iwCAR-T 2026 | The future of T-cell engagers and CARs in acute lymphoblastic leukemia

Bijal Shah:

Hi, I’m Dr. Bijal Shah from the Moffitt Cancer Center.

Ibrahim Aldoss:

Hi, I’m Dr. Ibrahim Aldoss from City of Hope in Duarte, California.

Bijal Shah:

We’re both here at the iwCAR-T 2026 meeting and both delighted to be here. Ibrahim, you gave a phenomenal talk about where we’re moving in B-ALL with bispecifics. What do you think were some of the key takeaways?

Ibrahim Aldoss:

Thank you, Bijal. I mean, it is an exciting time now with the new bispecifics that appear to be safe as well as highly effective and can salvage some patients who failed prior CD19 target therapy, including blinatumomab as a bispecific antibody, as well as CD19 CAR T-cells. An advantage of these bispecifics is the convenience of administration. It’s given intermittently rather than continuous infusion. So it’s more practical to implement in relapsed/refractory setting and possibly moving to the frontline therapy. But also the other advantage is the high efficacy we’re seeing with these bispecific antibodies that potentially can bring them to the frontline therapy to improve the outcomes of patients with newly diagnosed ALL and improve the curability later and possibly even shorten the duration of treatment and reduce the chemotherapy backbone part.

Bijal Shah:

You know, one of the things that I was really fascinated by in the presentation you gave was the activity of some of the newer bispecifics in places where traditionally we don’t see, you know, very high response rates or a propensity for relapse. I think one you mentioned was extramedullary disease.

Ibrahim Aldoss:

That is correct. At least in preliminary data from the SYRUS study with the use of single-agent surovatamig, we’re seeing the patient with documented pretreatment extramedullary disease involvement, that they are responding to surovatamig, unlike what we have seen with the continuous blinatumomab, something we see similar to the CAR-T cell therapy. So we’re very excited about this actual observation, and hopefully it can prevent some of the relapses we see when we implement blinatumomab as part of initial therapy.

Bijal Shah:

I’m going to ask you to put your prediction cap on. CNS disease. Do you think we’ll get there with AZD? I mean, we’re getting there with glofit and with epco. We’re starting to see some activity. Do you think AZD will get us there?

Ibrahim Aldoss:

It’s really hard to say. I mean, my impression so far, we haven’t seen CNS relapses on the SYRUS study, but I think there is a plan to actually check the concentration of the surovatamig in the CSF. I think the recent amendment of the study was approved. And hopefully we’ll learn more as we actually evaluate the concentration of the drug in the CSF.

Bijal Shah:

Fantastic. Fast forward. We’re now three years from now. Surovatamig is FDA approved. The MK-1045 compound is approved. Sub-cut blin is approved. Are these relapsed refractory agents?

Ibrahim Aldoss:

No, we’re more actually excited about how we can actually have more patients receiving this effective and potentially safer, more convenient drugs. So the goal, I mean, already thinking about it, how we can introduce these drugs in the older patient with kind of chemo-free light or chemo-free regimens and Ph-positive as well as a chemo-free regimen with TKI, as well as implemented in the AYA treatment where we can actually reduce some of the toxic chemo backbone. So, Bijal, let me ask you a question about your presentation, a very exciting presentation. I mean, where are we going with CAR T-cell therapy? And I think the question always, which patient is more prone to have these durable, excellent responses in the relapsed/refractory setting without the need of consolidation with transplant? Can you summarize what we know so far?

Bijal Shah:

I think it’s a phenomenal question. You know, one of the things that we’re seeing now in clinical practice as we treat, you know, much larger numbers of patients, well, one is the response rates are, if anything, better than what we saw on the pivotal trials. I think Caron Jacobsen had mentioned this when she was talking about large B-cell lymphoma yesterday evening. It’s interesting, as we treat sicker patients, we’re actually seeing improvements in outcome, and certainly that’s reflected with what we’re seeing with brexu-cel and obe-cel. And so I hope that trend continues. But we’re also now getting an opportunity to see, okay, yes, we’re seeing these very high response rates, but who are those patients that are prone to relapse over time? It’s not going to surprise you. It’s the TP53 mutant patients typically, or almost universally actually, progressing with CD19 negative disease. We’re seeing the same phenomenon in some of our Ph-like patients, but what’s interesting about the Ph-like patients is they’re not sort of true Ph-like in the sense that they also tend to carry these PAX5 rearrangements, these mutations that sort of compromise B-cell identity or at least give them the potential so that they may be able to escape it again through that downregulation of CD19. A few other genomic subsets, but I keep coming back to this idea of genomically driven care for ALL because I think those mutations are telling us a lot about the identity of the leukemia. And by that same virtue, hey, what are we going to do to get around it? What are we going to do to enhance our outcomes for these patients? And it may very well be transplant. I really like the study that you had conducted at City of Hope, and this is using your CD28 sort of T-cell memory enriched product. This is a CD28 product, right? So we know that the lifespan’s a little bit shorter, but in very high-risk disease, again, you enrolled TP53, you enrolled ZNF384s, you enrolled all these subtypes where, again, we’re thinking, hi, these are a little bit tougher, but you’re seeing durable responses. And one of the things that I thought was really neat, and I want you to comment on this, if you gave blinatumomab before the CAR. Do you think that might have had some impact?

