iwNHL 2024 | Bispecific antibodies in NHL: comparisons with CAR-T, managing toxicities, & combination approaches

Stephen Ansell:

Well, hi, my name’s Steve Ansell. I’m from Mayo Clinic. I’m joined with my colleagues here, and we’re at the International Workshop on Non-Hodgkin Lymphoma, talking about a recent session that we’ve just had on bispecific antibodies. But I’m going to let my colleagues introduce themselves. Start right over here.

Marion Subklewe:

So my name is Marion Subklewe. I work at the LMU in Munich, Germany.

Martin Hutchings:

My name is Martin Hutchings. I am a hemato-oncologist. I work in Copenhagen, Denmark.

Krish Patel:

My name is Krish Patel. I’m a medical oncologist and work at the Swedish Cancer Institute in Seattle, Washington.

Steve Ansell:

Well, thank you very much for joining me, and we really had a fun session talking, not only about the data we already know about bispecific antibodies, but also looking a little bit toward the future. So just as we’re starting off, I’d love to get your thoughts, Marion, maybe to start with you, your thoughts on bispecific antibodies, CAR T-cell therapy. There’s always this discussion about which will win. What’s your view?

Marion Subklewe:

So I think, currently, based on the data we have, CAR T-cells clearly have a longer follow up, they have more real-world data, and we are pretty optimistic that we can cure in second line, for example, in large B-cell lymphoma. And we don’t have that data yet from the bispecific. So I think, currently, the winner are clearly CAR T-cells. But one must say that bispecifics have an excellent safety profile, so are very suitable to be combined. And we heard a lot about that today. So I think there’s a lot of promise in the bispecifics, and it’s going to be difficult to see, or to foresee, where they finally will place and what kind of combinatorial strategies will be successful.

Steve Ansell:

Absolutely. Martin, maybe to ask you your thoughts on toxicities and administration, because as we’re thinking about bispecifics, a lot of debate about giving it forever, giving it subcutaneously. What do you see as the optimal way to go as we look to the future?

Martin Hutchings:

So we don’t have any head-set comparisons of any of the bi or trispecifics. So we do cross-trial comparisons and a few of us have worked with several of the compounds, but it’s still subjective and idiosyncratic what you believe is true. They are quite similar. They cause cytokine release syndrome in roughly half of the patients. And in the vast majority of cases, cytokine release syndrome is mild and transient. I think we’ve talked a lot about cytokine release syndrome, both in the context of CAR Ts and the bispecifics in the last five years. And perhaps we should just get used to the fact that it’s the neutropenic fever of our age. Everybody is going to learn this. Young physicians, they are quite comfortable already, if they’re on call. What we should talk a little bit more about is the very long-term lymphocyte, particularly B-cell, depletion and the quite high risk of both banal, but also serious infections. This is what we’re going to have to work with in the years to come when it comes to toxicity.

Steve Ansell:

Well, I do like your comment about it’s the neutropenic fever of bispecific antibodies. I think that’s a great concept. Krish, maybe to ask you, so thinking about how this translates to what is really the real world, we often think about how we experience things, but the challenge is often as you take it to true community practices. How do you see bispecifics making it to those practices? Is it going to be feasible? Or not really?

Krish Patel:

Yeah, I think it’s a great question. I think, certainly, they have a learning curve, but like Martin’s approach, is that, like all things that are new, we have to learn how to adapt them to the places where patients live. And we’re starting to see that. And it’s really, I think, driven by the prevalence of bispecifics across the spectrum of oncology. We’re starting to see them now in solid tumors. We see them in plasma cell diseases. And so, as more and more are approved and they are really approved across the spectrum of diseases that our community oncologists care for, I think that helps us to drive things forward. And the other thing that I was really impressed by in the session we had is, when we think about combinatorial strategies, that also gives us the opportunity to potentially modulate the risk of toxicity. Like for example, the order in which we give therapies, debulking with a different therapy, then coming in with bispecifics may alter the profile to a point where that makes it more accessible in a lot of different settings.

Steve Ansell:

So I really think that’s such an important point and really comes to what combinations look exciting. So Marion, there’s a lot of conversation about combinations. What really impressed you? What are you excited about?

Marion Subklewe:

So coming from T-cell biology and being sort of in love with T-cells, I sometimes struggle with the combinations of CHOP with the bispecifics, because I’m concerned that it might be harmful to the T-cell compartment and the bispecifics cannot completely fulfill what they are supposed to do. So I’m really fascinated about trials where additional bispecifics are applied or even trispecifics that integrate positive co-stim domain to further activate T-cells and thereby also maybe overcome an immunosuppressive microenvironment. But I think there are lots of questions. I’m really happy that, now, early clinical trials are running. Some of them have been reported at last EHA with really promising activity and a very good safety profile. So I am really excited that understanding T-cell biology is now translating into early clinical trials.

Steve Ansell:

Thanks. And Martin, you actually have done some of those trials. Maybe your thoughts on, are they really as easy to give? Do they really look more effective? Or is it really just two drugs giving the same amount as one?

Martin Hutchings:

So the co-stimulatory agents that I’ve given have been IV, which takes a little bit of time, and that’s been the only hurdle. So we haven’t seen any clinically significant added toxicity by adding a co-stimulatory signal. And this is in the acute phase, obviously. What happens after one or two or three years with the prolongation of the activity of the T-cells and the bispecific, whether that adds to the duration of the toxicity that I mentioned before, remains to be shown. But they’re very, very easy to give. And I, just like Marion, I think, while admitting, of course, that you need to develop drugs in the way that we are bound to, which, in the case of lymphomas, involves a lot of chemotherapy, I completely acknowledge that. But it’s great to see that there are still development programs combining in biologically meaningful ways as we see. This is tremendously encouraging.

Steve Ansell:

Right. And Krish, maybe the last word from you. So while we are excited about the biological combinations, there’s also the need to do this to get things approved combinations. Your thoughts on interesting studies that are really going to move these agents really forward and into frontline or wherever?

Krish Patel:

Yeah, it’s a great question. I think the tools that we already have that are approved are probably the lowest hanging fruit to pick. And so, there, we saw a lot of data in the combination of bispecifics with antibody-drug conjugates. I think, to Marion’s point, getting away from cytotoxic chemotherapy or at least delivering it in a more selective way, so that perhaps it’s not going to impact the health of the cells that we want to function immunologically. So I think those are the combinations I’m most excited about is the bispecific ADC combinations, because the activity looks good. We know that there are therapies that can be used already and people know how to use them. So I think that’s probably our earliest best chance to get these combinations approved.

Steve Ansell:

Well, as you can hear, a lot of excitement around bispecific antibodies. Big thank you to Marion, to Martin, to Krish, for their thoughts and comments. And thank you for joining us and hearing about bispecifics, as we’ve been discussing them at the IWNHL.