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CAR T-Cell Therapy for Multiple Myeloma

Panelists: Keith Stewart, MB, CHB, Mayo Clinic; Gareth Morgan, MD, PhD, University of Arkansas for Medical Science; Saad Z. Usmani, MD, Levine Cancer Institute/Carolinas Healthcare System; Ivan M. Borrello, MD, Johns Hopkins Kimmel Cancer Center; Thomas G. Martin, MD, University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center; Sagar Lonial, MD, Winship Cancer Institute of Emory University
Published Online: Tuesday, Jul 25, 2017



Transcript:

Keith Stewart, MB, ChB:
You brought up the subject of CAR T cells. There are 2 abstracts from the 2017 ASCO Annual Meeting, 1 from Bluebird Bio and 1 from China, reporting pretty interesting results with CAR T-cell therapy. Who wants to talk about that this?

Saad Z. Usmani, MD: I can talk about the Bluebird Bio study on CAR T-cell therapy. I think the other one is a late-breaking abstract?

Thomas G. Martin, MD: Right. That is correct.

Saad Z. Usmani, MD: At least in the abstract, I think in the 6 patients that they reported on, the most striking thing was not the response rate; we anticipated that that strategy would work. What was more impressive was the low rates of cytokine release syndrome. I think only grade 1 or 2 events were reported.

Keith Stewart, MB, ChB: This was reported last year, I think. 6 patients had all responded to CAR T-cell therapy, but with relatively short follow-up. I think we’re getting an update in a couple of days on a larger data set?

Saad Z. Usmani, MD: Yes.

Keith Stewart, MB, ChB: The Chinese abstract, the late-breaking one, reports 14 out of 19 patients entering a complete remission. Does that impress you, Tom?

Thomas G. Martin, MD: That does impress me. The Bluebird study impresses me, also. In fact, all of the CAR T data impress me. Of the patients treated at the National Institutes of Health, at Penn Medicine, and by Bluebird Bio, I think 16 of the patients had a response. The patients who didn’t have a response were almost all treated at the lower doses of T cells. If you take the patients who are treated at the higher dose of T cells, the response rate is really upwards of 70%-plus. We have to be impressed by these data.

Keith Stewart, MB, ChB: Sagar?

Sagar Lonial, MD: I think the response rate is probably not the right endpoint in these trials. We know from ALL and AML, or certainly ALL in large cell lymphoma, that the response rates are very high. But the cells are not persistent. And so, the PFS is not as long as one would like. Now, these data certainly look very impressive, and I think BCMA is, in my mind, the best target for something like this.

Keith Stewart, MB, ChB: We should have started by saying that both of these are targeting BCMA.

Sagar Lonial, MD: BCMA, yes. I think this is certainly a strategy worth trying to understand and explore, but can you make them? How practical is it to give them? Are you picking patients who can wait 6 months for cells to be made before you treat them? I mean, there are a lot of details there.

Saad Z. Usmani, MD: And to my knowledge, with the Bluebird study, I think they had a BCMA expression cutoff of 50% or more and the disease burden had to be less than 50% plasmacytosis. It was a little restrictive in the burden of disease you could have and the BCMA expression.

Keith Stewart, MB, ChB: At our Rochester site, we are doing the Bluebird study. I think what has been most interesting about it is the fact that there has not been a lot of toxicity as compared to some other acute leukemia and lymphoma trials and other constructs, even in myeloma, to the extent that the belief is we can move this to the outpatient setting, which is big. I’m pretty excited about it, actually. It looks really good.

Ivan M. Borrello, MD: No, it is. It’s very exciting.

Keith Stewart, MB, ChB: Do you think it will replace transplant one day?

Ivan M. Borrello, MD: It might.

Gareth Morgan, MD, PhD: How are you going to place them in the context of bispecific antibodies? That’s the $60-million question.

Keith Stewart, MB, ChB: I asked an expert who was visiting us at Mayo, recently, as a guest speaker, the same question. He said, “Well, look at acute lymphoblastic leukemia.” He said, “CAR T treated patients in remission for years—look at the data. They’re not so good.” I think he was making the case that the BiTEs have a role, but they are not going to have the deep, long remissions that you see with CAR T therapy.

Ivan M. Borrello, MD: What you see with CAR T cells is that the affinity of the antibody to the antigen is probably, if not higher, greater than with antibodies. I think the other thing that’s emerging from the CAR T-cell data is that we talk about all these responders, but really, the people who are doing well are the ones who achieve a CR. If you don’t achieve a CR, your progression...

Sagar Lonial, MD: Or if the cells are gone…

Gareth Morgan, MD, PhD: In most of the patients, the cells are gone after 6 weeks.

Ivan M. Borrello, MD: But if you achieve a CR with MRD minimal residual disease negativity, and you truly cure the patients, you don’t need the cells anymore.

Gareth Morgan, MD, PhD: So, that would argue for using a BiTE.

Ivan M. Borrello, MD: Using a BiTE?

Gareth Morgan, MD, PhD: Yes. You give them for a longer period of time.

Keith Stewart, MB, ChB: But BiTEs could come in after a CAR T-cell therapy.

Sagar Lonial, MD: I think the challenge is—and I like the BiTEs and bispecific ideas—it’s an off-the-shelf, easier way to deal with this.

Gareth Morgan, MD, PhD: Absolutely.

Sagar Lonial, MD: The problem is, you need to somehow activate immune function, which means you’re probably going to give a BiTE or a bispecific with an IMiD in order to try to get that T-cell effect that you’re getting built in with the CARs. I think there are trade-offs, and I suspect we’re going to be testing BiTEs, ADCs, and CAR T cells that are all going after the same target.

