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Considering Other CAR T-Cell Strategies in R/R Myeloma

Panelists: Sagar Lonial, MD, FACP, Winship Cancer Institute of Emory University; Amrita Y. Krishnan, MD, City of Hope Comprehensive Cancer Center; Thomas G. Martin, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Krina K. Patel, MD, MSc, University of Texas MD Anderson Cancer Center; Saad Z. Usmani, MD, FACP, Levine Cancer Institute
Published: Wednesday, Aug 07, 2019



Transcript: 

Sagar Lonial, MD, FACP: Krina, do you want to talk to us a little bit about some of the different CAR [chimeric antigen receptor] T-cell strategies that were presented at the meeting?

Krina K. Patel, MD, MSc: Sure. This was at ASH [American Society of Hematology] where we had 7 CAR-T talks in 2 different sessions. But there was an interesting poster out of China, from Nanjing, and this is actually a humanized BCMA [B-cell maturation antigen]. They were looking at 9 patients who got a fully humanized BCMA lentivirus transduced CAR T and a 4-1BB co-stimulation. And there was a 100% response rate. I think the interesting thing is—talking about can you treat BCMA again—3 of the patients had had a CAR T that was murine scFv [single-chain variable fragment] BCMA that had relapsed. And 2 of the patients on this trial ended up with CRs [complete responses], ongoing CRs, and 1 of the patients has a VGPR [very good partial response] still.

I think it is that question of, can you treat the vehicle, the target’s BCMA? But what you’re putting with it matters. And there’s some anecdotal cases of patients who got the ADC [antibody drug conjugate] or got a BiTE [bispecific T-cell engager] and then went on to a CAR-T trial, and they actually responded when they didn’t respond initially.

I think, yes, the BCMA world is saturated, but we don’t know enough about the actual antigen. And I don’t think you can compare it to CD19 and say, “Well, blinatumomab does this and then the CAR T doesn’t work as well.” I don’t know that you can say that about BCMA. I do think we have a lot to learn. I agree that there need to be a lot of other targets. Most of the trials have been with BCMA. Of course, in the New England Journal of Medicine paper that recently came out on BB2121, progression-free survival [PFS] was 11.8 months, and if you’re MRD [minimal residual disease]-negative, 17.7 months, with no other therapy, which is huge, compared to needing continuous infusions or therapy.

I think that was the biggest thing for our patients to have 12 to 17.7 or even more months where you have no other therapy. Quality of life, once again, was pretty impressive. I think in the other trials—Legend and Janssen—their data look pretty good. There was a little bit better PFS at 22, 23 months. But these patients had a little bit less in terms of therapy. They’re at about 3, 4 lines. The same thing with this trial in China, there are about 4 prior lines of therapy compared to BB2121, where there’s 7 to 8 prior lines. The more heavily treated population. So looking at those data, I think all the CAR T’s have pretty impressive data in that sense.

Of course there’s JCAR and Poseida, there’s so many that we’re all looking at. But allogeneic therapy is the other next thing and we do have a trial opening up with CS1 allo CAR T, where both the CS1 and the TCR [T-cell receptors] are knocked out. That hopefully will be opened in the next couple of weeks, and we’re really excited to see what happens. Because now, we have normal donor T cells. They haven’t been knocked out. You don’t have to wait a month, you don’t have to do bridging, you just go. The problem with allo, the question is persistence.

Sagar Lonial, MD, FACP: Right.

Krina K. Patel, MD, MSc: We have to do higher lymphodepletion, so the patients do have to be really ECOG-01 [ECOG performance status, grade 0/1], so we’ll see with this initial trial the logistics, how they are different. But I think it’s really cutting-edge and interesting stuff that’s going to be happening in the next few months.

Sagar Lonial, MD, FACP: Do you worry both with CS1- and CD38-directed CARs, that those targets are not quite as narrowly expressed as BCMA?

Saad Z. Usmani, MD, FACP: For sure.

Sagar Lonial, MD, FACP: And you might get into some trouble if you do that.

Amrita Y. Krishnan, MD: You read my mind. I was going to make that comment. I was just curious, what starting cell dose are you going to use for your patient?

Krina K. Patel, MD, MSc: We’ve actually lowered it because it’s allo, so it’s 3 times 10 to the 6th, and then there’s a minus 1, 2 to the 5th. One is on NK [natural killer] cells, it’s on regulatory T cells, it’s on T cells, and that’s where we knock out CS1 so there’s not fratricide.

