Robert Emmons, Francie Foss and Chelsea Peterson of Roswell Park discuss classifications of lymphoid malignancies and treatment recommendations and changes for T-cell lymphomas.
Welcome to the evening session. So it is my pleasure to introduce Doctor Robert Emmers. He basically is a physician and a lymphoma expert in the University of Louisville, Kentucky. So he's gonna be talking about the emerging therapies, uh, in T-cell lymphoma, including cell therapy. Thank you very much. Thanks very much to the organizers for inviting me and thanks, uh, especially to Matt who came and spoke at our immunotherapy meeting last week in Kentucky. So he's, uh, a very near and dear to my heart, uh, so that's wonderful. I think we have slides up good, so I have nothing, uh, conflicting in this talk financially, but we did participate in the production at our GMP facility of the CD4 CART trials that I'll talk about, uh, in a few slides. So, uh, as I'm here to talk about T cell therapy, uh, and I'm followed by 2 august speakers, Doctor Foss and Doctor Peterson, who are gonna go over standard therapies, uh, I want to lead off since I'm about to talk about wholesale slaughter of the T cells, to talk about the importance of the T cells for overall cancer understanding in cancer therapy. Uh, maybe the worst thing to do as a post lunch speaker is to talk, uh, about a basic science topic to start with, but, uh, this slide I think is really important because it's work that was done by a guy named Herb Weissman on the West Coast a few years ago, and he showed that in mice, if you, as they age, they have T cells that differentiate around two different lines down the lymphoid line and the myeloid line. As the myeloid line dominates as they get older, they go into senescence, and that causes more problems with cancer, more problems with infections over time. But you can completely reverse that by injecting antibodies that wipe out that myeloid line in the murine, uh, T cell line. When you do that, this study showed that they fight cancer and infections, and they have inflammatory markers exactly the same as the younger mice, which is to say, That there is hope, at least in that mammal, for having something that can essentially reverse ontogeny and create an environment such that you can do the things that you should be doing, uh, in terms of fighting, especially cancer that we're most interested in talking about, and this typifies the great importance of T cells, not just for infections, but for cancer origin. We are in the modern immunotherapy age of cancer, but that modern age has told us that. Cancer starts not only because of mutations within cells, but because of permissiveness of the immune system that allows those cellular changes to become full blown cancers. And so the better we understand T cell senescence and changes over time in adults, the better we'll be able to predict who gets cancer and not only understand how to prevent it but treat it better over time. And how do we know this? Well, This recent study that was just published in Nature a week ago is a very interesting study out of Boston in which they took standard chest CTs. And came up with a surrogate marker for thymic volume in adults. And so many people have thought that thymus has no role in uh what happens in adults. It's all peripheral T cell, not central T cell anymore. But what this paper shows is that in fact, thymic function goes on into adulthood and it varies quite widely in terms of how different different people are in terms of how much volume they have left of their thymus as they age. And why is that important? This is the methodology behind it slide in terms of how they did it and essentially anybody in the country can do this. It's a standardized paradigm in terms of how you can do this from a standard chest CT and who in this audience doesn't have a cancer patient who, uh, has not had a chest CT sometime along their course? Everybody gets a chest CT. So this is a parameter that could be derived on every patient that presents. And why is it important? Well, look, in melanoma, in breast cancer, and renal cancer, and bladder cancer, and esophageal cancer, pooled cancers, if you separate thymic volume according to good thymic volume, not so good and poor. The outcomes of cancer across the board are different. T cells matter. They matter again, not just in therapy as we've talked about with bikes and cars today, but they probably also matter with how cancer happens in the first place. And so understanding how T cells and thymic thymuses in adults change over time will be part and parcel of screening for cancer risk going forward. So this is one of the most important things I want you to take away from my talk today, uh, before I talk about the wholesale slaughter of T cells, uh, of how important they are and how important they are for cancer screening going forward. By the way, I'll mention the accompanying paper in that publication looked not just at cancer but other parameters of health in adults, and it turns out that as you can see for males and females there were slight differences, but for systolic and diastolic blood pressure, for set point for glucose, for set point for lipids, for inflammatory markers in adults, autoimmunity, all of those things also correlated with thymic volume as people aged. Badagers are people who have low thymic volume and earlier T cell senescence, not just for cancer, but all-cause mortality. All the metabolic bad stuff that gets us into trouble as we get older is intimately tied in with the immune system as well. So, that's a prelude now to talk about, uh, T cells, and oncologists need to be shepherds of the