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CAR T-Cell Therapy: Understanding Indicators of Response

Panelists: David Maloney, MD, PhD, Fred Hutchinson Cancer Research Center; Nilanjan Ghosh, MD, PhD, Levine Cancer Institute/Atrium Health; Leo I. Gordon, MD, FACP, Robert H. Lurie Comprehensive Cancer Center; Matthew Lunning, DO, University of Nebraska Medical Center; Michael Pulsipher, MD Children
Published: Wednesday, Jan 30, 2019



Transcript: 

David Maloney, MD, PhD: One of the key issues is trying to predict who’s going to respond to this therapy or who’s going to have toxicity. What do we know? Do we have any indicators on who’s going to respond to this type of therapy?

Nilanjan Ghosh, MD, PhD: I think one of the things that came across both in the real-world experience and some of the studies is patients with high tumor bulk have a lesser chance—not zero chance, but lesser chance—to have long-term durability responses. That translates to patients who have a little bit of a small volume disease may be better responders than patients who have tremendous tumor bulk, even though those people might have an immediate response, but they may not persist.

Michael Pulsipher, MD: Interestingly, on the ALL [acute lymphoblastic leukemia] side it’s a little bit different, aside from the recent study in older adults, which tended to have better response in lower disease. All the rest of the studies there have shown no indication that disease volume matters for response. High, low, in between, they all seem to respond about the same. But, it’s clear that high volume disease in ALL leads to a lot more CRS [cytokine release syndrome] and potentially, high grades of CRS lead to more neurotoxicities.

Leo I. Gordon, MD, FACP: Is there a difference between measuring volume of disease in marrow, peripheral blood versus say nodal disease, are there differences there at all?

Michael Pulsipher, MD: So far the only thing that has been measured is marrow disease. People haven’t commented on circulating peripheral blasts, etcetera. The only thing that really has been measured is marrow disease, and the higher the percentage the better, with a clear increase if you’re above 50% blast.

David Maloney, MD, PhD: But I think it’s clear that all of us have seen at our own institutions in large cell lymphomas patients these dramatic responses. You see a PET [positron emission tomography] scan and you just gasp and shake your head. You think this is hopeless and then it’s gone, and they go into remission. And so when you see that it’s incredibly gratifying. I agree with it, maybe the response rate’s not going to be as high in these horrible cases, but is that a criteria that we should say we shouldn’t treat those patients? I don’t really see that; I think we can maybe use it as a prognostic marker to say, look I’m nervous, this is going to lead to a high incidence of CRS neurotoxicity, but compared to anything else, your life expectancy is measured in weeks here in this setting.

Michael Pulsipher, MD: I think you have to have the conversation that it may be harder, but it doesn’t mean don’t do it.

Leo I. Gordon, MD, FACP: But you shouldn’t exclude it.

Michael Pulsipher, MD: Let me ask, when I’ve had bulky lymphoma, I’ve asked this question over and over again. You get a response, but maybe it’s not 100% response. Do you then take them to allotransplant?

David Maloney, MD, PhD: Well I think that we need more follow-up. I think in all 3 products there is a big drop off between the 1-month response and the 3-month response. We feel more comfortable if you get out around 3 to 6 months that this is going to be a durable remission. In those 1 to 3 months, I think you’re thinking, well this is good so far, but we’re going to have to see. So I think other options are in there. In our institution an allogeneic stem cell transplant for someone not in a complete remission with a diffuse large B-cell lymphoma pretty much doesn’t work.

Michael Pulsipher, MD: That’s what our experience has been.

David Maloney, MD, PhD: I think that it’s really controversial about what you do, because the one thing the allotransplant does for sure is get rid of the CAR T cells because you’re going to eliminate the host hematopoiesis, which is the CAR. Now what I would love to do, personally, and this is kind of farfetched, is actually add CARs to an allotransplant to provide the graft-versus-tumor effect as it were, if you could figure out how to do a very safe allotransplant. And I think that’s going to happen potentially in the near future.

Leo I. Gordon, MD, FACP: This discussion begs 2 questions. One is if the initial PET scan in lymphoma patients, day 30, is a good partial remission [PR]. How often might you see that progress to a complete remission [CR] or improved to complete remission on day 60 or day 90? And then the second question is, if that doesn’t happen, can you reinfuse cells? Those are the questions I think that are important.

