iwCAR-T 2025 | CAR-T in ALL: dual targeting strategies, CAR-T in pediatric patients, managing ICANS, and more

Claire Roddie:

We’re here at iwCAR-T 2025 and we’re going to be doing a session today on adult acute lymphoblastic leukemia. My name is Dr Claire Roddie. I’m an associate professor at University College Hospital in London. 

Rebecca Gardner:

And I’m Rebecca Gardner. I’m a pediatric oncologist at St. Jude and we will also talk about pediatric ALL and CAR T-cells. 

Bijal Shah:

I’m Bijal Shah from the Moffitt Cancer Center I also focus on ALL. I’ll give a little update on brexu-cel and we’ll hear more from me. 

Noelle Frey:

So I’m Noelle Frey from University of Pennsylvania. 

Claire Roddie:

Great okay so I think we can all agree that we had a fantastic session today. It was a lot of heated discussion about all the various presentations. I think we should probably start with you Noelle because you had some really lovely data to show us on dual-targeting CAR T-cells for adult ALL. Do you want to tell us a little bit, what was the most important finding from your presentation today? 

Noelle Frey:

Yeah, so I think we’re at a phase, when we think about treating people with acute leukemia with CAR T-cells, where we know we’ve been able, as a field, to establish really good response rates. And so one of the questions is, well, what’s the next step? And even though we have very good response rates, in the adult setting, independent of which product patients receive, relapse remains one of the biggest challenges. 

And so relapse can come in two flavors. So sometimes the leukemia still has that CD19 protein on it, which is what the CART19 targets, but other times the disease grows back without that protein. So even if you have received an excellent CAR T-cell, the disease has found a way to escape it. 

So one approach that a lot of different groups have been exploring is what if at the very beginning, instead of just targeting the CD19 protein, you target two proteins. And that way you might minimize that chance of having the disease grow back in that manner I was just discussing. So we’ve done a trial at Penn, which is actually now also opened at the Children’s Hospital at CHOP, where at the very beginning, instead of just giving CART19, we give two. We give CART 19 with CART 22. And one of the most important things is understanding if that approach has a safety difference from giving just one CAR – cell at a time. And so we were able to find that it is indeed safe. And the exciting thing is it’s a small number of patients, but we’re now four years out from that trial and the majority of the patients are still in remission, and so I think we have good evidence that this approach is also effective. 

What I think we don’t know and what we need more clinical trials for, more research in, is whether that approach actually… how much will that, in a large number of people over a long period of time, how much will that really move the field forward? So we need to do more work. 

Claire Roddie:

Well, the other thing that struck me listening to your presentation was also that, with the addition of the new target, there’s also an addition of some sort of other toxicities as well. Do you want to talk a little bit about the toxicities that you saw with this product? 

Noelle Frey:

Yeah. So there are a group of patients who have excellent persistence of their CAR T-cells in their body over time. And one of the benefits there is… what that means is that those CAR T-cells, they’re living and they can still go through the body and if any disease tries to grow, attack it. And we know that at least in this product that correlates with staying in remission a long time. However, what we learned in this trial is that in the patients that have that persistence, which again is what we want, there’s probably an inflammatory state that can cause kind of delayed side effects that are a lot more subtle than the side effects we see within the first few weeks of CAR T-cells. And so one of those side effects is low blood count. So we did have a couple patients on this trial who had low blood counts over time. And we actually, those two patients happened to have had a prior allotransplant from a donor and we gave them a boost of the donor cells, which helped improve their blood counts. 

I think it’s just a really good point is that when sometimes when we do clinical trials, there’s like a very specific endpoint, like are they in remission or how are they doing at one year? And I think we still have so much to learn about these therapies that that longer term follow-up is just really important. 

Claire Roddie:

And do you think that any of those side effects or any of the outcomes that you saw could be influenced by the fact that these are heavily pre-treated patients who most of them had seen CAR before? 

Noelle Frey:

I think so. Most patients on the trial had had multiple lines of therapy, had had prior bone marrow transplants, which just means it’s a relatively new bone marrow that might be more sensitive to having low blood counts. 

Claire Roddie:

And Bijal, sort of moving away from 19/22 CAR, I think one of the nice points at the end of your presentation was about, you know, what does the future look like? Because we’re all talking about these patients who’ve been through multiple lines of chemotherapy and we accept the risks, including toxicity. What about taking CAR-T and putting it right up front in the frontline setting and that lovely presentation from the team?

