxicity, because you just get there fast and [get] more inflammation in a very short amount of time. Adult ALL, kind of when you look at all the data together, [there is] not a substantial difference between the 1928 and the 4-1BB—at least the initial toxicity with the CRS and neurotoxicity, which is really acute. It’s really the first 2 weeks of an infusion where patients experience the CRS and neurotoxicity. 4-1BB—perhaps it may be a little bit less, but it doesn’t appear to be a substantial difference, which is different in lymphoma…the data. There may be a difference in the lymphoma between these 2 compounds. [With] adult ALL, regardless of what we use, [patients] tend to get the toxicity. So I think [there] may be [a] slightly better but not a substantial difference between those 2.

Bijal D. Shah, MD: It may even go beyond that. If there are differences in the hinge region; there are other differences in the construct that may actually influence us.

Jae Park, MD: I think the 1 thing to realize is, as you pointed out, there are so many moving components for the cells, and it’s not just the construct in itself in how you insert them, how you manufacture the cells. What you put into the cells are very different, and [so is] what kind of cells are you infusing, just because the construct is saying you can change so many different factors in between, can make a huge difference kind of after the post infusion. And what happens once the cells go into the patients and the expansion [decreases are] also variable.

Bijal D. Shah, MD: Absolutely.

Transcript edited for clarity.

 

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Transcript:

Mark R. Litzow, MD:
Jae, we’ve got to talk a little bit about CAR T-cell therapy. We sort of alluded to it, but it’s really emerging as a dominant form of therapy in B-cell ALL. Can you give us your perspective on short-term, long-term outcomes—kind of where you see it fitting in?

Jae Park, MD: For right now, in CD19-targeted CAR T-cell therapy…, [in] which we have the most advanced data now…, there are several clinical trials that [are] ongoing. But we also have approved product for patients in children up to the age of 25, pediatric patients and young adults up to the age of 25 in the relapsed, the…positive B[-cell] ALL. Now we have a new product, tisagenlecleucel, for those [in the] otheratient population. And then there [are] ongoing adult and several completed and ongoing [adult] clinical [trials] targeting same antigen, CD19, in CAR T cells. There are many different variations in the construct in itself and which costimulatory domain they’re using. Most of these T cells are derived from the patient themselves, whether they have prior transplant or not.

In the data that we’re getting…are very consistent results of a high complete response [CR] rate and most of which are MRD-negative, very deep response…. which is [upward] in close to 80%. Seventy [percent] to 80% is now [the] expected CR rate after CAR T-cells, regardless of disease burden that you’re starting, which is highly encouraging. Having said that, not all of these patients are remaining at 80%—so, meaning that there are some relapses that do happen, and these are mostly early relapses that we do see. Usually the first 6 to 8 months is where the majority of the relapses do happen.

The pattern of relapses also differ, too, meaning the CD19-positive relapse or that relapses with CD19 undetectable were lost. These are different based on different constructs. So the construct that’s associated with a longer persistence, 4-1BB containing ones, such as the tisagenlecleucel… Those patients tend to relapse more with the antigen loss or antigen undetectability by flow, CD19 negative.…About 60% of their relapses will be CD19 negative versus [the] majority of the relapses [that] will be CD19-positive with the 19-28-zeta CAR T-cells that [are] also being investigated in clinical trials.

[Although] the relapse pattern may be different, the relapse rate is usually about the same. So 40[%] to 50% of these patients will relapse after achieving very high response. So it was encouraging as the very high response for these patients. Again, keep in mind that these are tried, and they’re used in the third-line setting after they have failed kind of all the therapies that we have previously discussed. Despite the fact that we’re able to get a high response rate[, which] is where we got all the excitement, and it’s how the therapy got approved, I think there is clearly room for improvement. It’s hard to improve the initial efficacy being above 80%. I wouldn’t think it’s not impossible. We are still striving for that, but really the better way that we can improve is [by] reducing the relapse rate, whether there is antigen retention or not, and then the toxicity, which is really the major obstacle for adult ALL patients.

The CAR T-cell therapy [is] investigated in the DLBCL [diffuse large B-cell lymphoma] and other diseases, too, and the patient population again and again [in which] we see the most CRS [cytokine release syndrome] and the neurotoxicity is really adult ALL. We’re trying to understand why that may be the case—why this patient population compared [with] pediatric ALL and the CLL and the Hodgkin lymphoma patients? So there are ways to kind of improve upon the current efficacy. So, right now, even though it’s in the relapsed setting in the third line, the second line or third line, we’re really hoping to move this therapy earlier.

And I believe that this type of immunotherapy will work better in earlier lines of a setting. We still have to think about the toxicity when we start to move these things earlier. What are the patient [populations]? Can we really predict what…patient populations [are] going to get high toxicity? At least in ALL, it really correlates very well with disease burden and the T-cell dose. So these are some of the modification factors that we can make in terms of T-cell disease. And the disease burden is a little bit hard. I think we’re all trying to reduce the disease burden before the CAR T-cell infusion. Sometimes we are successful, but if they are really refractory to third lines of a setting, it is very hard to get somebody down from a 70% blast to kind of 20%. There’s 1 other reason to moving the therapy earlier before they become really refractory to all the lines of a therapy, so…adult ALL patients. If we can actually get the disease burden lower, we can safely administer this type of therapy and get better outcomes.

