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Next-Generation CAR T Therapy

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: Tanya Siddiqi, MD, presented some data with CLL [chronic lymphocytic leukemia] that I thought was pretty encouraging. This is from the phase I study with lisocabtagene maraleucel over the dose escalation part of the study, and it showed, again, a reasonably high complete remission [CR] rate and development of MRD [minimal residual disease]-negative remissions by even deep sequencing. Many of those remissions continued to improve even out past 6 months. It seems like a lot of those patients who were only “PRs” [partial responders] had very bulky disease, and it’s very hard to get less than 1.5 cm to qualify as truly a CR by iwCLL [International Workshop on CLL] criteria. We’ll have to see what happens, but I think that was very encouraging. I know the phase II study in CLL is ongoing with that agent.

Max Topp, MD: What I think is really very encouraging to see is that we also can tweak the immune system by actually pretreating these patients with ibrutinib. That was shown at ASCO [the American Society of Clinical Oncology meeting] quite nicely. So it just gives us a pathway that we can actually improve on.

David Maloney, MD, PhD: Yes, I think they’re hoping to present that cohort at one of the next meetings. We’re talking about hematologic malignancies. What about solid cancers? Is there anything on the horizon?

Frederick Locke, MD: Yes. Here we are at the American Society of Hematology [ASH] annual meeting, but the reality is cellular therapies are often administered in transplant programs in large academic centers that are familiar with cell therapies for blood cancers. We’re now seeing that we’re helping to facilitate the treatment of patients with solid tumors. I think that CAR [chimeric antigen receptor] T-cell therapy for solid tumors is a little more difficult than targeting CD19 or BCMA [B-cell maturation antigen]. The expression of molecules on the surface of most solid tumors, those molecules are often expressed on normal tissue, so the toxicity rates may be higher. And there are also issues of trafficking into the tumor.

I’m actually more encouraged by data from tumor-infiltrating lymphocytes, or TILs therapy. There were data presented at the ASCO annual meeting [in 2019] showing that melanoma patients who were refractory to checkpoint inhibitors were able to have tumors removed and tumor infiltrating lymphocytes grown out and actually had responses and durable responses to those therapies. And similarly, patients with cervical cancer were having responses. And so, we’re very encouraged. At our center, we help facilitate those treatments. I believe we may see FDA approvals for TILs, and that may become a platform to genetically modified T-cells as well in solid tumors.

David Maloney, MD, PhD: I think you’re pointing out, though, that the tumor milieu is not the same in a solid cancer as it is in a hematologic malignancy, where we’re seeing these dramatic expansions and, likely, cures. And so, we’ve got a ways to go with T-cell engineering and the like to try to figure out the molecules.

Jason Westin, MD: TILs have been impressive, but they’ve been impressive for some time and we have to figure out why these cells are infiltrating the tumor. In melanoma we’ve seen that, but it’s curing or having long-term responses in a minority of patients. Figuring out what it is about the tumor or what about the T-cells is causing them to infiltrate, and then, as you said, making those into gene-edited cells so that you’re actually producing those at scale as opposed to having to go through the whole exercise of producing buckets worth of tumor-infiltrating lymphocytes.

David Maloney, MD, PhD: OK, let’s get out the crystal balls here. Everybody can look a little bit at the future. These are early generation CARs, so I think we’re going to see rapid changes. What are the kinds of things we’re going to see going forward? What do you predict?

Jason Westin, MD: I think the idea of the so-called off-the-shelf CAR T-cells is very attractive. One of the challenges with CAR T-cells right now is having to wait. We talked a lot about bridging therapy today. If you could treat someone with a CAR T-cell therapy later this week, or even the next day after you plan to do that, much in the way you can do with chemotherapy, there would be a lot of advantages. There are other advantages of off-the-shelf, but that timeframe shortening would be very attractive.

Caron Jacobson, MD: Some of the other advantages: We also talked about T-cell fitness. If you take a healthy donor who doesn’t have a cancer that interacts with the immune system and also hasn’t seen chemotherapy, that is potentially very important. But on the flip side of that, giving someone else’s T-cells increases the risk that those T-cells will be rejected before they can have an anti-tumor effect. The other advantage to off-the-shelf CARs is that from 1 donor you can make up to 100 products. And so, that’s intriguing when we’re talking about the cost of this therapy.