Bijal Shah:

Yeah, so, you know, I think we’re seeing this evolve in tandem in pediatrics, I hope, but also in the adult setting where our outcomes are a little bit more dismal, right? When we talk about our expectations with chemotherapy and maintenance and all the things that we do before the inclusion of blina, it was around 35/40 percent was our long term survival expectation. A little better in young adults, but certainly we wouldn’t declare that as a victory. We’ve now incorporated blina into frontline, but we still don’t really have a sense of how the whole population did. So we were able to validate that adding blina to frontline therapy for adults improves outcomes, no question. But how much are we talking about going from 40% to 50%? Or are we really making a more meaningful difference for the entire population? And that’s what we still have yet to learn. 

Even when we take that into account, we’re still talking about multiple cycles of chemo, sandwiched now with four additional cycles of blina plus the maintenance and so one key question is could we simplify that? We at our center opened up an investigator-initiated trial using brexu-cel after induction. Any patient who’s MRD positive by the Clonoseq assay can receive brexu-cel as consolidation, no bridging, we go straight into therapy and we’ve been very pleased. I’m not ready to present the data yet but we’ve enrolled around 17 patients so far. 

We also have the data from Ibrahim Aldoss and he’s already done this in about a dozen patients, focusing on elderly patients where we also tend to accumulate a lot of very high-risk genetic findings, and really with over six months of follow-up seeing the patients doing extraordinarily well. He had one patient, I think it was, molecularly progressing, a Ph+ patient using TKI maintenance where they changed the TKI and got the patient back into MRD negativity, so really highlighting its feasibility. And so hopefully I’ll have more to say in that regard. I think there’s planned trials now with Autolus as well, I think there’s a couple. 

Claire Roddie:

Well that’s because it’s such an important area, you know, because the whole concept of the one and done as opposed to these extremely protracted regimens that we’re used to putting our patients and their families through. And Rebecca, that sort of leads me on to you. I know you have some strong feelings about blinatumomab that you may want to share with us today. 

Rebecca Gardner:

Well, I think, you know, in pediatrics, I think a struggle for us, that is not a bad struggle, is that our outcomes with upfront treatment are like 85%. So if we want to think about how do we move CARs into the upfront setting, that’s a really hard bar to overcome. And no matter how good our studies are, very few patients who have an outcome after CAR that you could say, this trial shows CD19 CAR gives you event-free survival of 90%. So until we get to that bar, I think we have to be really creative in pediatrics, how we move CARs up front. And I think where I’m really interested is, right now, the paradigm is give chemo, if you fail chemo, then give CAR. But if we can flip that and say, let’s give CAR and if that looks to be failing, then we can rescue you with chemo. There’s a lot of questions in doing that. And does receiving CAR first change your sensitivity to chemotherapy? I think probably not. And so I would love to push us to continue to think about how we can incorporate CARs in the front line to reduce a lot of the burden of therapy that we see for our patients right now. 

Claire Roddie:

Yeah, so the devil’s advocate would say, what about the financial toxicity with an approach like that, you know, how would you argue against those? 

Rebecca Gardner:

I think the financial toxicity for me is easy to argue against because I think when you compare CAR T-cells to blina, and I’m not like an economic oncologist, but my like rough back of the napkin math, it’s not that discrepant between several cycles of blina, especially if you’re talking about four cycles of blina plus CAR, I think they kind of cancel each other out. The harder thing in my mind is, well, maybe we could do this in an academic center, but if it’s successful, how do we transport that to the world? And I think that’s where I don’t have an answer. And I think it’s something that we really need to think about. It’s hard enough to get blina in places and the hurdle to overcome CAR, I think, is even greater. 

Claire Roddie:

Yeah, yeah, I would agree with that. So, well, if we take us back to where we are right now, which is not necessarily a first line setting, let’s imagine that we have these situations where patients do relapse with antigen-negative disease, that is the Achilles heel of our therapy. And of course, you described really nicely your 19/22 combination today, Noelle, where do you see this going in the future? I mean, you’ve got some really promising outcome data, but you know, what happens next for this? You know, we’re obviously treating the patients after multiple lines, is this something you’re going to try and bring sort of, you know, closer to the upfront setting or earlier in the treatment algorithm in place of CD19 CAR? Or what’s the goal? 

Noelle Frey:

So I think it’s a great question. So are we ready yet to take something like a dual-targeted approach with some preliminarily exciting data? And it’s not just our study, other approaches targeting both antigens have been very exciting as well. But I think, not to put down our approach at all, I think it’s very exciting, but I think another way to think about it is… I think as a field, we haven’t embraced non-CAR related combination strategies in a kind of systematic and investigative way. So I think Rebecca was outlining an approach potentially in pediatrics to not necessarily fully get rid of chemotherapy, but I think you can imagine other approaches to minimize that risk of antigen escape. Inotuzumab is approved to target CD22. I don’t think we know adding CAR22 is necessarily better than a targeted approach. So I think there’s lots of ways to be creative in the upfront setting that may be less daunting than a dual CAR strategy, at least at this time point. But I do think dual targeting is definitely an area that we should keep exploring, and there’s other targets besides 22, of course.

