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Potential for CAR T-Cell Therapy for R/R AML

Panelists: Krishna V. Komanduri, MD, Sylvester Comprehensive Cancer Center; David Maloney, MD, PhD, Fred Hutchinson Cancer Research Center; Sattva S. Neelapu, MD, University of Texas MD Anderson Cancer Center; Michael Pulsipher, MD, Children
Published: Monday, Mar 05, 2018



Transcript: 

Krishna V. Komanduri, MD: Let’s talk a little bit about something completely different. We’ve been talking about lymphoid and plasma cell malignancies. What about AML? It’s obvious to say that there are some unique challenges with AML because when you make AML, stems cells go away. What happens when you have an allogeneic transplant? There are some interesting data looking at CD123. You want to talk about that, Michael?

Michael Pulsipher, MD: I think the most important thing to say about that data is that it’s really too early to talk much about it. I think that AML has a tremendous need. In spite of our very best efforts with transplantation and intensive therapies, we still lose half the patients with AML. So, there’s a tremendous need for constructs. We all know that CARs should work, but we have to find the right targets. CD123 is a promising target. Some activity has been shown. There are a few studies that are open with small numbers of patients. People are working on CD33, and there are other antigens that are kind of in the wings. I think that we don’t have enough to say about AML right now, but we have a big need. And my hope is that within the next 2 years, we start seeing some real data in AML.

But the one thing to mention is what you’re saying. AML is going to be a different approach because we anticipate we’re going to destroy the marrow with most approaches and, therefore, a transplant will be an obligate part of that. And the thing you don’t want to do is do an intensive transplant in the middle of cytokine release syndrome. We have to find a way to get these patients through their early toxicities, get them stable, and then replace their marrow.

Krishna V. Komanduri, MD: There are other antigens in AML that are what we call “overexpressed autoantigens” like, for example, WT-1. You want to talk about that? And that’s not a target typical of the CAR.

David Maloney, MD: This is a different approach. WT-1 is an internal antigen, so it’s not expressed on the cell surface. You can’t really target it with a typical CAR against an antigen. So, there you have to actually do a TCR-transduced cell. We have some experience led by Aude Chapuis and Phil Greenberg at our center where you can actually put in a highly specific T-cell receptor for WT-1 and treat patients with AML who overexpress WT-1. So, this approach, again, is pretty much in its infancy. It doesn’t seem to have quite the potency of a CAR where we can make literally kilograms of tumor go away in some of these patients, where it seems to be better at this point in preventing relapse potentially in high-risk patients in the allotransplant setting. But if we get this more refined, I think it will go forward. And we’re now starting trials in patients with chemotherapy rather than transplant to see whether we can decrease this risk of relapse. So, I think the future is bright with T cells, transduced cells, as well as the CAR cells.

Krishna V. Komanduri, MD: I think that that is important. CARs recognize surface antigens where the native T-cell receptors recognize proteolytically-processed antigens and peptides. So, a TCR transgenic, while it has to be customized to the HLA of the patient, can recognize intracellular antigens. In our center, and there are certainly other centers too, all of the companies that are generally doing CAR T-cell therapies have TCR transgenics in their pipelines across other diseases. Adaptimmune, for example, at our institution, we have trials open in sarcoma, in lung, and even gynecologic malignancies, so one specific TCR transgenic. So, I think this shows you that, once we can handle intracellular antigens with TCR transgenics. Now, there are real caveats. These are tougher to produce. They have to be more customized, but there could be a broader range of specificities that could be in our future as we move beyond these first-generation agents, typically in lymphoid malignancy-targeted CARs to other solid tumors.

Transcript Edited for Clarity 

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Transcript: 

Krishna V. Komanduri, MD: Let’s talk a little bit about something completely different. We’ve been talking about lymphoid and plasma cell malignancies. What about AML? It’s obvious to say that there are some unique challenges with AML because when you make AML, stems cells go away. What happens when you have an allogeneic transplant? There are some interesting data looking at CD123. You want to talk about that, Michael?

Michael Pulsipher, MD: I think the most important thing to say about that data is that it’s really too early to talk much about it. I think that AML has a tremendous need. In spite of our very best efforts with transplantation and intensive therapies, we still lose half the patients with AML. So, there’s a tremendous need for constructs. We all know that CARs should work, but we have to find the right targets. CD123 is a promising target. Some activity has been shown. There are a few studies that are open with small numbers of patients. People are working on CD33, and there are other antigens that are kind of in the wings. I think that we don’t have enough to say about AML right now, but we have a big need. And my hope is that within the next 2 years, we start seeing some real data in AML.

But the one thing to mention is what you’re saying. AML is going to be a different approach because we anticipate we’re going to destroy the marrow with most approaches and, therefore, a transplant will be an obligate part of that. And the thing you don’t want to do is do an intensive transplant in the middle of cytokine release syndrome. We have to find a way to get these patients through their early toxicities, get them stable, and then replace their marrow.

Krishna V. Komanduri, MD: There are other antigens in AML that are what we call “overexpressed autoantigens” like, for example, WT-1. You want to talk about that? And that’s not a target typical of the CAR.

David Maloney, MD: This is a different approach. WT-1 is an internal antigen, so it’s not expressed on the cell surface. You can’t really target it with a typical CAR against an antigen. So, there you have to actually do a TCR-transduced cell. We have some experience led by Aude Chapuis and Phil Greenberg at our center where you can actually put in a highly specific T-cell receptor for WT-1 and treat patients with AML who overexpress WT-1. So, this approach, again, is pretty much in its infancy. It doesn’t seem to have quite the potency of a CAR where we can make literally kilograms of tumor go away in some of these patients, where it seems to be better at this point in preventing relapse potentially in high-risk patients in the allotransplant setting. But if we get this more refined, I think it will go forward. And we’re now starting trials in patients with chemotherapy rather than transplant to see whether we can decrease this risk of relapse. So, I think the future is bright with T cells, transduced cells, as well as the CAR cells.

Krishna V. Komanduri, MD: I think that that is important. CARs recognize surface antigens where the native T-cell receptors recognize proteolytically-processed antigens and peptides. So, a TCR transgenic, while it has to be customized to the HLA of the patient, can recognize intracellular antigens. In our center, and there are certainly other centers too, all of the companies that are generally doing CAR T-cell therapies have TCR transgenics in their pipelines across other diseases. Adaptimmune, for example, at our institution, we have trials open in sarcoma, in lung, and even gynecologic malignancies, so one specific TCR transgenic. So, I think this shows you that, once we can handle intracellular antigens with TCR transgenics. Now, there are real caveats. These are tougher to produce. They have to be more customized, but there could be a broader range of specificities that could be in our future as we move beyond these first-generation agents, typically in lymphoid malignancy-targeted CARs to other solid tumors.

Transcript Edited for Clarity 
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