iwCAR-T 2026 | Updates on T-cell engagers and CARs in CLL: liso-cel, novel agents, and resistance mechanisms

Alexey Danilov:

Thank you so much for watching. We come to you from International Workshop on CAR-T Cell Therapy 2026 in Tampa, Florida. And we just finished the session on chronic lymphocytic leukemia/small lymphocytic lymphoma. And there were quite a few developments in the field over the past several years. And I’m joined by my session co-chairs here, and I would like to ask them a few questions. So first, Dr. Siddiqi joined us from City of Hope. Dr. Siddiqi, you nicely outlined the recent advances with liso-cel and CAR T-cell therapy in CLL. Can you summarize for us where the field stands?

Tanya Siddiqi:

Of course. So in the TRANSCEND CLL-004 trial, we already showed that among 88 efficacy-valuable relapsed refractory CLL patients who had failed prior BTK inhibitor therapy plus two or three other lines of therapy, the CD19 CAR T-cell liso-cel produces about 20% complete remission rate and about 44% overall response rate. And this is now after three years of median follow-up as well. There was a separate cohort on that trial of combining liso-cel plus ibrutinib. And we have a couple of years follow-up on that cohort. And among 51 efficacy-available patients, the complete remission rate on that is higher. It’s 45% with an overall response rate that’s also higher. And undetectable minimal residual disease rates are also higher, 60% with the monotherapy, with the combination more like mid 80% range. And then finally, at ASH of 2025, there was a real-world analysis of liso-cel across the country, across 17 different sites, pooled data of 41 patients treated with commercial liso-cel now that it’s FDA-approved based on the TRANSCEND CLL data. And we found in that analysis, again, heavily pretreated patients, but the last line of therapy was primarily either pirtobrutinib or some BTK inhibitor therapy. And that, in a lot of patients, was maintained during their CAR-T and after their CAR-T infusion. And what was found was that the complete remission rates were higher at 56%, which kind of leads us to believe that combining liso-cel with pirtobrutinib or a BTK inhibitor of some sort for some amount of time after CAR-T is actually given, can lead to higher complete remission rates. And now we need to follow them longer to see whether it translates into a survival advantage as well in these heavily pretreated patients.

Alexey Danilov:

Thank you, Dr. Siddiqi. So building on that knowledge and going into a real world, do you believe then it should be a recommendation to continue pirtobrutinib through CAR-T in CLL?

Tanya Siddiqi:

Yes, I think it is. If it started before leukapheresis, continue during bridging of any sort, and then continue for at least, it’s arbitrary, at least three months after CAR-T is given, but some people continue it longer, even a year. That remains to be decided.

Alexey Danilov:

Yeah, thank you so much. I’m also joined by Dr. Mazyar Shadman, who talked about bispecific antibodies, T-cell engagers in CLL, and there’s been some news there as well. Can you tell us, Dr. Shadman?

Mazyar Shadman:

Of course. We first talked about the role of bispecific antibodies in the current CLL treatment landscape and kind of concluded that there are unmet needs. We are not curing patients. Patients still need treatment. Approximately 25% of patients, even with all the novel drugs, still require novel agents with new modes of action and also the role of bispecific antibodies in improving the T-cell function in CLL, which is a known problem and in form of either consolidation or maintenance therapy. We briefly looked at the data from epcoritamab for both CLL and Richter transformation, but mainly focused on two novel drugs that are under development. One is the CD20 Titan tri-specific antibody by AstraZeneca, which is unique in targeting CD20, but also CD8 and TCR with the idea of kind of favoring CD8 activation, which may then clinically translate to a better safety profile and lower CRS rate, something that has been shown in the preclinical model. So there’s no data publicly presented or published on this molecule for CLL, but we are waiting for the results. And there are studies that are under discussion and development with this molecule. So we also talked about the other molecule that is being developed by AstraZeneca. It’s a CD19xCD3 bispecific antibody called surovatamig. And this drug is more advanced. There’s some data with non-Hodgkin lymphoma, but not CLL yet. But interestingly, there is a study that’s now publicly announced and is looking at the role of this drug in consolidation for patients with high-risk CLL defined as having an unmutated IGHV. So patients who receive a fixed-duration therapy with either venetoclax and obinutuzumab or venetoclax and acalabrutinib or venetoclax and ibrutinib are eligible to go on this study, again, if they had unmutated IGHV, and they would be randomized to receive surovatamig versus observation with a primary endpoint of PFS. Again, this study’s in the activation phase. But I think it’s an interesting concept and something novel that we haven’t seen before in CLL. And in general, we talked a little bit about the practical points of designing studies that include bispecifics to kind of match with the current landscape, which in general is a pretty patient-friendly, mainly all oral and fixed duration. So for a drug to be successful, it can’t be logistically too burdensome. And again, the hope is that in the future meetings, we’ll have more clinical data or some clinical data to discuss with these new drugs.