immune system. Both screening and treatment are affected, and we need to all know this and, and realize it in our practices going forward. And we may be truly robbing Peter to pay Paul when we interfere with arms of the immune system, especially T cells. So, we're gonna talk about T cell lymphomas today, which are a small subset of lymphomas. They're about 12 to 15% of non-Hodgkin's lymphomas in adults, and in T-cell lymphoblastic, uh, leukemia, they're about 15% of childhood ALLs and 25% of adults. And lymphoblastic lymphomas 80 to 90% T cell. But this is not a huge cohort of patients, and obviously it is also a very diverse set of patients. It's not just multiple myeloma, which is more uniform than the 30 different subtypes of T cell lymphoma that we're going to talk about. So it's a confusing area. So, largely in adults, we're talking about peripheral T cell lymphoma. And when you think about those, the nodular T-cell lymphomas, those that occur in lymph nodes, are about 70% of what you talk about, about 6000 patients a year, and those are divided into those categories of sort of anaplastic large cell lymphomas, ALK positive, AK negative. The PTCL, uh, lymphoma is not otherwise specified, for which there are a variety of molecular signals that are sort of summarized under that. And the sort of T cell follicular lymphomas of which angioamenoblastic lymphoma is the dominant subset. Aside from those nodal T cell lymphomas, cutaneous T cell lymphomas, of which Doctor Foss will speak to us, uh, in great abundance in the next talk, are about 20% a year, about 2000 a year, and the rest are a smattering about, uh, leukemic, about 7%, and extra nodal T cells, about 3%, a very rare and diverse subset of T cell lymphomas. So. It's confusing because there's a lot of different T cell lymphomas out there, but of course the dominant ones are the peripheral T cell lymphomas that are nodal presentation. The other thing to realize is that there is uh a big disparity in terms of how these present around the world. So, in Asia, largely because of the endemic uh features of HTLV1, there's a lot more ATLL and angioaminoblastic, uh, and uh NKT cell lymphomas are a greater abundance. In Europe, uh, angioinoblastic and PTCL not otherwise specified are dominant over North Americans where it's sort of spread around, uh, the ALK positive, AL negative, anaplastic large cell angioinoblastic and peripheral T cell not otherwise specified. So there are world differences and therefore differences in terms of what's published around the world about these things. Now, standard therapy, as will be discussed more by Doctor Peterson in her lecture, uh, is typified by largely these group of nodal, uh, diseases as we'll talk about and the Swedish registry for regimens like, uh, CHOP, um, is really the one of the best registries in the world for showing the differences here and the one that stands out in terms of doing better with standard chemotherapy up front is AL positive anaplastic large cell lymphoma. A lot of those patients can go into remission even long term with chemotherapy, and as of echelon 2, which showed that the addition of rituximab replacing vincristine in a CHOP-like regimen for those that express CD30 even in moderate amounts, uh, gets you even better than CHOP does. But the ones that are below that dotted line do not do so well with chemotherapy alone. And so the question was, can we do better with autologous transplant? Can we push dose and get some people into better remission? And the reality is the one cohort that really benefits from high dose therapy is the anaplastic large cells who are out negative, those you do incrementally better by pushing dose of therapy, but you really don't do that much better by pushing dose of therapy for those other subsets. So what to do? So we know that if you're considering allo transplant, which is what many people do in this circumstance, that the key question then is how deep a remission can you get the patient into, because if you cannot get a deep remission, then it's almost folly to try to get an allo transplant to do its job of getting people into remission long term. So as you can see from this, excuse me, database, that partial, uh, progressive disease and partial remission did not do so well. But for those that could get a complete remission at the time of transplant, you were getting a survival curve that got at least over 40%. So it does make sense to consider that for those that you can get into complete remission. The problem has been heretofore that we've not been very good at getting people down into deep remissions with the therapies that we currently have available. So for ALK positive anaplastic large cell, we can do well with chemotherapy. AL negatives, uh, who are anaplastic large cell can do better with auto-transplant, pushing dose of chemotherapy up, but others need other considerations. If allo transplant is being considered, the depth of remission matters. Doesn't matter what the subtype is. Current therapies often achieve some duration of control, but not depth of remission historically. Aloe. Uh, CART, that is using normal donors for the production of CAR T, can get depth of remission, but they don't last very long in vivo. Can autologous T cells that is made from the patient's own cells do better and be more, uh, better duration, and do we even need that if we're gonna go to auto or allo transplant? Also, in addition to the sort of, uh, confusing motley of different T cells, uh, to consider, there's a lot of different genetics that are sort of being sorted out with these, um, uh, different diseases, and epigenetic dysregulation, especially in AATL is