Claire Roddie:

Of course, of course. And Bijal, in your experience, because we were talking a little bit about the sort of toxicity side of CARs, and you mentioned the real-world data using brexu-cel and there’s approximately 30% grade three or more ICANS. What’s your current practice in terms of managing that? What’s the innovative ways you’re dealing with that now? 

Bijal Shah:

It’s still pretty standard steroids for management of ICANS. We have not found much benefit from using anakinra. I think emapalumab, the UPenn group were the first to report this in peds, is a really exciting approach. We’ve seen rapid resolution of both ICANS and CRS using that particular agent, but it’s very early days. And when we talk about ICANS, it’s also, and we’ve all seen this, there’s ICANS and there’s ICANS, right? Someone’s a little bit confused, again, maybe just from their fever, but still you have to call it grade three because their eye score is off or whatever. There’s that ICANS, and then there’s, okay, I have to send you the unit, right? We have to prophylactically intubate you because you can’t control your airway. There’s that ICANS, and we conflate the two. 

And that’s one of the big challenges. What I’ve seen, particularly as we incorporate CAR-T into lower tumor burdens, again, highlighting really the strategy of bringing it in the frontline setting, but incorporating these lower tumor burden settings means that you escape a lot of that, right? I mean, now when you talk about ICANS, if you get it at all, right, it’s a day, sprinkle some steroids and they’re better, they’re discharged. They’re still home by day 10 or local lodging for monitoring by day 10. It’s a totally different phenomenon. And I see that even outside of the trial, right, when we’re talking about treating in clinical practice, most of our patients are actually getting to the hospital really fast. A, we’re recognizing it more quickly. B, they’re coming in with lower tumor burden. And C, like I said, it’s the nice ICANS. I don’t know how we, I don’t know, I’m curious to hear you guys’ thoughts. I was thinking about this as I was coming to the meeting. Is there a way that we could redefine even how we grade it based on what happens to them in the hospital, right? If they’re going to a sniff, to me, that’s grade four, okay? If you’re in the hospital and your discharge is not back to where you started from, that’s a big deal. That’s the way I’d love to somehow try to tailor what we’re doing. Because right now it’s very based on how do you intervene, right? If I see this, I do this. If I see this, I do this. And I think we’re missing something. 

Claire Roddie:

I agree. It’s sort of like refractory or prolonged events have got a sort of a very different flavor for sure and it needs more attention, clinical and research attention. And obviously the other interesting thing that Rebecca you brought up in your presentation today was about how obviously we want this CAR-T expansion and we want potentially in some products persistence but you have a very novel way of trying to induce re-expansion of cells when the numbers drop. Do you want to tell us a little bit about that? 

Rebecca Gardner:

I think, you know, we identified that there were certain groups of patients who were more likely to lose their CAR T-cell engraftment early. And we thought if we could give them extra antigen, could that help their CAR T-cells stick around longer? And so very preliminary data, but we developed a system in which we could manufacture what we call TAPCs, so it’s taking their T-cells rather than manufacturing CAR T-cells, we gave a vector that transduced the T-cells to express a C19 tag. And essentially, this was food for the CAR T-cells that had already engrafted. 

And what we saw in our pilot experiment was that they are really safe, well tolerated, they don’t cause recrudescence of any inflammatory toxicity, but they do allow for this episodic expansion of the CAR T-cells. And the data seems that they do help improve persistence of the CAR T-cell product. I think whether this can improve leukemia-free survival is unclear, and definitely more study is warranted to really interrogate the usefulness of giving TAPCs to more people. 

Claire Roddie:

And remind us again of the timeline, the interval between administering these TAPCs and then seeing that reciprocal expansion in your CARs. 

Rebecca Gardner:

Yeah. Yeah. So usually about three days after infusion of the TAPCs, you can see the re-expansion. And that makes biologic sense. So if the CAR T-cells are sort of more quiescent, they experience the antigen, they start to expand, then you can detect that expansion in the peripheral blood. 

Claire Roddie:

And do you think there’s any place in this sort of algorithm for something like pembrolizumab to potentially sort of boost the signal further? 

Rebecca Gardner:

Yeah, you know, in my experience in ALL, adding a checkpoint blockade has not shown much benefit. And I think, you know, it could still warrant additional sort of systematic evaluation, but it’s not something that I’ve really thought a lot about. 

Claire Roddie:

Well, it sounds like you’re gonna need to think a lot about your APCs in large B-cell lymphoma if our colleagues in the front row at the end of the session are anything to go by. 

Okay, I think we’ll wrap it up there. So I’d just like to sort of finish off by thanking our expert panel. So Noelle, Bijal and Rebecca, and I’m Claire. And thanks very much for joining us for this ALL deep dive. We’ll see you next year.

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