So welcome to iwNHL 2022, we’re here in Barcelona. I’m John Gribben from Barts Cancer Institute in London. I’m joined by two of my very good friends and members of the scientific Oversight Committee of iwNHL, Cath Bollard from Children’s Hospital in DC and David Maloney from the Fred Hutchinson Cancer Center in Seattle. So another very successful meeting, I think we can all agree. I think, Cath, you said it right at the beginning. It’s so nice to be able to reboot and be back together again, having been virtual for the last two years, and I think particularly for a workshop, we’ve all thought that the virtual format can work, but for a workshop, really being together makes all the difference, don’t you think?

I completely agree, and it was not only amazing to sort of be all together in person, but actually with us all together in person, it was very clear, bringing people from diverse backgrounds and expertise how fast the field has moved in these two years since we’ve been together in person and and while there has been, you know, a lot of virtual format meetings, it just really is more of a more energized feel and and more, you know, promote sharing of ideas, which I think is so critical to to this meeting.

You know, David, do you feel the same way that you know,

I think not for a first, But one of the big things of this is to try to get industry to actually interact. And we actually did this time. And so, um, so I think there was there was a good interaction both within the meetings and obviously at all of the more social gatherings, the breaks and lots of discussion with with some of the industry partners which, frankly, we wouldn’t be able to do even the research without industry partners. And so in this meeting, you know, capped it off.

So, yeah, I think that that absolutely sums our whole interaction up. You can have all the discussions you like in a virtual format, and we very much got used to it. But all those off camera discussions that can’t happen in a virtual format. meetings you have off the side, the ability to kind of come together, I think also there is a kind of palpable feeling for everybody that they were happy to be back together again, which kind of gave a very good atmosphere to the whole meeting this year. Anyway, let’s stop talking about the social aspects and get into into the science. Um, it’s kind of become traditional these meetings that we start with the T cells. Laurence, who’s also of course, on the committee. But you know, one of the world’s experts on the pathology of T cell lymphomas always puts together that first session, and I think she always does a great job in bringing together some of the world’s experts to talk about T cell lymphoma. I think none of us would claim to be experts in this field, But I think I certainly learn enormously from hearing the new science that Laurence presented as well as the clinical sessions. So what’s your feelings on? David I wanted to start with you on this one.

Well, you know, I I thought the science was intriguing, but then we also integrated a lot of the novel therapies. You know, we really kind of started to hear for the first time, you know, t cells against T cells. So you know, how do you cope with the issues of fratricide? How do you How do you target an antigen that’s expressed on the on the cell you’re actually trying to use as an effect or sell and and and a target? And so we we saw some promising effects, uh, promising studies on that. And I think that that was exciting to see.

Yeah, I think it’s a kind of a paradigm of looking to see the sessions mixing the science and the clinical work together. And I think we’ll come back and talk about that and all the other sessions we’re going to be talking about in just a moment.

And I think you know, that session really showed that integrating the sort of the pathology and and all this sort of, you know, sequencing and and just really identifying so many different potential targets. It’s almost like actually, where do you begin? But But I think it then showed, you know, with very elegantly, you know, then the translate ability of those sort of basic discoveries. And, you know, I really liked the way that session was built like that. And I think that’s sort of what we wanna see more of that. This meeting is well that you know, these basic discoveries from our patients own tumors and and how that can inform care for the broader population. It highlighted some of the challenges, though, too, because, you know, I mean, we were sitting with a situation where we’ve got a lot more drugs, and then we ever had some of them a lot of marginal, kind of like low level drugs. And then how do you rationally potentially combine them to to make progress? So a lot of excitement?

Yeah, absolutely. For me, some of the more exciting sessions here. I’m not just saying because it’s you but actually the sessions that you two put together. That is the CAR T cell session we did yesterday. But also the kind of count pointer point thinking about The big question I think many of us have in the field of B cell malignancies right now, which is, um, where do bispecifics fit vis-a-vis CAR T cells. And of course, none of us know the answer. But we had some great sessions, really looking at that in detail over the last two days, interspersed also with a whole science section. You know, Stephen Ansell etcetera, presenting work again on the kind of the basic tumor immunology of thinking about What is it about the microenvironment of the malignancy we have to think about and how that might impact these therapies?  So your thoughts?

I mean, I think that’s you’re absolutely right. Actually, we should have actually started our session with someone like Dr Ansell talking about tumour immunology, and these sort of unique attributes of these different tumors immunologically because that doesn’t form our immune-based therapies. And what I liked about our first session that we,

you know, focused on CAR T cell therapies. Actually, um, was that we did have, you know, the real world experience of CD19 CAR T cells. But then it was the focus was, Where are we going to next? And, you know, David, you know, focused on next-generation CD19 CARs. Um, but then we heard great talks from, you know, clinical trials, which are really promising, targeting different antigens, and outside of of the B cell malignancy space. Because I think there’s always been this concern that, um, CARs, you know cannot be effective for anything outside of a B cell malignancy. But I think we’re now realizing that it is not true. And, uh so I think, you know, coming back next year, we’ll we’ll just see even more data and more excitement in this area.