David Maloney, MD, PhD: But you have to then deal with the risk of causing graft-versus-host disease.

Caron Jacobson, MD: Most of these off-the-shelf CARs have been engineered in a way to try to limit the risk of graft-versus-host disease, so they all involve gene-editing technology that edits out the TCR [T-cell receptor], and edits in the CAR in its place. I think we have seen enough data up to this point, although they are all very immature and it’s all very small studies where the risk of graft-versus-host disease is incredibly low and really limited to transient rash, which to be honest, may also just be a sign of CRS [cytokine release syndrome], right? It’s hard to know.

David Maloney, MD, PhD: What about other products other than T-cells?

Max Topp, MD: I think NK [natural killer] cells are a very attractive approach. There are emerging data using NK cells as a platform being engineered to deliver cellular therapy. I think this is very interesting. When you look at the toxicity profile from early data, neurotoxicity is definitely less using NK-derived products. But obviously, the trial has to evolve.

David Maloney, MD, PhD: Jason, I think you guys have that data from….

Jason Westin, MD: Yes, with the IL-15 [interleukin 15] built into it as well. It seems very promising so far, with low toxicity rates. Obviously, we need more patients and more data. But yes, it is intriguing.

Caron Jacobson, MD: I think the most impressive things noted on that data set included that there were several patients with Richter transformation from CLL who were treated, and there were at least 2 CRs in Richter, which is not something that we’ve seen.

David Maloney, MD, PhD: That was data from MD Anderson [Cancer Center] regarding the cord blood-derived NK cells with co-expressing IL-15, which is a very interesting trick. That’s really good. However, we still have to deal with relapse, so how are we going to do that?

Frederick Locke, MD: One of the things that I’m most excited about is starting to understand, or looking to understand the biology of these relapses. We understand there can be loss of target antigen in CD19-treated ALL [acute lymphoblastic leukemia]. Maybe up to 50% of patients who were relapsing could lose CD19. In large B-cell lymphoma, about a third of patients who are relapsing are losing CD19. So dual-targeting CARs may help to increase the durable response rates, but I think we’re starting to see emerging data from our group and also from some of the pivotal trials that demonstrate that there are suppressive myeloid cells that may contribute to lack of durable responses in these patients. So, strategies that could help mitigate those suppressive myeloid cells may also be important.

David Maloney, MD, PhD: What about combinations? The obvious is checkpoints, right?

Caron Jacobson, MD: Yes. The ZUMA-6 trial combined axicabtagene ciloleucel with atezolizumab, which is a PD-L1 [programmed death-ligand 1] antibody. We presented the results from the phase I portion last year at ASH, and we await the results of the expansion in phase II. But in the phase I portion, 12 patients were treated. It’s really hard to compare 12 patients against 100 patients on ZUMA-1, but the response rates were at least as good if not maybe the slightest bit better.

What’s interesting in that cohort is that there were at least 3 patients who had conversion from a PR or stable disease out past 6 months. So there was a delayed conversion of PR and stable disease to a complete response, which is hypothesis generating. I think that maybe these cells are sticking around longer, are being revitalized, and are able to treat the active tumor. That was borne out by looking at the area under the curve of T-cell expansion, and the T-cells did seem to persist at a higher rate for a longer period.

David Maloney, MD, PhD: I think we’re looking forward to the readout of those trials. It also sets the stage to add ibrutinib, lenalidomide, and maybe even bispecific antibodies, based on the study we saw at the plenary session where a patient’s basically receiving a CD20/CD3 antibody, and had activity after failing CAR T-cells. So, thought provoking.

Jason Westin, MD: Thought provoking. Obviously small numbers so far, but yes, there’s a response rate there, and we don’t yet have any therapies that are looking that promising, so we need more data.

David Maloney, MD, PhD: All right, thank you very much for your attention. This has been very informative. I thank you. On behalf of our panel, we hope that you found this Peer Exchange discussion to be useful and informative for your practice.

