iwCAR-T 2026 | An update on T-cell engagers in follicular lymphoma and large B-cell lymphoma

Loretta Nastoupil:

Hi, I’m Loretta Nastoupil, and it was a great honor today to co-chair the session on T-cell engagers in lymphoma, and very happy to have my colleagues here today. Lorenzo? 

Lorenzo Falchi:

Hi, I’m Lorenzo Falchi. I’m a lymphoma specialist. I’m at the Memorial Sloan Kettering Cancer Center in the USA. 

Loretta Nastoupil:

And Jason? 

Jason Westin:

Hi, Jason Westin from MD Anderson Cancer Center. 

Loretta Nastoupil:

So, Lorenzo, I’m going to start with you. So you kicked off our session talking about frontline approach in follicular lymphoma, particularly focusing on mosunetuzumab, which is a CD3xCD20 bispecific antibody. So where are we currently with the treatment landscape, and how do these studies that you sort of highlighted potentially going to change that? 

Lorenzo Falchi:

Yeah, we are at a very exciting time. We’re at a moment where when I sit in the room across all my patients, I can tell them that we’re on the brink of a new era where we have transformative drugs that are truly chemotherapy-free, that can have the same potential as chemotherapy, potentially. And the data that I presented today, I think, really underscore the role of mosunetuzumab as a bispecific antibody targeting CD3 and CD20 in follicular lymphoma. We at MSK used it in an investigator-initiated trial as a single agent subcutaneously, and we enrolled about 80 patients. And really, we saw response rates and duration of benefit at the moment that compare at least in equivalence, if not sometimes favorably, with chemoimmunotherapy or other standard of care approaches. Naturally, there’s a difference between proof of concept and then evolutionarily speaking, like regulatory pathway or development of an agent. And so I think that what the landscape has moved towards or the field has moved towards is combination therapies. And bispecific antibodies being immunoglobulin-like molecules really lend themselves to a lot of combinatorial strategies, from chemotherapy to targeted agents to immunomodulatory agents. And so mosunetuzumab, for instance, has been coupled with BTK inhibitors, such as zanubrutinib in our experience, but also lenalidomide in the initial sponsored trial that then engendered the currently ongoing phase three randomized trial of Mosun-Len versus standard of care chemotherapy. And that is only the first of a series of randomized control trials that are testing chemo-free immunotherapy-based approaches or bispecific-based approaches to standard of care chemoimmunotherapy. There are four of those trials, very large, designed to establish superiority. So if one or more of those trials is positive, that may very well shift the landscape. 

Loretta Nastoupil:

Jason, you talked about sort of where we’ve come just in the last few years in frontline large cell lymphoma. And then your task was really to say, are we going to have bispecifics in frontline large cell lymphoma? So walk us through the complexities there. 

Jason Westin:

Yeah, thanks. So it’s a great time for drug development and for our patients where we’ve got a lot of new agents coming in the hematology and specifically into frontline large B-cell lymphoma. But that wonderful opportunity creates a lot of problems, and that includes having too many drugs without a clear way to select which patient should get which treatment. I think that’ll be a challenge for bispecific antibodies because we’re seeing glofitamab, epcoritamab, and odronextamab all have randomized phase-three trials in the frontline setting. I think all of them have a great chance of being positive studies, but on the other side, we won’t have a clear way to choose which patient should get those treatment options versus other treatment options, which are also being evaluated in phase three trials. And they’re also partnering a really exciting new treatment, the T-cell engagers, with 1970s chemotherapy, which theoretically could be T-cell suppressive in a way that’s actually pulling the brakes a little bit on what an optimal partner could be. So it’s a great time, but we really need to start thinking for the future about what are we going to do if we have all these options in the clinic? How do we select which patient benefits most? 

Loretta Nastoupil:

And I think both of you highlighted the efficacy of these agents – really quite compelling. How do we mitigate some of the toxicity? And so, Lorenzo, I’ll start with you. In frontline follicular lymphoma, it’s always a balancing act of maintaining good quality of life because these patients are anticipated to live for decades. Is a single agent going to get us what we need? Or if we need the combination, as you suggest, to enhance that efficacy, what are the practical strategies of making sure we keep these patients safe? 