very important. Uh, aberrant T cell receptor signaling is important. Other signaling pathways are frequently dysregulated. There's alteration in tumor suppressor genes and aberrant signaling. The reason I bring this up is because if you're using autologous T cell C T production, many of these defects, unfortunately, affect the T cells of these patients. There are T cell problems in lots of cancer patients, but especially in T cell lymphoma. So auto T cell therapy suffers not only from production defects for a variety of other reasons, including therapies that they've received ahead of time, but also because of the intrinsic nature of the T cells in these patients. I'm not advancing. There we go. So when we talk about CAR4 T cell lymphoma, the key question is what targets are best to consider, and there are a variety of different targets. I realize this is a very busy slide, and it sort of shows many of the different therapies that we throw at various T cell lymphomas to try to affect change. But the important thing that I want to get at for the purposes of this talk is the surface receptors that are the most amenable and widely expressed and reliably expressed on T cell lymphomas that might form the basis for good strategies to use CAR T cells. As you can see, CD7 is a pretty good target. It's pretty widely expressed, but it's quite variably expressed. It's not expressed very well at all on cutaneous T-cell lymphoma, so it's not a great target for that. CD5, on the other hand, is quite well expressed in that and is sort of expressed across the board. So not surprisingly, CD7 and CD5 are the dominant two that have been in, uh, widest clinical trial to date. CD2 we'll talk about as an emerging therapy. CD30 headed by Bryntuximab, of course, on the clinical side, is another target that's being targeted with CART. Uh, TCR BC1 is another one of recent, uh, uh, targeting that we'll talk about as is CCR4, and we'll talk briefly about CD4 as well, which is, uh, quite disparate in terms of its expression across the board. So CD7, expressed in over 90% of T-cell lymphoblastic lymphomas and leukemia is often down regulated, though in more mature T cell lymphomas, less associated with disease progression, uh, especially in Cesarean syndrome of cutaneous T cell. CD5, though, expressed in 85 of T cell malignancies, highest in T follicular and peripheral T cell not otherwise specified, um, inhibitory receptor and loss associated with disease progression, so. Um, that is a problem, obviously, uh, because a lot of these patients come to us late in the course of their therapy. CCR4 is expressed in CTCL and is a particularly good target in that category of T cell lymphoma and ATLL. CD4 has quite variable expression. The big advantage of, of it, uh, that we'll talk about is that in production it doesn't kill off the CD8 cells, so that's one of the big advantages in, uh, using that. And CD 30 is variable expression and CD2 as we'll talk about a newer kid on the block has fairly wide expression as well. So what's the intrinsic problem of producing CAR T cells? And by the way, you might ask why are there no bite therapies in T cell lymphomas? Well, of course, bite therapies are intrinsically toxic to the T cells that you're trying to target. So there haven't really been bite therapies developed for T cell lymphomas, but there. RCRT therapies that are developed, but the problems are largely problems of fratricide because obviously when you manufacture the T cells X vivo, you're introducing targets that are intrinsically targeting the cells to the cells you're trying to produce. So there's an added layer of production here in that you have to somehow down regulate. The target that you're trying to address on the T cell lymphoma in the effector cells that you're trying to make X vivo. So the so-called fratricide effect had stymied the field for quite some time, with the exception of targets like CD4, in which the CD4 cells are not the activated cells, but rather the regulatory cells, and so you can have CD8 cells grow out despite having a CD4 target produced car. In addition to that, when you introduce T cells this effective at killing off intrinsic T cells, you're going to cause T cell aplasia. If you do it against CD4, you make somebody that's essentially an HIV patient. If you do it for wholesale slaughter of all T cells, you set them up for all kinds of bad things, including all the bad things I just discussed in terms of what happens to patients who have low thymic volume, and they still have T cells, but if you really eliminate them long term. You're not only setting the patient up for bad infections, but you're setting them up for secondary cancers and autoimmunity and any number of other terrible things. So, as a long-term strategy, abrogation of T cells with something as effective as CAR is not a good idea. But for short term, getting them into deep remission, which might set the stage for, for example, getting them through a successful allo transplant, that's a paradigm that might work. And finally, uh, T cells, when influenced by these genetics can sometimes hide intrinsically. So if you infect the actual, uh, malignant T cell clone during your transfection and production of car, that can cause antigen masking. And of course, you can just like all T cell products, lose the antigen on the surface of the cell that you're trying to go after over time. So there can be intrinsic resistance, uh, to the T cell uh targeting. And let's see here. There we go. Right, so we're gonna talk about the currently available autologous, that is using the patient's own T cells to target their uh various surface epitopes and allogeneic