Transcript Edited for Clarity

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Transcript: 

David Maloney, MD, PhD: Tanya Siddiqi, MD, presented some data with CLL [chronic lymphocytic leukemia] that I thought was pretty encouraging. This is from the phase I study with lisocabtagene maraleucel over the dose escalation part of the study, and it showed, again, a reasonably high complete remission [CR] rate and development of MRD [minimal residual disease]-negative remissions by even deep sequencing. Many of those remissions continued to improve even out past 6 months. It seems like a lot of those patients who were only “PRs” [partial responders] had very bulky disease, and it’s very hard to get less than 1.5 cm to qualify as truly a CR by iwCLL [International Workshop on CLL] criteria. We’ll have to see what happens, but I think that was very encouraging. I know the phase II study in CLL is ongoing with that agent.

Max Topp, MD: What I think is really very encouraging to see is that we also can tweak the immune system by actually pretreating these patients with ibrutinib. That was shown at ASCO [the American Society of Clinical Oncology meeting] quite nicely. So it just gives us a pathway that we can actually improve on.

David Maloney, MD, PhD: Yes, I think they’re hoping to present that cohort at one of the next meetings. We’re talking about hematologic malignancies. What about solid cancers? Is there anything on the horizon?

Frederick Locke, MD: Yes. Here we are at the American Society of Hematology [ASH] annual meeting, but the reality is cellular therapies are often administered in transplant programs in large academic centers that are familiar with cell therapies for blood cancers. We’re now seeing that we’re helping to facilitate the treatment of patients with solid tumors. I think that CAR [chimeric antigen receptor] T-cell therapy for solid tumors is a little more difficult than targeting CD19 or BCMA [B-cell maturation antigen]. The expression of molecules on the surface of most solid tumors, those molecules are often expressed on normal tissue, so the toxicity rates may be higher. And there are also issues of trafficking into the tumor.

I’m actually more encouraged by data from tumor-infiltrating lymphocytes, or TILs therapy. There were data presented at the ASCO annual meeting [in 2019] showing that melanoma patients who were refractory to checkpoint inhibitors were able to have tumors removed and tumor infiltrating lymphocytes grown out and actually had responses and durable responses to those therapies. And similarly, patients with cervical cancer were having responses. And so, we’re very encouraged. At our center, we help facilitate those treatments. I believe we may see FDA approvals for TILs, and that may become a platform to genetically modified T-cells as well in solid tumors.

David Maloney, MD, PhD: I think you’re pointing out, though, that the tumor milieu is not the same in a solid cancer as it is in a hematologic malignancy, where we’re seeing these dramatic expansions and, likely, cures. And so, we’ve got a ways to go with T-cell engineering and the like to try to figure out the molecules.

Jason Westin, MD: TILs have been impressive, but they’ve been impressive for some time and we have to figure out why these cells are infiltrating the tumor. In melanoma we’ve seen that, but it’s curing or having long-term responses in a minority of patients. Figuring out what it is about the tumor or what about the T-cells is causing them to infiltrate, and then, as you said, making those into gene-edited cells so that you’re actually producing those at scale as opposed to having to go through the whole exercise of producing buckets worth of tumor-infiltrating lymphocytes.

David Maloney, MD, PhD: OK, let’s get out the crystal balls here. Everybody can look a little bit at the future. These are early generation CARs, so I think we’re going to see rapid changes. What are the kinds of things we’re going to see going forward? What do you predict?

Jason Westin, MD: I think the idea of the so-called off-the-shelf CAR T-cells is very attractive. One of the challenges with CAR T-cells right now is having to wait. We talked a lot about bridging therapy today. If you could treat someone with a CAR T-cell therapy later this week, or even the next day after you plan to do that, much in the way you can do with chemotherapy, there would be a lot of advantages. There are other advantages of off-the-shelf, but that timeframe shortening would be very attractive.

Caron Jacobson, MD: Some of the other advantages: We also talked about T-cell fitness. If you take a healthy donor who doesn’t have a cancer that interacts with the immune system and also hasn’t seen chemotherapy, that is potentially very important. But on the flip side of that, giving someone else’s T-cells increases the risk that those T-cells will be rejected before they can have an anti-tumor effect. The other advantage to off-the-shelf CARs is that from 1 donor you can make up to 100 products. And so, that’s intriguing when we’re talking about the cost of this therapy.