So the question is, are you going to have more lymphodepletion now? All these CAR Ts have been great, but one of the big issues, besides CRS [cytokine release syndrome] and neurotoxicity, that we have learned to take care of and those are actually pretty reasonable, are the neutropenia and the thrombocytopenia. In some patients it’s more than 6 months so you have to make sure they’re PCP [pneumocystis pneumonia] prophylaxis; you have to make sure about Levaquin and other things bacterial, fungal when their CD4 counts are still low. So for a CS1, are we going to have more lymphodepletion and then actually end up with longer thrombocytopenia and neutropenia? So those are very relevant questions.

Amrita Y. Krishnan, MD: I think the other big question—this is one in the CAR-T space, right—is the cytopenia immune mediated, or conditioned? I think most of us believe it’s probably….

Others: Immune mediated.

Sagar Lonial, MD, FACP: It’s interesting. I won’t say to play devil’s advocate, but if you look at another way to get to BCMA, the GSK ADC, median PFS was 12 months. So yes, there’s ocular toxicity, but you don’t have CRS, you don’t have prolonged cytopenias, at least in that small experience. And I think we need a larger data set to really know. But for PFS, they were similar.

Amrita Y. Krishnan, MD: But my comment would be, how long does it take you to get an ophthalmologist to see your patient?

Sagar Lonial, MD, FACP: Quicker than it takes to make CAR T cells.

Saad Z. Usmani, MD, FACP: The argument can be made that you were actually seeing, even in those relapsed/refractory myeloma patients who received multiple lines of treatment, that it’s really the good ones who are getting the CAR Ts because those patients who cannot get bridging therapy, or who are going through bridging therapy, are not the ones who are being screened and enrolled on those trials.

Krina K. Patel, MD, MSc: I think the 60% response rate, once again, with continuous therapy versus an 85% response rate for BB2121, a one-time shot, right? And I get it, yes, that first month is a lot harder if you get the neutropenia. But I do think that if you’re someone who’s otherwise healthy, you’re working, I would pick the CAR T then, but not everyone can get it.

Amrita Y. Krishnan, MD: But in the GSK group, only about 40% if I’m correct got prior daratumumab too, is that right?

Thomas G. Martin, MD: Right.

Amrita Y. Krishnan, MD: So it’s not as fair a comparison either.


Transcript Edited for Clarity

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Transcript: 

Sagar Lonial, MD, FACP: Krina, do you want to talk to us a little bit about some of the different CAR [chimeric antigen receptor] T-cell strategies that were presented at the meeting?

Krina K. Patel, MD, MSc: Sure. This was at ASH [American Society of Hematology] where we had 7 CAR-T talks in 2 different sessions. But there was an interesting poster out of China, from Nanjing, and this is actually a humanized BCMA [B-cell maturation antigen]. They were looking at 9 patients who got a fully humanized BCMA lentivirus transduced CAR T and a 4-1BB co-stimulation. And there was a 100% response rate. I think the interesting thing is—talking about can you treat BCMA again—3 of the patients had had a CAR T that was murine scFv [single-chain variable fragment] BCMA that had relapsed. And 2 of the patients on this trial ended up with CRs [complete responses], ongoing CRs, and 1 of the patients has a VGPR [very good partial response] still.

I think it is that question of, can you treat the vehicle, the target’s BCMA? But what you’re putting with it matters. And there’s some anecdotal cases of patients who got the ADC [antibody drug conjugate] or got a BiTE [bispecific T-cell engager] and then went on to a CAR-T trial, and they actually responded when they didn’t respond initially.

I think, yes, the BCMA world is saturated, but we don’t know enough about the actual antigen. And I don’t think you can compare it to CD19 and say, “Well, blinatumomab does this and then the CAR T doesn’t work as well.” I don’t know that you can say that about BCMA. I do think we have a lot to learn. I agree that there need to be a lot of other targets. Most of the trials have been with BCMA. Of course, in the New England Journal of Medicine paper that recently came out on BB2121, progression-free survival [PFS] was 11.8 months, and if you’re MRD [minimal residual disease]-negative, 17.7 months, with no other therapy, which is huge, compared to needing continuous infusions or therapy.

