So I’m John Gribben, welcome to the 19th iwNHL meeting. We’re here in very sunny Barcelona. We’ve had a great morning session already. Here we’re going to talk about the session, we’ve just completed looking at the immune environment in lymphomas and how that environment kind of opens up opportunities for us to understand why some of our failures, some of our treatments fail. But more importantly how we can think about logical ways to use immune treatments going forward.

So Steve if I can start with you, one of the course, whole leaders in the field of thinking about this whole question of the immune microenvironment. We often think of course of targeting the lymphoma. Then more recently, thinking about the t cells in the lymphoma but you’re highlighting in your talk the complexity of exactly which cells it is we’re talking about, the whole complexity of the immune environment and how we get the right cells into the tumor microenvironment to kill our lymphoma cells. So what’s your view about how we can use advances in the science of this field as you’re doing in your lab into thinking about logical ways to modify how we treat, to look to improve the outcome of our patients.

John I think there are a lot of opportunities that we’re beginning to understand. I think we’ve always thought about the cells that are right there must be the cells that are targeting the tumor and are just being held back or suppressed and I think we’re learning those may not be the most useful cells, maybe cells that are more naive cells that are more in the peripheral blood could be recruited in, and bispecific antibodies may for example do that. The other thing that I think we’re learning about is that not every cell that is present in the tumor is a helpful cell many times those cells were actually recruited by the malignant cells and have created this environment conducive to malignant cell growth. So targeting those cells to remove them or to inhibit them may actually be very valuable. And then finally really understanding exactly what we’re trying to do with the effector cells. So when we’ve recruited the effector cell in how can we protect activate and utilize that cell? I think we’ve kind of naively thought you can do one thing and everything will be good. I think we’re learning you may need to do a complex of different things to make that cell behave itself.

Well that’s a perfect segue into talking to John because you of course talked about the impact of the microenvironment specifically thinking about CAR-T. So there we’ve got the effector cell that we think is doing the job and then we look at how and what happens when we put that very powerfully affect your cell into an immunosuppressive environment and how that could potentially impact and again, most importantly how we might be able to modify that to enhance the activity of the CARs.

Yeah So much like Steve said there’s so many ways that you can look at this and you have to think about. Firstly, you know, the timing of the intervention and we see there are many opportunities on the CAR platform to do that. The timing and the patient’s management earlier in the disease course versus you know, second or third line as they’re given now and then, you know, potentially where that impact may play out whether it’s in the peripheral blood or potentially ultimately as those cells get into, you know, the tumor itself. So I think lots of different places that you can think about manipulating now of course a whole class of cells we know to be important in terms of prognosis for diffuse large B cell lymphoma are macrophages. We know a lot about what many of those cells are doing and the increased complexity of the subsets of cells. But one whole approach of course, is to prevent the inhibitory effects that we know that some of those macrophages have through for instance, the alpha pathway. You Gael talked about a very interesting concept of a very novel bispecific approach looking to target a lot of this, of course was in you know, pre clinical models. But I’m guessing this is coming to the clinic soon. We hope so. Tell us a little bit about your approach of why it is you think blocking or looking to have this approach particularly by specific antibody you talked about is an attractive way for us to be thinking about in this disease.

Yes. So in our lab we are interested in using macrophages. Starting therapy that could restore the activity of these macrophages against the tumors. So most is done have been done in the last years on T cell based therapy, BiTEs, CAR-T and but let’s uh Much work has to be done regarding how we can activate macrophages. So CD47 is the first approach which is showing some activity. It’s very important to evaluate and to determine the best combination therapy because what we know from immune checkpoint blockers and other even dependent therapy is that combination approaches are crucial. So what we are doing there is showing that okay we can restore the activity of macrophages. But the infiltration within the tumors and the activity can be augmented by different approaches. Either blocking CD20 or PI3 Kinase this is what we’ve done in the lab

Steve. So, coming back to you of course about the cells which are there within the microenvironment. We go from a one to a two to a three to a multiple kind of complexity model and then start thinking about the subsets of the subsets of the cells that were there. And not so much in the talks but lots of the discussions to come up with the questions of how do we augment the cells that we want but at the same time not augment the cells that we don’t want within that human microenvironment, how in a clinical trial setting can we take into account the huge amount of variables we start to talk about here.So I do think that’s very complex and I don’t think there’s an easy answer to that. One potential way to think about it is you know, chemotherapy may still have a role because in some respects kind of rebooting if you like the system to as much as possible getting rid of as many cells and then as the fresh cells come back augmenting the changes at that point, that may actually be an effective strategy because I think you’d be using the chemotherapy itself to not just target the tumor cells but target those bad cells

Yeah. And so in some respects, you really kind of want to clear out a very toxic and inhibitory environment and then try and augment bringing back cells that are valuable and protecting them. Either with you know, preventing inhibitory signals or promoting activating signals. So I think there’s an opportunity to take what we know works, chemotherapy or transplant and the like and utilize that in a more effective fashion with some of the newer therapies. So we know very well with CAR T cells is that of course we want to increase the efficacy of those CAR T cells against the tumor but we know the price that we pay by overstimulating the immune cells in terms of the ICANS and CRS and we’ve had plenty of examples before of looking to augment the wrong type of activity. How do we go about increasing the activation of the CAR-TS in the tumor bed without having the risk of you know, increasing those cells in the periphery where you’re going to gather the potential side effects without the potential benefit.

