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Allogeneic CAR T-Cell Approaches for NHL

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: Thursday, Mar 01, 2018



Transcript: 

Krishna V. Komanduri, MD: Before moving on—because we’ve had a great discussion about lymphoma—I want to just mention a couple of other things that in addition to these conventionally targeted CARs, we do have some constructs that are doing things where we have a CAR recognizing Fc, for example, that might be a more universal CAR. We also have the possibility of allogeneic generation, at least theoretically of an off-the-shelf product. I think that we don’t really have much in the way of mature clinical results for those approaches. Right now, what we’re talking about is autologous cells that are gene modified, and we have remarkable results in those areas. Anybody want to comment on those developments?

David Maloney, MD, PhD: I think this is a really great field because the question is, can you make a CAR that’s more universal? And so, the one approach we were talking about at the ASH meeting this year is where you use a CAR that’s just specific for an antibody Fc, you can potentially then give a patient a CAR but then switch targets by giving different antibodies. That’s an approach that’s quite intriguing, and there’s very, very early phase I data that suggest that that might be appropriate with using rituximab to target CD20. And I think that’s a really intriguing approach. I don’t know where it will be as good as a dedicated CAR. I can envision in the future, you come in, you donate 10 ccs of blood, someone makes 3 targeted CARs, and they give you the CAR and end of story, right, for whatever your cancer is.

Krishna V. Komanduri, MD: And the results right now are very early and we have some responses, but we still have cytokine release syndrome. It hasn’t solved all of the problems here.

David Maloney, MD, PhD: We’ve got a lot of toxicity to solve first. And then that second question was really, can we do this in an allotransplant setting? There were some intriguing data. And we’ve actually done quite a few patients where they’ve relapsed after allotransplant, and we then make cells from the patient, which are actually donor cells. But this group actually took T cells from the donor and were able to give it back and induced remissions using those kinds of CAR T cells. So, that opens up interesting ideas of whether you could do a T cell-depleted transplant or some kind of a transplant where there’s no GBH but then provide the graft-versus-tumor effect with essentially a donor CAR. So, there’s a lot of options that we can look forward in the transplant community to look at this.

Stephen J. Schuster, MD: We have certainly done the same, and we pheresed patients with graft versus host disease (GvHD), made CARs, and treated them without seeing graft versus host disease. Particularly in the large cell patients who have multiple prior therapies, sometimes their T cells are not very robust. And the idea that you may be able to use an allogeneic approach, I think, is exciting. The other things are the universal CARs, knock out the MHC or the T-cell receptor and just have your chimeric receptor on, something that you pull off the shelf and give to anybody without worrying about GvHD.

Krishna V. Komanduri, MD: Rejection of the cells.

Michael Pulsipher, MD: Universal CARs, I think, are intriguing, but we have a long way to go.

Stephen J. Schuster, MD: Yes, I know, but it’s nice to dream.

Michael Pulsipher, MD: It is nice to dream and we should, and it’s a very intelligent way to think about it. But one thing you brought up with this transplant issue is it is true that sometimes we simply can’t grow and expand T cells. Yet, if you give someone an allogeneic transplant and they relapse 6 months later, they have their donor’s T cells, much better CARs can be used or we can use them directly from the donor.

Stephen J. Schuster, MD: And they’re tolerized to the donor if the donor doesn’t have GvHD. It actually is a strategy that I think could work for some patients.

Transcript Edited for Clarity 

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Transcript: 

Krishna V. Komanduri, MD: Before moving on—because we’ve had a great discussion about lymphoma—I want to just mention a couple of other things that in addition to these conventionally targeted CARs, we do have some constructs that are doing things where we have a CAR recognizing Fc, for example, that might be a more universal CAR. We also have the possibility of allogeneic generation, at least theoretically of an off-the-shelf product. I think that we don’t really have much in the way of mature clinical results for those approaches. Right now, what we’re talking about is autologous cells that are gene modified, and we have remarkable results in those areas. Anybody want to comment on those developments?

David Maloney, MD, PhD: I think this is a really great field because the question is, can you make a CAR that’s more universal? And so, the one approach we were talking about at the ASH meeting this year is where you use a CAR that’s just specific for an antibody Fc, you can potentially then give a patient a CAR but then switch targets by giving different antibodies. That’s an approach that’s quite intriguing, and there’s very, very early phase I data that suggest that that might be appropriate with using rituximab to target CD20. And I think that’s a really intriguing approach. I don’t know where it will be as good as a dedicated CAR. I can envision in the future, you come in, you donate 10 ccs of blood, someone makes 3 targeted CARs, and they give you the CAR and end of story, right, for whatever your cancer is.

Krishna V. Komanduri, MD: And the results right now are very early and we have some responses, but we still have cytokine release syndrome. It hasn’t solved all of the problems here.

David Maloney, MD, PhD: We’ve got a lot of toxicity to solve first. And then that second question was really, can we do this in an allotransplant setting? There were some intriguing data. And we’ve actually done quite a few patients where they’ve relapsed after allotransplant, and we then make cells from the patient, which are actually donor cells. But this group actually took T cells from the donor and were able to give it back and induced remissions using those kinds of CAR T cells. So, that opens up interesting ideas of whether you could do a T cell-depleted transplant or some kind of a transplant where there’s no GBH but then provide the graft-versus-tumor effect with essentially a donor CAR. So, there’s a lot of options that we can look forward in the transplant community to look at this.

Stephen J. Schuster, MD: We have certainly done the same, and we pheresed patients with graft versus host disease (GvHD), made CARs, and treated them without seeing graft versus host disease. Particularly in the large cell patients who have multiple prior therapies, sometimes their T cells are not very robust. And the idea that you may be able to use an allogeneic approach, I think, is exciting. The other things are the universal CARs, knock out the MHC or the T-cell receptor and just have your chimeric receptor on, something that you pull off the shelf and give to anybody without worrying about GvHD.

Krishna V. Komanduri, MD: Rejection of the cells.

Michael Pulsipher, MD: Universal CARs, I think, are intriguing, but we have a long way to go.

Stephen J. Schuster, MD: Yes, I know, but it’s nice to dream.

Michael Pulsipher, MD: It is nice to dream and we should, and it’s a very intelligent way to think about it. But one thing you brought up with this transplant issue is it is true that sometimes we simply can’t grow and expand T cells. Yet, if you give someone an allogeneic transplant and they relapse 6 months later, they have their donor’s T cells, much better CARs can be used or we can use them directly from the donor.

Stephen J. Schuster, MD: And they’re tolerized to the donor if the donor doesn’t have GvHD. It actually is a strategy that I think could work for some patients.

Transcript Edited for Clarity 
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