I think that was the biggest thing for our patients to have 12 to 17.7 or even more months where you have no other therapy. Quality of life, once again, was pretty impressive. I think in the other trials—Legend and Janssen—their data look pretty good. There was a little bit better PFS at 22, 23 months. But these patients had a little bit less in terms of therapy. They’re at about 3, 4 lines. The same thing with this trial in China, there are about 4 prior lines of therapy compared to BB2121, where there’s 7 to 8 prior lines. The more heavily treated population. So looking at those data, I think all the CAR T’s have pretty impressive data in that sense.

Of course there’s JCAR and Poseida, there’s so many that we’re all looking at. But allogeneic therapy is the other next thing and we do have a trial opening up with CS1 allo CAR T, where both the CS1 and the TCR [T-cell receptors] are knocked out. That hopefully will be opened in the next couple of weeks, and we’re really excited to see what happens. Because now, we have normal donor T cells. They haven’t been knocked out. You don’t have to wait a month, you don’t have to do bridging, you just go. The problem with allo, the question is persistence.

Sagar Lonial, MD, FACP: Right.

Krina K. Patel, MD, MSc: We have to do higher lymphodepletion, so the patients do have to be really ECOG-01 [ECOG performance status, grade 0/1], so we’ll see with this initial trial the logistics, how they are different. But I think it’s really cutting-edge and interesting stuff that’s going to be happening in the next few months.

Sagar Lonial, MD, FACP: Do you worry both with CS1- and CD38-directed CARs, that those targets are not quite as narrowly expressed as BCMA?

Saad Z. Usmani, MD, FACP: For sure.

Sagar Lonial, MD, FACP: And you might get into some trouble if you do that.

Amrita Y. Krishnan, MD: You read my mind. I was going to make that comment. I was just curious, what starting cell dose are you going to use for your patient?

Krina K. Patel, MD, MSc: We’ve actually lowered it because it’s allo, so it’s 3 times 10 to the 6th, and then there’s a minus 1, 2 to the 5th. One is on NK [natural killer] cells, it’s on regulatory T cells, it’s on T cells, and that’s where we knock out CS1 so there’s not fratricide.

So the question is, are you going to have more lymphodepletion now? All these CAR Ts have been great, but one of the big issues, besides CRS [cytokine release syndrome] and neurotoxicity, that we have learned to take care of and those are actually pretty reasonable, are the neutropenia and the thrombocytopenia. In some patients it’s more than 6 months so you have to make sure they’re PCP [pneumocystis pneumonia] prophylaxis; you have to make sure about Levaquin and other things bacterial, fungal when their CD4 counts are still low. So for a CS1, are we going to have more lymphodepletion and then actually end up with longer thrombocytopenia and neutropenia? So those are very relevant questions.

Amrita Y. Krishnan, MD: I think the other big question—this is one in the CAR-T space, right—is the cytopenia immune mediated, or conditioned? I think most of us believe it’s probably….

Others: Immune mediated.

Sagar Lonial, MD, FACP: It’s interesting. I won’t say to play devil’s advocate, but if you look at another way to get to BCMA, the GSK ADC, median PFS was 12 months. So yes, there’s ocular toxicity, but you don’t have CRS, you don’t have prolonged cytopenias, at least in that small experience. And I think we need a larger data set to really know. But for PFS, they were similar.

Amrita Y. Krishnan, MD: But my comment would be, how long does it take you to get an ophthalmologist to see your patient?

Sagar Lonial, MD, FACP: Quicker than it takes to make CAR T cells.

Saad Z. Usmani, MD, FACP: The argument can be made that you were actually seeing, even in those relapsed/refractory myeloma patients who received multiple lines of treatment, that it’s really the good ones who are getting the CAR Ts because those patients who cannot get bridging therapy, or who are going through bridging therapy, are not the ones who are being screened and enrolled on those trials.

Krina K. Patel, MD, MSc: I think the 60% response rate, once again, with continuous therapy versus an 85% response rate for BB2121, a one-time shot, right? And I get it, yes, that first month is a lot harder if you get the neutropenia. But I do think that if you’re someone who’s otherwise healthy, you’re working, I would pick the CAR T then, but not everyone can get it.

Amrita Y. Krishnan, MD: But in the GSK group, only about 40% if I’m correct got prior daratumumab too, is that right?

Thomas G. Martin, MD: Right.

Amrita Y. Krishnan, MD: So it’s not as fair a comparison either.


Transcript Edited for Clarity
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