using native healthy T cells produced ex vivo to address T cells, uh, T cell lymphomas. Um, so, on the autologous side, the big target, as you can see here has been CD7, and so there have been 4 trials, um, that still have some effect of fratricide in terms of the, um, cells themselves, but have been able to be produced, uh, uh, in ex vivo and infused into patients. Uh, the numbers of these trials are certainly small, so we're not talking about the bigger trials in myeloma or some lymphomas that have been talked about earlier today. But you can see the overall response rates have been encouragingly quite high. So, um, in anywhere from the 80 to high 90% range, and more importantly, the MRD achievement in these patients has been quite high. In the over 90 to in some cases, 100% of patients. Have MRD based on both flow and molecular characterizations. So these are very, very deep remissions. So autocarts can affect deep remissions in T cell lymphomas that are otherwise resistant. This comes at the price in some cases of cytokine release syndrome, which certainly happens in the majority of patients. Thankfully, for the majority it is not high grade cytokine release syndrome. And occasional patients have had graft versus host disease introduced uh by doing this, but it's been rare, thankfully. As you can see, as of Ash last year, Ash abstract 704, the CD4 target was published, of which we were part of the study, uh, in terms of producing the cells in our GMP facility. 14 patients have been treated with again an overall response rate of 71% and MRD achievement in about 60%. There was less cytokine release syndrome and no graft versus host disease observed in this cohort of patients, um, and so CD4 is a reasonable target. Obviously it's not a good long term target. You're making people functionally HIV by doing this, but as a short-term strategy for allo transplant and all 14 of these patients did go on to get allo transplant, uh, it is a reasonable strategy to try to get deep remissions. CD30 has been used in, uh, post-beam uh peripheral blood stem cell transplant patients, of which 6 have been T cell patients that have been published, and we don't have much data on that. And again TCRB1, which is a new, uh, the newest kit on the block. I've only been 10 patients with an overall response rate of about 66%. So CD7 is really the dominant player, but it can get deep remissions, uh, and those are lasting remissions at least a few months such that you can get patients to allo transplant. Now what about on the alloe side? On the alloe side, CD7 is still a very important target and has been produced in a number of different ways. And in this case there have been attempts to try to use CRISPR to eliminate certain other receptors on the T cells to make them agnostic to the effects of the car and therefore better expanded and and able to stay. In the patient's system longer, but as aloe car across the board doesn't last that long, no matter what you're talking about, whatever the target is, it's only a few months of survival typically within the patient. It's not a long term strategy, but it's certainly a good strategy to get people into remission short term and again get them to transplant. So this is the BCAR 7 trial that was published recently in the New England Journal of Medicine, and this is just to sort of outline how this works. T cells are obtained from healthy volunteer donors. Again, this is aloecar, the seat that they're base editing to remove surface receptors for the T cell receptor itself, the CD7, which is of course the target, and CD52 as well. When you do this, the, the cells are still functional. You, it can then insert the targeting gene, that is the car vector gene that targets them towards CD7 and reinfuse them into patients. And these CD7 aloecarts, when introduced, as for example, in the, the BE7 CART trial that was published in the New England Journal of Medicine. And 9 patients were in remission at day 28 and proceeded to stem cell transplant, so they got very deep remissions, molecular remissions with the CD7 car, and that got them to the, uh, to get to alloe transplant. And 7 patients in this trial are in ongoing remission after stem cell transplant. And these again were resistant patients that came to this, and this is the swimmer plot of those, uh, that cohort of patients who went through. So again, these are resistant patients who had failed 1st and 2nd line therapies. In many cases they'd failed 3rd and 4th line therapies before they came to transplant, who were successfully put into deep remission with a CD7 aloecar and then taken to alloe transplant to recapitulate their immune system and therefore get them over the long-term damaging effects of losing a T cell immunity. The Washington University CAR 7 has a similar idea, uh, in terms of, uh, doing CRISPR modification to eliminate the CD7 and T cell receptor, and their phase 12 was reported at Ash in 2025. They have very rapid manufacturing, and the CRS rate was about 30% with an ICANNS rate of about 8% in one transient graft versus host was seen. 13 patients with CRs and 70%, and a registration trial is starting. They're not sending all these patients to alloe transplant in their protocol. They're actually trying to use this as a transient, uh, treatment because the cells don't survive long-term to get them into long-term remission. As far as, uh, auto trials, the CD5 Sensa Viper was published at Ash this year as well. It's an open phase one with 5 day manufacturing, limited CRS and neurotoxicity, only one grade 5 infection, and an overall response rate of 100% in the 3 patients, all achieving CR. In another multi-center MB 105 