I’m Laura Pasqualucci from the Institute for Cancer Genetics at Columbia University in New York. And I’m here at the 19th iwNHL meeting, which is held in Barcelona, Spain. I’m joined my my colleagues doctor Jessica Okosun, from the Barts Cancer Institute in the UK, where she’s an assistant professor with a long research interest in follicular lymphoma. And Doctor David Qualls from Memorial Sloan Kettering Cancer Center, where he is a clinical oncologist. So we just came out of a very interesting session that was focused on follicular lymphoma management. I think this was quite an important topic because follicular lymphoma is an indolent disease. Yet there’s a group of patients who do not respond to therapy and particularly relapse within 24 months from initiation of therapy or transform into a more aggressive, diffuse, large B cell lymphoma who continue to represent an unmet clinical challenge. So the understanding of the pathogenesis and biology of this disease, and possibly the identification of factors that may help us identify patients who are at early risk of failure will be critical for better management of these diseases. So, Jessica, you were the first to speak. You gave us a very interesting overview on the role of mutations in histone chromatin modifier genes, which we’ve learned our genetic hallmarks of the disease. Can you give us a high level summary of your presentation?

Thanks very much, Laura. So I was tasked with, focused, trying to tell the audience what we’ve learned so far, our understanding of these sort of mutations in epigenetic alteration of follicular lymphoma. I think what we know from the sequencing studies over the last decade is that many patients, as many as 90 perhaps even 100% of patients have mutations in perhaps one or two or more of these, uh, mutations and histone modifiers in particular. And there are specific ones KMT2D, CREBP and EZH2, and they are mutated at very different frequencies. But what we now understand is that we have a better understanding of the biology of what these individual mutations are doing in the context of the pathogenesis of disease. And I guess the next questions are could we target these mutations? And we’re starting to see that with epigenetic therapies like, for example, tazemetostat that has been FDA approved for patients with mutations in, you know, EZH2. So, um and so I think that the some of the next steps is trying to understand what is the role of kind of epigenetic therapies, particularly given the sort of central role of these epigenetic alterations in the pathogenesis of follicular lymphoma.

And David, you gave also a very intriguing talks on possible new approaches for synergy in follicular lymphoma patients. Can you tell us a bit about that?

Absolutely. Um, you know, for many years now, we’ve had sort of established therapies in the front line for follicular lymphoma, often involving chemo immunotherapy using a chemotherapy background. Either CHOP or bendamustine, uh, with an anti-CD20 like bendamustine or rituximab. Um, but more recently we’ve developed a number of newer generation therapies, especially in the relapsed refractory setting, um, that have that have really advanced our treatment in that area. And we’re trying to determine how best to combine those therapies or how best to sequence those therapies moving forward. Um, and one of the keys to that is really developing understanding the mechanisms of action of these therapies. And, um, there’s an array of different options now we discussed the epigenetic therapies, things like tazemetostat. Um, there are also targeted therapies PI3 kinase inhibitors, though those have been withdrawn from the market to some degree.

Um, there’s also in development of novel, uh, immunotherapies, like bispecific antibodies CAR T cells. Um, and there are a number of things on the horizon, including agents that engage or block CD47 bring, uh, macrophages into the play and everything else, and these therapies interact in a number of different ways. So I discussed how those interact within the T cell synapse, um, and how they can potentially, uh, improve the efficacy of one another for our patients

Jessica, back to you. Uh, where do you think we stand In terms of translating these findings on epigenetic mutations of KMT2D and CREBP? We know has been done for the two mutations. Where do you think we are?

Yeah, that’s a great question. I mean, as as David had alluded to already, there are lots of other therapies, particularly immunotherapies that have very high efficacy. So the question is, where is the place of these epigenetic therapies when they’re already existing therapies that are coming through. I think one thing I would say that what we’ve learned from the biology is most of these epigenetic alterations are very early, very clonal events. And they we think that they reside within this sort of reservoir population that may be responsible for the disease coming back so potentially. If you had therapies that could target this epigenetic therapies, it may go some way in reducing the risk of relapse, perhaps curing some patients. So I think that, you know, my opinion is that the place of this kind of epigenetic therapies may be more in combination with these immunotherapies. I feel there’s a role in they may have a role in perhaps eradicating this kind of reservoir repopulating population that we are that is very elusive to to eradicate with our current standard therapies.