Keith Stewart, MB, ChB: It’s still hard to find trials for our patients to go on. There’s this issue of how we’re going to scale this. And for the community doctors that may be listening in, it’s still hard to find slots for patients. But it’s coming fast.

Transcript Edited for Clarity

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Transcript:

Keith Stewart, MB, ChB:
You brought up the subject of CAR T cells. There are 2 abstracts from the 2017 ASCO Annual Meeting, 1 from Bluebird Bio and 1 from China, reporting pretty interesting results with CAR T-cell therapy. Who wants to talk about that this?

Saad Z. Usmani, MD: I can talk about the Bluebird Bio study on CAR T-cell therapy. I think the other one is a late-breaking abstract?

Thomas G. Martin, MD: Right. That is correct.

Saad Z. Usmani, MD: At least in the abstract, I think in the 6 patients that they reported on, the most striking thing was not the response rate; we anticipated that that strategy would work. What was more impressive was the low rates of cytokine release syndrome. I think only grade 1 or 2 events were reported.

Keith Stewart, MB, ChB: This was reported last year, I think. 6 patients had all responded to CAR T-cell therapy, but with relatively short follow-up. I think we’re getting an update in a couple of days on a larger data set?

Saad Z. Usmani, MD: Yes.

Keith Stewart, MB, ChB: The Chinese abstract, the late-breaking one, reports 14 out of 19 patients entering a complete remission. Does that impress you, Tom?

Thomas G. Martin, MD: That does impress me. The Bluebird study impresses me, also. In fact, all of the CAR T data impress me. Of the patients treated at the National Institutes of Health, at Penn Medicine, and by Bluebird Bio, I think 16 of the patients had a response. The patients who didn’t have a response were almost all treated at the lower doses of T cells. If you take the patients who are treated at the higher dose of T cells, the response rate is really upwards of 70%-plus. We have to be impressed by these data.

Keith Stewart, MB, ChB: Sagar?

Sagar Lonial, MD: I think the response rate is probably not the right endpoint in these trials. We know from ALL and AML, or certainly ALL in large cell lymphoma, that the response rates are very high. But the cells are not persistent. And so, the PFS is not as long as one would like. Now, these data certainly look very impressive, and I think BCMA is, in my mind, the best target for something like this.

Keith Stewart, MB, ChB: We should have started by saying that both of these are targeting BCMA.

Sagar Lonial, MD: BCMA, yes. I think this is certainly a strategy worth trying to understand and explore, but can you make them? How practical is it to give them? Are you picking patients who can wait 6 months for cells to be made before you treat them? I mean, there are a lot of details there.

Saad Z. Usmani, MD: And to my knowledge, with the Bluebird study, I think they had a BCMA expression cutoff of 50% or more and the disease burden had to be less than 50% plasmacytosis. It was a little restrictive in the burden of disease you could have and the BCMA expression.

Keith Stewart, MB, ChB: At our Rochester site, we are doing the Bluebird study. I think what has been most interesting about it is the fact that there has not been a lot of toxicity as compared to some other acute leukemia and lymphoma trials and other constructs, even in myeloma, to the extent that the belief is we can move this to the outpatient setting, which is big. I’m pretty excited about it, actually. It looks really good.

Ivan M. Borrello, MD: No, it is. It’s very exciting.

Keith Stewart, MB, ChB: Do you think it will replace transplant one day?

Ivan M. Borrello, MD: It might.

Gareth Morgan, MD, PhD: How are you going to place them in the context of bispecific antibodies? That’s the $60-million question.

Keith Stewart, MB, ChB: I asked an expert who was visiting us at Mayo, recently, as a guest speaker, the same question. He said, “Well, look at acute lymphoblastic leukemia.” He said, “CAR T treated patients in remission for years—look at the data. They’re not so good.” I think he was making the case that the BiTEs have a role, but they are not going to have the deep, long remissions that you see with CAR T therapy.

Ivan M. Borrello, MD: What you see with CAR T cells is that the affinity of the antibody to the antigen is probably, if not higher, greater than with antibodies. I think the other thing that’s emerging from the CAR T-cell data is that we talk about all these responders, but really, the people who are doing well are the ones who achieve a CR. If you don’t achieve a CR, your progression...

Sagar Lonial, MD: Or if the cells are gone…

Gareth Morgan, MD, PhD: In most of the patients, the cells are gone after 6 weeks.

Ivan M. Borrello, MD: But if you achieve a CR with MRD minimal residual disease negativity, and you truly cure the patients, you don’t need the cells anymore.

Gareth Morgan, MD, PhD: So, that would argue for using a BiTE.

Ivan M. Borrello, MD: Using a BiTE?

Gareth Morgan, MD, PhD: Yes. You give them for a longer period of time.

Keith Stewart, MB, ChB: But BiTEs could come in after a CAR T-cell therapy.

Sagar Lonial, MD: I think the challenge is—and I like the BiTEs and bispecific ideas—it’s an off-the-shelf, easier way to deal with this.

Gareth Morgan, MD, PhD: Absolutely.

Sagar Lonial, MD: The problem is, you need to somehow activate immune function, which means you’re probably going to give a BiTE or a bispecific with an IMiD in order to try to get that T-cell effect that you’re getting built in with the CARs. I think there are trade-offs, and I suspect we’re going to be testing BiTEs, ADCs, and CAR T cells that are all going after the same target.

Keith Stewart, MB, ChB: It’s still hard to find trials for our patients to go on. There’s this issue of how we’re going to scale this. And for the community doctors that may be listening in, it’s still hard to find slots for patients. But it’s coming fast.

Transcript Edited for Clarity
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