CD5 directed car, again, rapid, uh, degradation, uh, phase two rapid manufacturing, only one CRS and no neurotoxicity, and the overall response rate was again 100%. And here's the swimmer's plot of that, uh, with the people who got remissions achieving very deep remission, complete remission that they kept for many months. And again, these are patients that didn't go on to get, uh, alloe transplant. CD4, uh, again, an interesting target just because the manufacturing is easier. You don't affect the CD8 effector cells by making these cells, and it's variably expressed, as we mentioned before, across the board on lymphomas, but, um, it's also variably expressed on, uh, immature T cells as well. So it's not as great a target for lymphoblastic lymphomas and leukemias, uh, it's more a mature marker. And I showed you the data already with regard to the CD4 and it had very good CD8 uh uh con uh uh production and expansion uh in vivo. So our goal should be to get patients who relapse under 1 year post-therapy successfully through allo transplant with deep remissions prior to transplant. A graft versus lymphoma and healthy immunity after allo transplant can be achieved fairly reliably if you get the patient into deep remission before transplant. CAR T can achieve deep remissions, but relapse is common in T cell suppression. There's a fall-off effect with immune paralysis as well. There are certainly cost realities that make aloe off the shelf approach very attractive over the bespoke autologous approach for this particular therapy. Other therapies should be analyzed carefully for effects on immune populations, and there's a critical issue for all cancers in immune health, as we've mentioned. Two final things to mention is that uh there are different targets that seem to be of interest going forward. The UCAR 2 CRISPR deletion of the TCR and CD2 is in early production. This is a WSU, um, uh, uh, production. They're uh transfected at the same time with IL-7, which, uh, also, uh, increases the half-life of the transgen and the cells, and this is just in murine, um, uh, studies so far but has very high efficacy rate. So they're gonna take that to human trial. CCR4 is another interesting target because it's highly expressed in CTCL and many ATLL patients. It has some other interesting, uh, uh, sidelines in terms of how it affects T-reg cells as well, so that's another one to watch going forward. Uh, finally, a couple of comments about adult T cell leukemia, which is an HTLV-1 virally infected lymphoma. Obviously you don't want to abrogate T cell response in these patients, uh, so we don't want to use CART in something like this or even, uh, any other sort of T cell depleting strategies. And with that in mind, I'll just mention a couple of interesting studies from Ash that talk about how the immune system can be augmented with therapy rather than doing car or other therapies. So this was a phase 2 study of AZT interferon with Belinostat. Belinostat is an HDAC inhibitor which activates HTLB1 and suppresses HPZ, a component of it, which induces apoptosis in the infected cells. It was a single arm study for molecular response of which 15 patients were enrolled. The interesting thing I want you to take away from this though is that by doing this, responders show an expansion of cytolytic CD8 cells specific for the virus. So there may be therapies that we can use that in vivo improve the immune system against the viral vector and therefore against the lymphoma itself without having to do fancy things like car or alloe transplant. Also in CTCL this uh BI 1808 uh trial, which is an IgG1 anti-interferon antibody blocking TNF alpha signaling molecule, and this is a phase 2A uh study in CTCL. 21 patients, 19 had CTCL, and the important thing I want you to take away from this is that as a result of this therapy, there were increased CD8 T cells infiltrating with higher granzyme B in skin biopsies, which shows. That we can improve immunity through certain manipulations of chemotherapy and antibodies rather than doing again CA or any other kind of manipulation of the T cells. Finally, I just want to close on this allo transplant, uh, which was published in the New England Journal of Medicine. Standardly, as you know, we use T cells, uh, chemotherapy to ablate the immune system, and then therapies to prevent graft versus host disease. Here is a published report in which a CD7 directed autocar was used against AML expressing CD7, which was successful in knocking down the AML. Conditioning the patient's own immune system such that they could put in an allograft, and then with no graft versus host disease prophylaxis, they had complete engraftment. No chemotherapy, no post-transplant GVH prophylaxis, no chemotherapy to treat the intrinsic leukemia. The CD7 card did everything here. And as you can see by the swimmer's plot. There are many of these patients who have full donor chimerism with no AML post-transplant. Again, no additional therapy beyond that. 3 patients did get grade 2 graft versus host disease, and 2 patients did die of infection during the trial. But again, a sort of paradigm here, not only that, you know, CART can work in AML because we'll talk about AML tomorrow, but, uh, that has sort of been a problem in the world. We haven't been as successful at targeting myeloid diseases, and it can also abrogate immune systems. Now we have to keep in mind costs. CART costs about $100,000 per quality adjusted life year. That is a thing we've got to wrestle with going forward. And the final thing to mention is that CAR T therapy itself can cause T cell lymphoma. So this is from the, uh, large registry, largely of, of, uh, silta