I agree. And along these lines, actually, David, you had very interesting results on the ability to induce expression of CD 58. Um, can you expand on that?

Yeah. Happy to. So one of the things that we, uh, I reviewed was a recent study looking at, uh looking at using tazemetostat as an EZH2 inhibitor. Um, and by inhibiting EZH2, we essentially unblock the expression of certain genes. Um, one of those being CD58 which is an important ligand, uh, in developing the T cell synapse with follicular lymphoma cells. And it essentially engages CD2 on the surface of follicular lymphoma and helps build a stronger synapse and binding between the two. So, um and and we know that loss of CD58 has been associated with worse outcomes in certain lymphomas. So by upregulating CD58 expression we may be since, uh, stabilizing that synapse, um, and further allowing T cells to exert cytotoxic functions on follicular lymphoma cells. So it may have a unique opportunity to work aside other agents like bispecifics or lenalidomide that further potentiate T cell activity against follicular lymphoma to improve patient outcomes. And I guess, uh, in this setting so you would want to screen patients for the presence of mutations of genetic alterations in CD58 which represents the group of patients are not responding to this effect.

Definitely. Yeah, that was something that they saw in the study as well is that CD58 mutations that was present obviously, then you’re not going to be able to express that. So I think that targeted approaches and understanding that genomic changes for these follicular lymphomal is going to be very important going forward.

So one question that came up during the discussion actually was Jessica, I think, and it may be more general in terms of, uh, epigenetic therapies is whether you would see this as a sequential treatment whereby the epigenetic agent would be used first and then maybe followed by immune therapies.

Yeah, I think that’s a really interesting idea, and one that should be explored. More of you potentially get that CD58 expression. You also may get more antigen presentation in general via MHC-dependent mechanisms. Um, there’s some evidence to show that in DLBCL, it may also be true in follicular lymphoma. Um, in which case you may get different immune, Um uh, response to the follicular lymphoma after that. And I think there was some, uh, recent data out of the green lab as well that showed that the EZH2 mutant follicular lymphoma tend to influence the microenvironment differently in FL. And so you know whether inhibiting EZH2 in that kind of setting would change the microenvironment in a way that makes it more amenable to other immunotherapies. I think that’s something that would be really interesting going forward here.

So maybe one quick and last question for you, Jessica, What do you think a clinician should do nowadays when they see a follicular lymphoma patient?

I think it’s a great question. I think. In a way, it sort of speaks to Dr Gilles Salles talk, which is, you know, how do you sequence therapies? How do you, you know, use all these drugs how to use all the biology? Um, I think where we are currently is that we have a better understanding. Certainly from a genetic perspective, when we probably still lack information from the microenvironment perspective, we probably need to bring that together.

Um, we’ve long focused on prognostic tools, and I think that we probably need to move away from prognostic tool, and we probably need to be looking at maybe more predictive tools because there’s so many drugs out there. How do we get the right drug to the right patient? And I think we need to try and understand the biology of responders to these novel therapies versus those that are resistant. Um and so I think that going forward, I think a lot of the clinical trials has to try to address this parallel correlative questions as we are asking clinical questions. We should also be asking biological questions as well. I think I still think we’re quite far away from bringing the biology or for from a clinician perspective, I don’t think there’s any role currently of using NGS apart from perhaps selecting patients for EZH2 inhibitors. But aside from that, we’re not quite there yet in terms of using the biology in a clinical setting. Currently, that’s very true.

So I think, uh, we we can stop here. I want to thank you very much for speaking and giving very enlightening thoughts today and thank you very much.

Thank you.

Thank you.