Matthew Lunning, DO: But I think we have to be very careful with those day-29 PET scans. Because there are a lot of interesting things that you see in PET scans, which as we all know are very sensitive but not very specific. And so telling somebody that they’re progressing I think still needs confirmation.

Leo I. Gordon, MD, FACP: The false-positives.

Matthew Lunning, DO: False-positive PET scans.

Michael Pulsipher, MD: Right. When do you say pseudo progression, because of edema?

Matthew Lunning, DO: Right, exactly.

Nilanjan Ghosh, MD, PhD: T-cell infiltration.

Matthew Lunning, DO: Right, T-cell infiltration.

Nilanjan Ghosh, MD, PhD: But we have seen that in the patients who are PR, the median duration of response is in the order of 2 to 3 months probably. But in addition to that, we have seen patients who have been in PR, a fraction of them do convert to CR. So I think we can tease that out, sometimes maybe by a biopsy, if it’s accessible enough.

David Maloney, MD, PhD: Actually, it’s very difficult to interpret these clinical trials. Because those are usually as best response. So if your best response is a PR, you’ll do terribly, OK? But it doesn’t matter if you started as a PR, if you can eventually get into a CR. But there were a lot of CRs that still relapsed. And so those initial CRs at 1 month are a bit dicey until you get to 3 to 6. And so I think that’s where we’re going to need to see longer follow-up.

Nilanjan Ghosh, MD, PhD: I wonder if T-cell health at the time of collection of cells….

Michael Pulsipher, MD: This is where duration may be important. Looking at those patients who have a PR and maybe getting a little bit close to a CR, if there are no CAR T cells around, are they going to make it? I don’t know.

Leo I. Gordon, MD, FACP: The question of T-cell health actually brought up a thought that we’ve had for a while and no one I think has done these studies yet, and that is adding something like a PD-1 [programmed cell death protein 1] inhibitor, not at the time of infusion but the time of collection of the cells, to increase the central memory population of T cells that you’re trying to collect.

Michael Pulsipher, MD: People are trying to study that.

Leo I. Gordon, MD, FACP: OK.

Michael Pulsipher, MD:  And what we hope is that occurs, because there was a nice publication from the Penn [University of Pennsylvania] group showing a particular profile that led to durability of response in their lymphoma patients. So they have their little group of cells that lead to that, but the question is, can you engineer T cells to get to that point and then take them through a process of manufacture and not lose that phenotype? And that’s going to be a real challenge, but it’s what we should be doing.

Transcript Edited for Clarity 

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Transcript: 

David Maloney, MD, PhD: One of the key issues is trying to predict who’s going to respond to this therapy or who’s going to have toxicity. What do we know? Do we have any indicators on who’s going to respond to this type of therapy?

Nilanjan Ghosh, MD, PhD: I think one of the things that came across both in the real-world experience and some of the studies is patients with high tumor bulk have a lesser chance—not zero chance, but lesser chance—to have long-term durability responses. That translates to patients who have a little bit of a small volume disease may be better responders than patients who have tremendous tumor bulk, even though those people might have an immediate response, but they may not persist.

Michael Pulsipher, MD: Interestingly, on the ALL [acute lymphoblastic leukemia] side it’s a little bit different, aside from the recent study in older adults, which tended to have better response in lower disease. All the rest of the studies there have shown no indication that disease volume matters for response. High, low, in between, they all seem to respond about the same. But, it’s clear that high volume disease in ALL leads to a lot more CRS [cytokine release syndrome] and potentially, high grades of CRS lead to more neurotoxicities.

Leo I. Gordon, MD, FACP: Is there a difference between measuring volume of disease in marrow, peripheral blood versus say nodal disease, are there differences there at all?

Michael Pulsipher, MD: So far the only thing that has been measured is marrow disease. People haven’t commented on circulating peripheral blasts, etcetera. The only thing that really has been measured is marrow disease, and the higher the percentage the better, with a clear increase if you’re above 50% blast.

David Maloney, MD, PhD: But I think it’s clear that all of us have seen at our own institutions in large cell lymphomas patients these dramatic responses. You see a PET [positron emission tomography] scan and you just gasp and shake your head. You think this is hopeless and then it’s gone, and they go into remission. And so when you see that it’s incredibly gratifying. I agree with it, maybe the response rate’s not going to be as high in these horrible cases, but is that a criteria that we should say we shouldn’t treat those patients? I don’t really see that; I think we can maybe use it as a prognostic marker to say, look I’m nervous, this is going to lead to a high incidence of CRS neurotoxicity, but compared to anything else, your life expectancy is measured in weeks here in this setting.