cell that's out there, and about 6 patients have come down with T cell lymphomas after Silta cell therapy. Some of these are very wimpy T cell lymphomas though. One was a GI presentation most recently which was put into long-term remission with just cyclosporin alone. So they're not necessarily terrible malignant diseases that we can't treat, but it is a reality that our ability to manipulate the immune system is a tool which also sometimes can get us into trouble with the very thing we're trying to prevent. So that's a very important point about the use of these and how not just retrovirus, but CRISPR will be technology coming to try to improve this in the future. So with that I will pause and Move on to the next speaker. That. PA in a few minutes. Hi, thank you, and of course I wanted to introduce, uh, certainly a legend. So it's a pleasure to welcome again Doctor Francisco. She's a professor of medicine and dermatology in John University, is the director of the T cell lymphoma program, and certainly a world authority in T cell lymphoma and skin lymphomas. Francis, welcome again to Buffalo. So thank you very much. Thank you. That's a tough act to follow there. Now I feel guilty for using these T cell targeted therapies. Anyway, so let's uh talk about CTCL. Um, so this is, uh, talk is mainly geared toward trying to help you to understand the treatment landscape for CTCL, uh, and what you might do for an individual patient. So I want to point out the NCCN guidelines because that's where we, we all start. Um, we actually have divided up the disease into different stages, and I think this is important for you, uh, when you're thinking about an individual patient. The tumor stage disease is broken down into limited and more generalized, and the Cesory syndrome is broken down based on tumor burden in the blood. So low tumor burden versus high tumor burden. Um, and you can see that there are lists of potential therapies, and again, they're not listed in, um, order of preference, but alphabetical order. Um, and if you look carefully at this, uh, when you have time, you can take a look at it. You'll see that, uh, it's built-in, uh, photophoresis, um, which is ECP, uh, primarily for the patients with Cesory syndrome and primarily for those with, with blood burden. Um, and so, what is the next iteration beyond kind of standard therapy? What are our new therapies and how are we thinking about CTCL? So, the, uh, immunology behind this disease is very complicated. There are lots of, uh, chemokines and cytokines, and now we're, we're discovering molecular mechanisms as well. Um, and some of our newer therapies have really focused on this, focused on targeted targets, cell surface targets such as CD4, uh, CD, um, CCR4 and CD30. Um, the epigenetics, uh, of the disease, which is targeted by the histone deacetylase inhibitors, um, and then, and to some degree, some of the immunology is being targeted with checkpoint inhibitors, and I'll talk about some, uh, new data there. Um, and then, um, as we move down, um, some pertinent mutations that we're now targeting are the JACST mutations and there are agents available, uh, for that. Um, and we're now looking at, uh, other, uh, drivers, uh, ITK driven. Um, proliferation and some of the other drivers that we have small molecules for. So, just in terms of thinking about the therapies we have and how we utilize them, I'm just gonna briefly touch on a couple of things. Brituximabiddodin is a therapy that we use very often. And in fact, it was FDA approved based on the Alkansas study where it was given to patients with advanced. CTCL, uh, and they were randomized between methotrexate orbexeretine versus rituximab. And you can see clear benefit in this population for rituximab. I want to point out that these were all CD30 positive patients, um, that was required, uh, to enter the study. Um, and the other important take-home message from this study is if you actually look in yellow, you can see. That, uh, this therapy was effective across different stages of disease. So in the patch plaque patient, the early stage patient, 40%, 50% response rate in the tumor stage patient, stage 2B, and even in the, the very few patients with more advanced. with Cesare, you can see a very similar response rate, uh, and a median response duration of 16.7 months. So again, I think a very important drug when we start thinking about these patients, particularly advanced patch plaque and tumor stage patients. Well, uh, this is the question that oftentimes comes up. Well, what if my patient is CD30 negative? Um, and so that's actually been addressed, uh, in a number of trials, and I know you can't, you can't read the, uh, the table, but there've been a couple of tribal, trials where they've looked at patients with CTCL irrespective of, uh, CD30 expression, or they've looked at low versus high. So, if you just focus on the bar graph, you can see, um, the difference in terms of low versus high versus no CD30 expression. Um, and you can kind of see as you move across the different studies that there really isn't a significant difference between the low expressor and the non-expressor. Uh, the positive, the high expressor obviously does a little bit better, but you're seeing responses across the board, uh, irrespective of the level of expression. Um, and just an example of that from my clinic is this case I'll present this 46 year old gentleman with tumor stage MF, um, who had weak CD30 staining, and you can see, um, The clinical picture and you can see the pathology report, uh, which shows very low level of CD30 expression. Uh, nevertheless, I, I gave this patient rituximab. He had 3 cycles and he