Ibrahim Aldoss:

I think it’s the depth of the remission in this patient maybe what impact, and maybe it actually didn’t impact the quality of the T-cells we transduce with CAR. Because I mean, in my study, most of the patients receive either chemo-free or chemo-light induction, because it was more geared toward older patients. I think it was like 83% had prior blinatumomab, either induction or consolidation. So that may be [unintelligible]. But I mean, it’s really hard to know. We have to look at the single-cell analysis of the quality of these T-cells and kind of look, compare it with the patient who received more chemotherapy rather than blinatumomab. So that could be a part of it. And this actually brings me, Bijal, to the question, where do you see CAR T-cell therapy in the frontline therapy and how close we are to become, hopefully, in the near future, a standard of care where we can shorten the duration of treatment.

Bijal Shah:

I’m really excited by what CAR-T has brought in the relapsed/refractory setting. You know, we’ve improved survival by, you know, two to five fold. And it’s massive. And I think it warrants the study of incorporation in earlier lines. I think people are rightfully concerned about the toxicity of CAR-T. You know, what is that going to contribute to the, you know, longevity? You know, what we’re seeing, again, from these relapsed/refractory studies, actually, it’s probably less toxic than prolonged chemotherapy. You know, mortality rates in the first 90 days on a range of 5%. And even when we extend it out, you know, two, three years, we’re talking about more, again, non-relapse mortality should be more specific, non-relapse mortality is quite low, is quite low on the range of, you know, probably 10 to 15%. And that’s, you know, all comers, right? Not even things that necessarily related to CAR T-cell therapy. So I’m really excited about what we’re doing to bring this front line, and I think that the trials that are being studied, your study in older patients, our study focusing on MRD, MD Anderson’s study focused on those patients who have high-risk genomic features, but with the goal of giving the CAR in an MRD-negative state are all shots on the goal. One study that I’m really excited about is one that’s coming, and I think you guys may be participating on this study. It’s no longer going to ask the question about risk. In fact, it’s simply going to say, after induction chemotherapy, if you’re MRD-negative, can we deliver CAR T-cell therapy? Meaning, can we take our lowest risk patients and eliminate two and a half years of therapy and derive cures? And I think even if we only hit that at 70% or 75%, even if that’s where we land, we just saved patients years of therapy and by virtue of taking on lower risk patients, retain the ability to salvage them with AZD, with, you know, Merck, the 104.5 compound, with, you know, sub-cut blin, with whatever we want. And I think it’s such an incredible next step forward. I think that what we’re going to increasingly see are going to have to be randomized designs. But certainly knowing what we know about how these drugs perform, or how these CAR T-cells perform, boy, I mean, put me in that position. Dr. Shah, you can take three years of therapy, or you can shortcut it and do a CAR.

Ibrahim Aldoss:

But do you think we need a randomized study to kind of get this, actually, CAR T-cell therapy in front line?

Bijal Shah:

For high-risk patients, no. But for newcomers, I suspect the FDA is going to ask for… I mean, it does meet the definition by the FDA of an ultra-rare disease, right? 3,000 adult cases in the U.S. per year. But at the same time, I suspect they’re going to want a randomized design for FDA approval. Now, NCCN is a different story. And what happens in that context is a little harder to predict. But I think that it’s probably where we’re going. You know, I’m also really excited about what we’re doing outside of the CAR itself. You heard me allude to that when I talked about giving blinatumomab to improve T-cell biology going into the CAR. There are also things we can do with lymphodepletion that we haven’t even begun to explore. We’re still in a fludarabine-cyclophosphamide era. And I think that that’s terrible. We have so many directions, so many immunomodulatory things we can do as a component of that LD that we haven’t even begun to dig into. And then, of course, we have to talk about all the new technology with the CARs themselves, right? What we’re doing with dual antigens, in vivo, and I could go on and on. But it’s really an exciting time.

Ibrahim Aldoss:

I would add also, I mean, as we actually have a more targeted therapy for the different subtypes of the leukemia, TKIs for Ph-positive, menin inhibitor for KMT2A. I mean, do you envision that, I mean, it will be similar to the transplant patient going to remission, receive CAR, then they will be on the maintenance.

Bijal Shah:

I’m glad you asked me that. Why do we transplant? You know, my transplanters keep telling me there’s this thing called GVL, right? Where the graft attacks the leukemia. Is CAR any different? And, you know, I’m saying that as a provocative question. When Scott Roderick went and biopsied patients with lymphoma 10 days after, 98% of the cells were actually non-transduced T-cells. They were just part of the product that was infused. And when we talk about T-cell health, when we talk about what it means to derive cure in ALL, we may be transplanting by virtue of giving CAR-T in and of itself. And so we have some room to go. And again, I’m excited by some of the trials that are going to enhance T-cell health, enhance T-cell biology to help us inform those outcomes, including the bispecifics.

Ibrahim Aldoss:

Thank you, Bijal.

Bijal Shah:

And thank you, Ibrahim.

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