So I think our data [show] that in the patients that get low disease burden, they get not only low toxicity, but these [also] are the patients who actually do better long-term even without the transplanted subset of the patients. So I think for all these reasons we talked about…, there’s a lot of incentive and the strong rationale to move this therapy earlier lines of setting. I think when we do, hopefully, we can make it safer for adult ALL patients and get the product approved and available for wide patients.

Bijal D. Shah, MD: Do you think the changes in management will improve some of the toxicity profile we’re seeing?

Jae Park, MD: Yep, absolutely. I think we’re already seeing that, and I think in the CAR T-cell trials in the report that we’re going to see that we’re going to see less of grade 3 and 4 toxicity, the CRS at least, and, hopefully…, less neurotoxicity, as well, because we’re intervening a little bit earlier. As we get more data that these agents don’t interfere too much or at all with kind of T-cell activity, at least with the tocilizumab and the short doses duration of a steroid, I think all of us now feel more comfortable intervening, really. It’s not truly prophylactic yet, but…the early intervention is preventing kind of severe toxicity that will make things a little bit easier, certainly easier to manage.

Mark R. Litzow, MD: Do you think we’ll get the prophylactic where if somebody has a high disease burden, you’re pretty sure they’re going to get into big trouble?

Jae Park, MD: Yeah…, these are the next steps I think they definitely are working on. I think several groups are looking at many different approaches of a true prophylaxis, like before [patients] get even fevers, where early sign of fever is already being investigated. But, even before they get fevers, with the T-cells, can you administer some other therapy? And there are many others that people are looking at and to see whether we can [take a] prophylactic [approach].

Bijal D. Shah, MD: Exactly. I’m not sure that we need to “prophylax” CRS in the majority of cases, meaning it seems like that’s been manageable for most patients. But the neurotoxicity is the thing that we really are trying to figure out how to get a better grasp on. So does it make sense to intervene early? And, again, there [are] fascinating data that came out of [Memorial] Sloan Kettering [Cancer Center] looking at anakinra as an IL-1 receptor antibody that may mitigate the neurotoxicity. And so the question is, is there a time point where we can think about administering that? Again, maybe we use some of these [features]—disease burden, the timing of onset of CRS, something along these lines to guide some of that decision making, so that we can improve the overall toxicity profile.

Jae Park, MD: It has to be done in the clinical trial setting, of course.

Bijal D. Shah, MD: Exactly.

Jae Park, MD: Because the 1 thing that we want to make sure is that it’s not interfering with an activity. We want to ideally maintain the activity, antitumor efficacy of these CAR T-cells while minimizing toxicity—[that] is kind of where we want to head. So I think it has to be done in a controlled setting after looking at them. But, absolutely, there’s very strong rationale to looking at IL-1 along with the other cytokines, perhaps to see whether the preventative approach will be there. I think the neurotoxicity…really the big thing in adult ALL patients—that the fever here and there is tolerable.

Bijal D. Shah, MD: For most patients.

Jae Park, MD: For most patients. If we can prevent that even, even better, to get away without any fever, then it would be even ideal. But the neurotoxicity, I 100% agree, that’s kind of the 1 area that we need to improve.

Bijal D. Shah, MD: Now I’m going to be a little bit difficult.

Anthony S. Stein, MD: So, is there any difference between the toxicity profile between if you’re using a CD28 versus 4-1BB?

Jae Park, MD: Yeah, I think that’s a good question, too. I think the cellular kinetics of these 2 products [is] different, and we do know the faster cell expansion tends to get more toxicity, because you just get there fast and [get] more inflammation in a very short amount of time. Adult ALL, kind of when you look at all the data together, [there is] not a substantial difference between the 1928 and the 4-1BB—at least the initial toxicity with the CRS and neurotoxicity, which is really acute. It’s really the first 2 weeks of an infusion where patients experience the CRS and neurotoxicity. 4-1BB—perhaps it may be a little bit less, but it doesn’t appear to be a substantial difference, which is different in lymphoma…the data. There may be a difference in the lymphoma between these 2 compounds. [With] adult ALL, regardless of what we use, [patients] tend to get the toxicity. So I think [there] may be [a] slightly better but not a substantial difference between those 2.

Bijal D. Shah, MD: It may even go beyond that. If there are differences in the hinge region; there are other differences in the construct that may actually influence us.

Jae Park, MD: I think the 1 thing to realize is, as you pointed out, there are so many moving components for the cells, and it’s not just the construct in itself in how you insert them, how you manufacture the cells. What you put into the cells are very different, and [so is] what kind of cells are you infusing, just because the construct is saying you can change so many different factors in between, can make a huge difference kind of after the post infusion. And what happens once the cells go into the patients and the expansion [decreases are] also variable.

Bijal D. Shah, MD: Absolutely.

Transcript edited for clarity.

 
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