actually discontinued for neuropathy, but all of his skin lesions cleared, so he had a CR, um, and likewise, you can say, say the same story about patients with even that turned out to be negative. So, how does this work then if, if you're CD3 negative? Um, if you look at, uh, CD30 itself on the tumor cell, um, we know that immunohitic chemistry isn't that sensitive. There might be low levels of expression, and also we know that there's intralesional and intralesional heterogeneity. If you biopsy multiple lesions, uh, from a patient, you'll get different levels of expression of CD30 and how many lesions can you biopsy. Um, we also know that CD30, uh, may not be stable and there's receptor, uh, shedding. Um, and also there might be some independent mechanisms by which it's working. Um, if you look at the expression of CD30 in normal tissues, actually, there's, there's very little really literature about this and even in the context of CTCL, not enough literature looking at, uh, the bystander expression versus expression on the malignant cells. But CD30. Can be expressed on a number of different types of cells, be immunoblasts and subpopulations of CD4 positive, R positive, and CD8 positive cells as well. Normal cells can express it. So, there's probably a bystander, uh, immune mediated mechanism as well. OK. Another interesting drug and one that we use all the time is mogamelizumab. So how do we understand this drug and how do we understand when to use it? So mogambalizumab is a monoclonal antibody directed against CCR4. It basically works by ADCC. CCR4 is, uh, an important receptor in CTCL. If you look at the immunohistochemical staining, you can see it is expressed across different stages of disease, even early-stage patch plaque patients right up to the Cesory syndrome. Uh, the clinical trial that was done randomized patients, uh, uh, between mogamelizumab and oral variostat. Um, and those patients were stratified by stage. There was a crossover in the study as well. Um, if you focus in on the, the clinical response and like where are we seeing responses with this drug, you can see that out of 186 patients treated, the highest response rate was in Cesare syndrome at 37%, whereas MF was 21%. And then if you look at the different compartment, um, responses, patients have, uh, skin, blood, lymph node, and visceral compartments examined in this study. Um, you can see the response rate in skin was 42%, uh, and 68% in blood, so very significant response there. However, in lymph nodes, it was only 17%. Um, and one of the, the clinical issues with this drug, uh, in, in practice is That oftentimes you'll get a patient started on the drug and you'll have very good clearance of the skin and the blood, but then as you move on in time, you might see emergence of disease in the nodes because that's not really targeted as well. So, then you might have to add something or think of a different strategy. But other things you can, uh, use in terms of like thinking about markers and how do I follow a patient on this drug, um, this is one thing that we, uh, actually uncovered as we were studying those patients in that, uh, in the Maverick clinical trial. So we observed that some of these patients developed lymphopenia, uh, during the course of treatment, probably because of the effect of the MOGA on normal CD4 populations because we know it does deplete, for instance, depletes T. regs. Whether that's clinically important or not was really addressed here in the. Retrospective analysis. And what we found is if you actually look, um, at the different grades in the shifting of lymphocyte counts, so to what degree you developed lymphopenia, you can see that there were a significant number of patients who went from grade 0 to 2 or 0 to 3. And if you just strictly then looked at, um, any patient who developed lymphopenia versus those that didn't. Um, and you compare the response rate, it turns out that there was, there was a significant P value of 0.001, indicating that patients who developed lymphopenia had a higher chance of a clinical response. Uh, and you can see that graphically demonstrated in the, in the bar graph as well. So basically, out of the 104 patients who had any shift in lymphopenia, 43 or 41%, uh, had a response versus 11% of those patients who didn't develop lymphopenia. So it appears as though lymphopenia is a meaningful marker that we can follow in the clinic. Um, if perhaps a patient isn't developing lymphopenia after several cycles, you know, we could ask ourselves why, of course, but, um, based on this data, maybe they're not going to evolve to a clinical response. Another one, is the skin rash. The skin rash associated with MOGA is an immune-mediated event. It occurred in 23% of patients and the median onset was 4 months. Um, the treatment duration interestingly was longer for the patients who developed a rash than those patients who didn't develop a rash, uh, and 70% of the patients who had the rash had it occur after their clinical response. Um, it turned out that overall response rate, when you looked at this statistically was higher in the patients who developed the rash than those patients who, who did not. Um, and you can see for sensory syndrome, it was 56% versus 29%. Uh, so what is the skin rash? The skin rash, uh, is shown in, in, uh, in the diagram here, one of my patients. Uh, you can see the first diagram of the total body is the, is the Cesare syndrome prior to treatment. And the second, um, photograph shows you a skin rash that emerged on this guy after, again, after he was on MOGA and he developed a clinical response. The Biopsy of that rash basically shows a drug rash. There were no