The challenge next year is going to how we fit it all into a two day meeting.

That’s a real challenge. I mean, for me, it’s kind of gratifying to see reproducibility in the real world for what was happening in clinical trials so often. What we see in clinical trials, you know, is that it’s such a select group that by the time you get to the population that really has the disease, that they don’t really match up. Uh, to my surprise, both with, uh, with all the CAR T cell products were seen essentially the same thing in the real world setting. And people who would not have even qualified for the clinical trials like more than 50%. So that’s I think that’s at least that makes our process. It validates our process right of the clinical trials. Uh, that could be I think maybe they shouldn’t be so selective, and we should aim for more of a real world population in the front line in the trials. But it’s at least validates, uh, that approach.

You’re absolutely right, David. And one would expect that when you start going to an older patient population more frail, the ones that wouldn’t fulfill the criteria in terms of other toxicities, that the efficacy would be less. But not only was the efficacy at least equivalent, but a lot of the side effect profiles were less, which, I think add adds into that We’re actually getting better at managing these patients and knowing how to handle many of these toxicities and stepping in earlier, earlier to see. And of course, a big advance clearly was knowing that we could use steroids in the very early days we didn’t we weren’t sure whether we even could. Now it’s like second nature. That, of course, has really informed the way in which people are able to handle the side effect profile of the bispecifics.

I was about to say that I think the bispecific world has really learned from the lessons from the CAR T cell world and and so that’s what I was interested in from our debate session that we just finished is you know, we probably in the old days if we just started with bispecifics, I think we would have seen way more challenging, um, outcomes because, you know of the lessons that hadn’t been learned at that point. But they are now starting, uh, at a later time point, and

I will be very interested in what happens in that bispecific space. There is clearly a lot of new agents coming down the pipeline and because it fix that fits the drug model. Right. So, um, we will see a lot of these head to head comparisons. I think over time,

I certainly agree with that. Interestingly, you know, what would we have called infusion reactions in the past? Right. So, like rituximab infusion reactions, we would call that now we would call them CRS and, like, we would never leave the patient at home if they had a fever of 101 and, you know, rigors, which we always did, right? We just said Okay, let me know if you don’t get over it. Right. But now so, yeah, take some Tylenol and, you know, call me in the morning so they But now with because of CAR-T I think because it is really ramped up the the extreme in CRS and neurotoxicity that all the things in between I think bispecifics actually suffered a little bit from it. Because now what do you do with someone who has a fever at home after they got it by specific Do you really need to go full blown?

You know, reaction like a CAR-T which what I would always admit the patient to the hospital or is there going to be some middle ground where you’re going to, um, leave the patient at home and tell them to take time off? So I think that’s what we need to learn. And that’s what I learned from the last session is that translating the bispecifics from the clinical trial space to actual practice, It’s not going to be quite as easy as I thought it was gonna be, you know? So I think there may be a big favor, and I know you guys have some experience with the subcutaneous form of administration for some of the bispecifics and you know, maybe that that that would maybe be a future to

Oh, I think for us that the revolution in terms of the clinical trial development, you’re right in Europe For some reason, I don’t know why it’s happened that usually in Europe we get it after you guys get in the States. But we’ve already moved into a much more subcutaneous administration. That’s been a game changer. You asked the question about inpatient admission after cycle one, Um, and even then it’s only mandated because it’s in the clinical trial to admit they’re usually in for 24 hours. But after that, we were doing this solely as an outpatient in the outpatient setting and seeing very much lower uh, you know, toxicity profile that we did with the the Intravenous, where we were seeing some really vicious cytokine release syndrome, even in the setting of knowing how to handle it in terms of having experience of seeing this with CAR-T. So I think that is a game changer.

We saw some great great talks from CD20 as an alternative basal target and CD30 which was actually I thought some great progress made with Barbara’s talk. That was very, very interesting.

Um, they started obviously thinking about other novel agents and, of course, this time with a whole section on again, immune based, you know, antibody drug conjugate. So I got a whole variety of drugs coming out in that space. It’s great. We’ve got so many drugs, but one of the problems we’ve got in terms of thinking, how do we manage to put these together logically in the face of, you know, all the other advances we have? And of course, what we’re seeing is not only are CAR-Ts moving earlier, but the bispecifics are now even coming right into frontline in combinations. So with all that said, how do we, what’s the pipeline for development of many of these agents that we’ve heard about that this meeting.

