CD19-Targeted CAR T-Cell Therapy in Managing DLBCL

Ian Flinn, MD: So let’s talk a little bit about alternative targets. We’ve been used to using CD20-based therapies for years now since the introduction of rituximab, I think it was in 1997—so, a long time since that was introduced.

But there are other B-cell targets. For instance, polatuzumab targets CD79b, which is part of the B-cell receptor complex. Other B-cell targets include CD19. So to me, CD19 is an attractive target because it’s expressed broadly in B-cell malignancies and not expressed really outside of B-cell lineage cells. So, when cells mature and become plasma cells, they start to lose CD19 expressions. It is, many others, like CD20, expressed on healthy B-cells as well, and so when we target that we could express, we could expect loss of CD19 circulating cells in our button.

And this has really made itself clear with CAR T [chimeric antigen receptor T] cells. One of the markers there is that when you don’t, can’t find T-19 positive cells, hopefully the CAR T cells are still present. Have you been working with any of the CD19-directed therapies? I know you’ve been working with the CAR T cells.

John Pagel, MD, PhD: Yeah, and by the way, thanks for reminding me how long we’ve been working with rituximab—that made me feel old, so I don’t necessarily appreciate that. But, anyway, the good news is we have new things to talk about and that will help us perhaps feel younger, I suppose. I think the CD19 agents are interesting and appealing. We’ve been working with those as obviously you have, as well.

You know CD19 is very important for B-cell receptor signaling, and so it’s a natural target for treating patients who have B-cell malignancies. And most of our work up until this point has largely been targeting CD19 with chimeric antigen receptor T cells.

And I think that has been … a game changer, certainly for people who have had diffuse large-cell lymphoma, who were unsuccessful with an autologous transplant—or perhaps, have even been refractory to that type of therapy. This has been a game changer for many of them. The response rates are quite good. They’re on the order of up to 70%, 80%, 90%with long-term survival, meaning people potentially cured with CAR T cell therapy, maybe somewhere around the order of 40% to 50% of those patients.

CAR T cells though are really not, completely in my opinion—I wonder how you feel—the complete answer, and there are many reasons for that. One of the things is what I just mentioned: still, many people relapse even after a CAR T-cell treatment, and the toxicity is not insignificant. Many of these people have—as we always talk about—significant complications from cytokine release syndrome, perhaps neurotoxicity, and that’s not to mention the requirement for hospitalization and for, of course, recognizing the cost of treatment.

So, we’ve been working with CAR T cells, have been a major advance, but we need to continue to do better, and we do need more agents. What’s your experience been with the CAR T cells, Ian?

Ian Flinn, MD: Yeah, I think it’s similar. I mean, before the introduction of CAR T cells, basically we would have told patients: “Unfortunately, there’s no real curative therapy for you. Our goals are palliative.” Now at least we have that, we have the hope of curing, as you say, 84% of patients with relapsed after autologous transplant refractory to frontline therapy.

And so that’s a huge advancement. But it also points out some of the issues as you mentioned. Now it’s not for everybody, right? I mean, there are significant risks of cytokine release syndrome. Risks of—and we’re getting better at that—how to treat that, how to moderate, or mitigate some of those adverse events. But the neurotoxicities are quite impressive in some patients, and it can be pretty scary for them.

And so a minority of patients who have relapsed and those with refractory large-cell lymphoma are really good candidates and ultimately benefit from this very impressive form of therapy. Now the good news is that these new next-generation CAR T cells look like they’re getting better and better. We’re getting smarter about treating some of the adverse events and trying to prevent some of them. But there’s some logistic hurdles.

At last at our center, you couldn’t turn this around immediately. You have to screen someone just like you would for a clinical trial: harvest the cells and send them to a central facility where they’re reproduced. And so there’s a time line and unfortunately, some people will progress during that, or they just can’t wait; they’ll have to have some other salvage therapy. And so in Seattle, are you facing the same hurdles that you’re facing or different hurdles?

John Pagel, MD, PhD: I think 1 of the things that we really forget when we talk about our enthusiasm with CAR T cells is that the people that we’re really doing the best are the ones with the more favorable disease who have large-cell lymphoma. So the unmet need is for those CAR T cells to really help those more aggressive patients, those with the double hits, double hit lymphomas; those are the ones with mixed rearrangements, double expressors. Those ones who have been refractory that they’re upfront R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, prednisone]. Those are the ones where we have a problem, even thinking about getting them to a CAR T cell. Or, if we can actually get T cells harvested, they progress so rapidly during the 2 to 3 weeks when we’re engineering those cells—just like you talked about—that they never get them reinfused. This is something we see not uncommonly.

So, we need to figure out ways to really approach those more difficult patients—and in particular, patients who are refractory to their standard upfront chemotherapy. It’s not that uncommon for us to see that. It seems like we see it more and more. I don’t know if that’s really accurate or not. I’d like to know what you think about that.

But where I’d love to see us be able to use this technology is in the patients who really need it, those people that are more aggressive, more refractory. And maybe we need to be thinking about other therapies for them as opposed to the CAR T-cell therapies.

Ian Flinn, MD: Yeah, I’d like to add 1 other group, too. There’s a group that’s the same one that you couldn’t take to a transplant. Oftentimes, they’re in the same group that can’t take to a CAR T cell— older patients, patients with heart conditions, patients with lung conditions. There’s a whole group of patients that never come into our centers because the referring doctors are like, “Eh, that’s just not going to fly, I know that,” and so they do their best what they can at their local institutions and their offices.

There’s certainly a need for better-tolerated, less-aggressive therapies to help our patients, those patients who are not eligible for CAR T cells and not eligible for stem cells, right?

John Pagel, MD, PhD: Yeah. And you mentioned that many patients are ineligible for a transplant, and you also said that they’re often ineligible for a CAR T-cell treatment, and I agree with that. We like to think that the toxicity is less with a CAR T-cell therapy perhaps than an autologous transplant. I would say that’s probably true. They’re different tradeoffs, different toxicities. But the bigger problem that I have, and I think many people do, is that they’re ineligible for a transplant because their disease is too aggressive, or refractory. Either they’re not chemosensitive as you mentioned, but that same thing prevents them from getting to a CAR T-cell treatment, in many cases.

Ian Flinn, MD: Yeah, I think you said that they will, that’s exactly right.

Transcript edited for clarity.