It’s a great question. And I think from an engineering perspective that may be where you can use more complicated CARs that have other domains that thus become more activated when they’re in the in the tumor as an example. Yeah. Um you know, there may be again examples where you can add additional signaling domains. So again at like a JAK-STAT signaling domain to potentially stimulate activity there.

Um It there’s probably no easy answer. And I think once again we’re seeing the yin and the yang of the combination of toxicity and benefit play out. And you know, much like Stephen mentioned earlier the opportunity, there may be both with simplistic things where you might again in increase or change the lymph. Oh, depletion regimen that could then potentially lower tumor volume and maybe change the equation or potentially a little more elegantly by adding additional novel therapy at the same time now because we think of T cell responses as being very specific and T cell receptor mediated. You’re talking now about the potential that we’re bringing in cells which are not really antigen specific but working in just activating a milieu, so to speak, to provide cytokines and other factors which are impacting the whole kind of tumor micro environment. How do we how do we kind of balance the question of T cell specificity with the kind of more general type of approach you’re thinking about here steve

Yeah. So again, a very good but complicated question. And I guess the challenge is just we still don’t really know and be able to identify cells that are truly targeting the tumor in a very efficient fashion to really know have we got cells there that are going to do the business. The hope though, is if you bring in a cell that is in better shape and now it can actually engage with the antigens that matter. You can begin to trigger a more physiologic immune response which would be more effective whether or not you’re actually going to achieve that. I don’t know. Also there’s a lot that we don’t understand about the other cells that you can now engage and more kind of a broad innate response that you could potentially engage. So I think we’re still at the beginning of the beginning in some respects of truly understanding things. We’ve had a few lucky wins, but I think the lucky wins have largely been kind of through ignorance rather than through really selectively understanding what we what we want to

So, coming back to you again, so one on the one hand, we want to suppress that macrophage activation we don’t want and then at the same time activate the T cells that we do from a clinical perspective, what’s a logical way to think We can combine suppression of one group of cells but activation of another at the same time. What we have shown that specific T cell derived like cells can be activated at the same times uh with macrophages. So both both activities can increase the anti tumor response at least technically. So we have to check where they’re using opsonizing antibodies can activate both effectors in vivo. But I truly think that this could work using this kind of combination therapies

Now we’d like of course to believe. I mean you’ve talked already about chemotherapy may still have a role but we’d like to of course think we’re going to get kinder gentler more specific ways of treating our patients going forward, particularly looking at those higher risk patients in whom the responses to chemotherapy, chemoimmunotherapy have already been suboptimal. Um

I don’t want to take away from where we’re going to talk about CARs specifically. But of course the ZUMA-12 study gives us some clues that the earlier you bring the CAR into the treatment particularly we can identify the group of patients that need it, the more efficacious it might be. And many of us thought that might just be the fitness of the car but then perhaps a whole variety of other factors that impact here. That in terms of looking at many of the studies that you presented today, John, in terms of thinking how that environment might be different in a patient frontline compared to somebody who’s been exposed to multiple lines of chemotherapy.

Yeah, definitely. And so we know that it’s possible to believe that you’re going to see additional changes in the tumor microenvironment as you continue to hammer it with chemotherapy that ultimately isn’t gonna work and then salvage therapy that that isn’t that effective and and the consequences there and, and on healthy effectors that are not the CAR that do not become the CAR-T but are still in the patient when the cells are infused. It seems like that could be a very plausible mechanism to support better efficacy earlier and again, hopefully the clinical trials with the right samples will tell that story out in the next few years.

So, I mean, we could spend the rest of the morning talking about just this one session. But I think what you’ve got here is a flavor of the complexity, the amount of work that’s happening behind the scenes to try to understand this complexity that happens within the tumor microenvironment in these lymphomas and how we can use that knowledge to design more logical approach is to go forward. I think what we’re also hearing is you’ll have to come back next year and the year after and the year after that to hear these guys talk about exactly how that’s going to impact the improvement for our patients. With that I’d like to thank you all for your attention. And I hope you come back to hear more sessions talking about the advances we’re seeing at this year’s iwNHL.