Alexey Danilov:

Yeah, this is the very interesting SOUNDTRACK study. And maybe this is the space where T-cell engaging therapy needs to be before the immune system is further compromised by multiple therapies. But I want to ask you this question, and maybe that comes from my naivety. You know, we do have decent data with bispecific antibodies in CLL with epcoritamab, CD20 targeting bispecific antibody, but CD20 is famously expressed at a fairly low level in CLL. So do you think CD19 is a better target for bispecific antibodies?

Mazyar Shadman:

Well, that’s a great point. CD20 is, as you mentioned, usually has a dim expression on cells. But, you know, we should also remember that rituximab was a drug that provided an overall survival advantage when it was added to chemotherapy backbone. So yes, CD19 has a stronger expression, and we do have liso-cel as a CD19 targeting CAR. So that would be a hope. Whether or not that would also translate to maybe a more toxic profile, we need to see because at the same time, when you have a stronger expression, you also have to worry about the safety profile. And that’s why we need the clinical data.

Alexey Danilov:

Thank you. And finally, Dr. Bishop from University of Chicago, you somewhat tempered our enthusiasm about cell therapies in CLL. And that’s based on reality, where at least with the data that we see, it seems like maybe we are not really curing that many patients. So why is that so? What are the mechanisms of resistance, and how do we overcome that resistance to cell therapies in CLL?

Michael Bishop:

You know, it’s an extremely fair question. And I really think my point in all of this is why, as compared to other B-cell diseases, we don’t get the same responses in terms of complete remissions. And so I think there’s been a number of very excellent studies trying to go back and look at the patients and make a difference between the responders and non-responders. And this came down to essentially three major things in terms of the CLL cells themselves. It comes down to the T-cell function, and it came down to microenvironment. And so the next thing is, well, based upon those mechanisms of action, how can we target them. And I think you’ve heard from all this prior discussion is, you know, Bruton tyrosine kinase inhibition is really, really important. And the discussion went on to say how that was important, but not only for the T-cells, but also for the microenvironment. There’s a number of other agents that we can employ to try to enhance this. And so I talked a little bit about PI3 kinase inhibitors, immunomodulatory agents, and then as you just brought up, going after different targets on the surface of the CLL cells. So I didn’t mean to dampen the enthusiasm. I think that actually, you know, we’ve heard this updated data on liso-cel and the incorporation of Bruton tyrosine kinase inhibitors. I actually think we’re moving in the right direction. So I am optimistic that we’re going to be able to benefit patients with relapsed and refractory CLL.

Alexey Danilov:

Yeah, I stand corrected. Thank you so much, Dr. Bishop.

Tanya Siddiqi:

So, Dr. Danilov, you talked about Richter’s transformation and the use of bispecific antibodies, T-cell engagers. So how does that compare with CAR-T in that aggressive disease?

Alexey Danilov:

Right. So thank you for that question. Indeed, Richter’s transformation remains probably the most unmet medical need in the space of CLL. We still have poor outcomes in these patients. And with cell therapies, we have all the same issues in Richter’s transformation that Dr. Bishop has outlined with deficient immune environment. I will say that we are making improvements in this space with novel therapies. And while CAR T-cells do not seem to be curative, there is a fraction of patients who obtained meaningful response, which can last up to two years after CAR T-cell therapy. And this is, of course, not good enough. So with bispecific antibodies, we have now data with glofitamab, epcoritamab, that shows that they are effective, although we will need longer follow-up to know how durable those responses are. And just like in CLL, I do believe the future is combination therapies. And there are several studies which are being initiated out there. For example, a SWOG study, S2504, which randomizes patients to R-CHOP with pirtobrutinib or R-CHOP alone in patients with Richter transformation. There is a German study coming out, which randomizes patients to epcoritamab, pirtobrutinib, or R-CHOP. So there is some promise in this space as well. And I believe we will be better armed in treating Richter transformation five years from now than today.

Tanya Siddiqi:

We didn’t talk about BTK degraders at all, but I think that’ll be another good, useful combination in the future.

Alexey Danilov:

Yeah, very little data with BTK degraders so far, really a handful of patients, but also promising. And, you know, there are different BTK degraders out there with different functions. So very important field as well, which we can leverage in the future. Well, I would like to thank everybody in the room, my panel members, and thank you so much for watching.

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