Lorenzo Falchi:

Yeah, it’s a great question because bispecific antibodies are drugs that have a very reproducible safety profile, but where things like cytokine-release syndrome is a very prevalent adverse event. And early on, this was a scary adverse event. And the early data, the phase one data, particularly with glofitamab or even epcoritamab, especially when these drugs were not step-up dose, there was perhaps less emphasis on prophylaxis. These CRS were really severe, meaning grade three and higher. In follicular lymphoma, particularly with advent of step-up dosing, subcutaneous administration, we’re now at the point where, yes, CRS is seen in about half of the patients, but it’s really only grade one. And I always remind my patients and some of my colleagues that grade one CRS means fever, period. Grade one infusion-related reaction from Rituximab could not manage at home. You need a nurse to manage it. Grade one CRS, you can manage it at home, and none of our patients comes to the clinic. This is a key ingredient if you want to disseminate a treatment in the community where with subcutaneous administration, the chair time is very limited. CRS is, I would say, controlled, and it’s a cycle one phenomenon, it really doesn’t happen beyond that that maybe cycle two. And then after that really patients are on a treatment that they barely feel. The emerging adverse event related to bispecific antibodies in follicular lymphoma and beyond is related to immunosuppression and these drugs are definitely B-cell suppressive in a way that rituximab is not. But they’re also probably T-cell suppressive, we just don’t pay enough attention to it because we don’t have an immediate assay spendable in the clinic that tells you, oh, this patient is T-cell suppressed unless you do very advanced T-cell subset analysis. But we know that’s true because these patients get opportunistic infections and whatnot. So definitely prophylaxis with, you know, antivirals, antibacterials, sometimes, you know, globulins, depending on the level of hypogammaglobulinemia. These agents can be associated with neutropenia, so GCSF prophylaxis or secondary prophylaxis is certainly something to also think about. But nothing that us hematologists haven’t really seen before. So I think that safety itself should not be scaring us more than chemotherapy or rituximab have in the past. 

Loretta Nastoupil:

Jason, you hit on some really key aspects of we’re going to have probably several trials read out in the next few years. We saw POLARIX had a modest impact on PFS, no difference in overall survival. But we are starting to see that landscape evolve because the toxicity is very similar to vincristine when you replace it with polatuzumab. If we have, you know, four positive studies, including tafasitamab, the naked CD19 antibody, what tools or what expertise can you share on the average treating community oncologist to help them pick a frontline therapy for large cell lymphoma? 

Jason Westin:

I wish I had a short, easy answer to that because that’s the real challenge that’s going to happen for people who don’t treat large cell lymphoma every day, how do you have a shorthand rule of this condition means I should use this approach, this condition means this approach. And we’ve tried to pull things apart looking at the cell of origin with the idea that polatuzumab might be more effective in that situation. With becoming bispecific antibodies, as of yet, we don’t really have a biomarker to say this patient will or will not benefit. And so I think it’s going to become increasingly complicated when we have these studies that enroll all comers, really don’t have a biomarker, but they use IPI as a selector. And so I think we’ll be stuck with that for the time being of those patients with the highest risk, very high LDH, very aggressive disease phenotype, will be treated with these novel approaches. But for those patients that are kind of in the middle, IPI2, IPI3, not quite as sick, it’s going to be difficult for treating physicians to say, is this somebody I can just give R-CHOP to? Or is that inadequate? Do I need to use one of these targeted therapies? And if I do, which one? I think what we’ll see at the ASCO meeting this summer, 2026, is that tafasitamab plus lenalidomide is going to enter the conversation as another positive frontline study when combined with R-CHOP. And that uses lenalidomide, which we know also works a little bit better in the non-GCB subtype. So even the cell of origin predictor we’ve used over the past few years might be more complicated. So this is a big need for our field to help treating physicians to better understand: this means I should use treatment A, this means I should use treatment C. And as of right now, we don’t have answers to that. 

Loretta Nastoupil:

I really appreciate being able to ask both of you sort of your insights into this novel and emerging landscape. And I think this is just good news for patients. 

Jason Westin:

Absolutely.

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