David Maloney, MD, PhD: But you have to then deal with the risk of causing graft-versus-host disease.

Caron Jacobson, MD: Most of these off-the-shelf CARs have been engineered in a way to try to limit the risk of graft-versus-host disease, so they all involve gene-editing technology that edits out the TCR [T-cell receptor], and edits in the CAR in its place. I think we have seen enough data up to this point, although they are all very immature and it’s all very small studies where the risk of graft-versus-host disease is incredibly low and really limited to transient rash, which to be honest, may also just be a sign of CRS [cytokine release syndrome], right? It’s hard to know.

David Maloney, MD, PhD: What about other products other than T-cells?

Max Topp, MD: I think NK [natural killer] cells are a very attractive approach. There are emerging data using NK cells as a platform being engineered to deliver cellular therapy. I think this is very interesting. When you look at the toxicity profile from early data, neurotoxicity is definitely less using NK-derived products. But obviously, the trial has to evolve.

David Maloney, MD, PhD: Jason, I think you guys have that data from….

Jason Westin, MD: Yes, with the IL-15 [interleukin 15] built into it as well. It seems very promising so far, with low toxicity rates. Obviously, we need more patients and more data. But yes, it is intriguing.

Caron Jacobson, MD: I think the most impressive things noted on that data set included that there were several patients with Richter transformation from CLL who were treated, and there were at least 2 CRs in Richter, which is not something that we’ve seen.

David Maloney, MD, PhD: That was data from MD Anderson [Cancer Center] regarding the cord blood-derived NK cells with co-expressing IL-15, which is a very interesting trick. That’s really good. However, we still have to deal with relapse, so how are we going to do that?

Frederick Locke, MD: One of the things that I’m most excited about is starting to understand, or looking to understand the biology of these relapses. We understand there can be loss of target antigen in CD19-treated ALL [acute lymphoblastic leukemia]. Maybe up to 50% of patients who were relapsing could lose CD19. In large B-cell lymphoma, about a third of patients who are relapsing are losing CD19. So dual-targeting CARs may help to increase the durable response rates, but I think we’re starting to see emerging data from our group and also from some of the pivotal trials that demonstrate that there are suppressive myeloid cells that may contribute to lack of durable responses in these patients. So, strategies that could help mitigate those suppressive myeloid cells may also be important.

David Maloney, MD, PhD: What about combinations? The obvious is checkpoints, right?

Caron Jacobson, MD: Yes. The ZUMA-6 trial combined axicabtagene ciloleucel with atezolizumab, which is a PD-L1 [programmed death-ligand 1] antibody. We presented the results from the phase I portion last year at ASH, and we await the results of the expansion in phase II. But in the phase I portion, 12 patients were treated. It’s really hard to compare 12 patients against 100 patients on ZUMA-1, but the response rates were at least as good if not maybe the slightest bit better.

What’s interesting in that cohort is that there were at least 3 patients who had conversion from a PR or stable disease out past 6 months. So there was a delayed conversion of PR and stable disease to a complete response, which is hypothesis generating. I think that maybe these cells are sticking around longer, are being revitalized, and are able to treat the active tumor. That was borne out by looking at the area under the curve of T-cell expansion, and the T-cells did seem to persist at a higher rate for a longer period.

David Maloney, MD, PhD: I think we’re looking forward to the readout of those trials. It also sets the stage to add ibrutinib, lenalidomide, and maybe even bispecific antibodies, based on the study we saw at the plenary session where a patient’s basically receiving a CD20/CD3 antibody, and had activity after failing CAR T-cells. So, thought provoking.

Jason Westin, MD: Thought provoking. Obviously small numbers so far, but yes, there’s a response rate there, and we don’t yet have any therapies that are looking that promising, so we need more data.

David Maloney, MD, PhD: All right, thank you very much for your attention. This has been very informative. I thank you. On behalf of our panel, we hope that you found this Peer Exchange discussion to be useful and informative for your practice.

Transcript Edited for Clarity
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