Michael Pulsipher, MD: I think you have to have the conversation that it may be harder, but it doesn’t mean don’t do it.

Leo I. Gordon, MD, FACP: But you shouldn’t exclude it.

Michael Pulsipher, MD: Let me ask, when I’ve had bulky lymphoma, I’ve asked this question over and over again. You get a response, but maybe it’s not 100% response. Do you then take them to allotransplant?

David Maloney, MD, PhD: Well I think that we need more follow-up. I think in all 3 products there is a big drop off between the 1-month response and the 3-month response. We feel more comfortable if you get out around 3 to 6 months that this is going to be a durable remission. In those 1 to 3 months, I think you’re thinking, well this is good so far, but we’re going to have to see. So I think other options are in there. In our institution an allogeneic stem cell transplant for someone not in a complete remission with a diffuse large B-cell lymphoma pretty much doesn’t work.

Michael Pulsipher, MD: That’s what our experience has been.

David Maloney, MD, PhD: I think that it’s really controversial about what you do, because the one thing the allotransplant does for sure is get rid of the CAR T cells because you’re going to eliminate the host hematopoiesis, which is the CAR. Now what I would love to do, personally, and this is kind of farfetched, is actually add CARs to an allotransplant to provide the graft-versus-tumor effect as it were, if you could figure out how to do a very safe allotransplant. And I think that’s going to happen potentially in the near future.

Leo I. Gordon, MD, FACP: This discussion begs 2 questions. One is if the initial PET scan in lymphoma patients, day 30, is a good partial remission [PR]. How often might you see that progress to a complete remission [CR] or improved to complete remission on day 60 or day 90? And then the second question is, if that doesn’t happen, can you reinfuse cells? Those are the questions I think that are important.

Matthew Lunning, DO: But I think we have to be very careful with those day-29 PET scans. Because there are a lot of interesting things that you see in PET scans, which as we all know are very sensitive but not very specific. And so telling somebody that they’re progressing I think still needs confirmation.

Leo I. Gordon, MD, FACP: The false-positives.

Matthew Lunning, DO: False-positive PET scans.

Michael Pulsipher, MD: Right. When do you say pseudo progression, because of edema?

Matthew Lunning, DO: Right, exactly.

Nilanjan Ghosh, MD, PhD: T-cell infiltration.

Matthew Lunning, DO: Right, T-cell infiltration.

Nilanjan Ghosh, MD, PhD: But we have seen that in the patients who are PR, the median duration of response is in the order of 2 to 3 months probably. But in addition to that, we have seen patients who have been in PR, a fraction of them do convert to CR. So I think we can tease that out, sometimes maybe by a biopsy, if it’s accessible enough.

David Maloney, MD, PhD: Actually, it’s very difficult to interpret these clinical trials. Because those are usually as best response. So if your best response is a PR, you’ll do terribly, OK? But it doesn’t matter if you started as a PR, if you can eventually get into a CR. But there were a lot of CRs that still relapsed. And so those initial CRs at 1 month are a bit dicey until you get to 3 to 6. And so I think that’s where we’re going to need to see longer follow-up.

Nilanjan Ghosh, MD, PhD: I wonder if T-cell health at the time of collection of cells….

Michael Pulsipher, MD: This is where duration may be important. Looking at those patients who have a PR and maybe getting a little bit close to a CR, if there are no CAR T cells around, are they going to make it? I don’t know.

Leo I. Gordon, MD, FACP: The question of T-cell health actually brought up a thought that we’ve had for a while and no one I think has done these studies yet, and that is adding something like a PD-1 [programmed cell death protein 1] inhibitor, not at the time of infusion but the time of collection of the cells, to increase the central memory population of T cells that you’re trying to collect.

Michael Pulsipher, MD: People are trying to study that.

Leo I. Gordon, MD, FACP: OK.

Michael Pulsipher, MD:  And what we hope is that occurs, because there was a nice publication from the Penn [University of Pennsylvania] group showing a particular profile that led to durability of response in their lymphoma patients. So they have their little group of cells that lead to that, but the question is, can you engineer T cells to get to that point and then take them through a process of manufacture and not lose that phenotype? And that’s going to be a real challenge, but it’s what we should be doing.

Transcript Edited for Clarity 
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