I mean, I think that’s you know, and you didn’t mention the BTK inhibitors. We also had a whole session on that, and, you know, as someone who’s more in the pediatric space, it was mind blowing. How many new agents are being developed in that space as well? And I agree at the time I was thinking, How do we solve thoughtfully pull put together these combinatorial strategies And, um, I think, you know, we saw some early, um, progress in terms of combining BiTEs, bispecifics with CAR-T um, clinical trials, planned clinical trials that are ongoing. And I think that’s what’s going to have to happen step by step. And we shouldn’t be, um, fooling ourselves that because they don’t call chemo, that these are going to be toxicity light regimens. And I think, um, the potency of the immune system and combining with, say, a BTK inhibitor. You know, we are gonna have to be really mindful about toxicity, so that to me is, um, you know, safety first.

And then I guess the other. The other thing I took from it was, although we’re talking about clinical development, although we’re talking about these agents, how often people are taking into account the science behind what’s a logical combination? We seem to have gone past the era of thinking We’ve got drug a and we’ve got drug b. Let’s put a and be together and much more of what’s the rationale for thinking This is a logical combination, both in terms of its efficacy, but also in terms of non overlapping toxicity profiles.

Yeah, I think it’s also still important, though the drugs have single agent activity. I mean, I don’t I don’t like this approach of Well, this drug didn’t work here, but it will work in combination. I mean, maybe it will, but that’s really much, much more of a you know, I think a leap. What I What I appreciated was that some of the window studies where you’re we’re starting to see, you know you can You can use the novel agents and maybe get some tumor response is in an area where we thought we had to give you know, R-CHOP. We saw R-CHOP actually lose finally, right with the kind of the pola-R-CHP data suggesting at least progression-free survival has improved. And so it’ll be really interesting to see if it’s more R-CHOP plus drug X, or whether we continue that or whether we go. As you said more scientifically driven, it’s going to be challenging. I I personally still have issues with targeting the same antigen that we’re going to eventually maybe get to a definitive CAR. So I’m I’m really reluctant to give 19 targeted agent either an ADC or an antibody if I’m then going to come in with a CAR, which I think is going to try to be a definitive therapy. Obviously, we’re not curing everybody with a car. And there’s, you know, 60% of people still have progression of disease, and there’s a lot of room for these other agents. But sequencing is really going to be important.

So, for you, then David would a bispecific targeting CD20 be a better approach than a CD19 Or, of course, the alternative, you do a CD19 CAR, then you go to a CD19 bispecific and then a CD20 CAR.

Potentially. Yeah,

Okay, um, the you already raised the issue. I mean, when we had one whole session talking just about, uh, all the different BTK inhibitors, which are now in development and how many respects they’re competing against each other. In some respects, I thought I thought Loretta Nastoupil did a really nice job actually listening to the remit of saying why she thought there were some specific indications why she would choose one over the other rather than just a presentation on what that antibody was. She actually did also a great job in doing that. Also, when it came to the bispecifics about making the case for using mosen in the follicular setting and perhaps not in diffuse large B cell. So I thought she was really thoughtful in terms of thinking about the questions we were trying to ask. But it is hard to have one talk after another after another, talking about the same class of drugs and trying to make a sense of, you know, how do we select which is the right one for the right patient?

Yeah, it would actually be good to have had her at the end, just sort of trying to tie it all together because, yeah, there you go, because I think you’re not going to get you know too many head to head trials to make these decisions. So it’s really the boots on the ground person in the clinic, you know, being thoughtful about which patient population is better served by certain agent X over Y, and I think that’s our

Yeah, surprisingly. I mean, some of the companies are taking these on right? And because it’s trying to, you know, to throw in a broad number to get into the at least show equivalency. And so we’ve seen several randomized studies that seem to support similar efficacy and, uh, maybe reduce toxicity with the second generation. I think the question remains is what’s the effect on T cells, right? And so, um, ibrutinib has kind of the most robust data in that set. And the other thing, I think we didn’t have as much discussion as what I thought we would have. It was on pirtobrutinib which, You know, It looks like it could be kind of a game changer, too, because if it if it works in the BTK resistance, uh, population So that

Another perfect example of how you need the speaker in the room to be able to be part of the whole discussion. Uh, Anthony Mato gave the top and again focused just on CLL. And, of course, we’ve got all the data and mantle cell lymphoma and other histology in that BRUIN study. Um, I guess what we’ve got to be thinking about is already thinking about next year’s meeting. I’ve got lots of ideas of where I thought things really work and where I want to be asking the next question to kind of put together a meeting for next year. I’m sure you will have to. But believe it or not, that’s us run out of time here today. So all that remains for me to do is to thank you for joining us today. I hope you’ve enjoyed um, taking part in the what parts of the meeting you had and all the other podcasts and things we’ve done with this to be. I would say we’ve certainly enjoyed being in Barcelona at this meeting. We all look forward to Miami in September of 2023 we hope to see you from there next year to be able to tell you much more about the huge rate of advances that are happening in this whole field in non-Hodgkin lymphoma. Thank you very much.