malignant cells in that biopsy. And so what did we do? We started steroids, uh, in this case, we gave prednisone. We held the treatment briefly and then we restarted it. Uh, and the other interesting thing is that we found that the use of photophoresis, which is an immune modulating therapy, can actually help to immune. Ameliorate the inflammatory response with those skin rash, uh, patients, and that actually worked well for us. So again, uh, if you look at the bar graphs on the, on the right, you can see that, uh, there's definitely an association between MOGA associated drug rash and clinical response in both MF patients and incesri patients. So again, if you, if you see this, it's not necessarily a bad thing. Um, OK, so the other new drug that I want to talk about, and many of you haven't used this yet because it's just getting into the clinic now, uh, is the interleukin 2 fusion toxin E7777. Uh, the trade name for this is Limphir, and this is basically the old OnTac. So this drug was in the clinic for a number of years, approved in CTCL, taken off the market for re-engineering and purification issues, and then, uh, went back into a clinical trial to get it, uh, registered again. Uh, the important thing about this molecule is it targets IL-2 receptor on the malignant T cells, but also it can also target the microenvironment. In particular, we know that it can eliminate Tregs. And so that's going to be important, uh, in, in terms of thinking about the clinical activity that we're observing in CTCL patients. So, the clinical trial that we did was in a similar population, um, the, as, as, uh, was the old ONTAC trial, namely, uh, relapsed patients with CTCL who are relapsed, um, and all of these patients had to have some level of CD25 expression, which was the target. For the drug. Um, we, initially, we treated patients of all stages and then we narrowed down a population of stage 1 to 3, which is similar to what we had for the other molecule in order to expedite the approval. So, uh, the data that I'm going to show you for efficacy is primarily stage 1 to 3, and there were 69 patients in the trial. If you look at the, um, the overall response rate of CR and PR, um, overall, it was, uh, it was 36%. Um, it was slightly higher in tumor stage patients. It was 45% there. Um, and it was slightly lower in the advanced, uh, CSI patients, but there were only 15 of those in this trial. In terms of side effects for this drug, uh, we, it's exactly what it was before when we used OnTec before, uh, elevated transaminases occur and that's reversible. There are some infusion-related events and what we called capillary leak, uh, which is very similar to CRS and I think we're all used to dealing with that now. So, um, the data from the trials show that there are some patients who had very good responses and, uh, very durable responses. So the median duration was 6.4 months, um, but 52% of patients, half of them had a duration greater than 6 months, and then 20% had a duration, uh, greater than 12 months. Um, and so again, these are CD25 positive patients entering this trial. So, uh, what's really the next iteration for this molecule, and do we need to worry about CD25? I showed you data with rituximab that we don't need to necessarily worry about CD30. What about this molecule in CD 25? Um, it turns out that there was a study that was done in Japan where they treated both CTCL and PTCL, um, and they didn't require a CD25 expression. So they have data now looking at the response rate, uh, in those populations. Uh, and for CTCL it was 31%. Uh, the response rate in CD25, less than 20% was 16, and CD25 greater than 20% was 38. So, again, uh, it was slightly higher in the CD25, uh, high expressors than in the low expressors, but there was still a response rate in the low expressors. Now, uh, very interestingly, um, when the FDA approved rituximabidodin, they approved it for a CD30 positive T-cell lymphoma. However, when, uh, when this molecule came along years later, the FDA did not require IL-2 receptor expression in the label for this molecule. So, again, evolution of their thinking, right. Um, the other interesting thing about this molecule, where is this going next? And I think it's, it's seguing itself into solid tumors. Uh, and that's really because, again, it can deplete T. regs, and there's been some early data with this in animal models, uh, in, um, patient, in models. With melanoma and other solid tumors. But this is actually, uh, a clinical trial that was presented, uh, where they basically looked at the combination of E7777 with, uh, pembrolizumab, um, in this case, in a, a GYN cancer setting. They had a 27% overall response rate and a clinical benefit of 33% with the median progression-free survival of 57 weeks. Um, again, this is solid tumor, you know, we, those aren't good numbers for us, but it's solid tumor. They were very happy with that. Um, and so they felt that this was actually, um, a meaningful, um, piece of data that would suggest that they could move forward in other solid tumor settings in conjunction with, um, checkpoint inhibitors. So we'll see where that's going. Um, and then the other, uh, new molecule that's, um, becoming available now for CTCL is this monoclonal antibody called lautumab. This basically targets, uh, the IPH 4102, which is the CA 3DL2 receptor. It turns out that that is expressed on Cesare cells, very high level of expression. Uh, this, uh, clinical trial that was done treated 56 patients with Cesare. Um, 60% stage 4A and then 32% more advanced stage 4B, uh, heavily pre-treated. Um, and the response rate was 37% with two CRs, um, 46% response in the skin and 48% in the blood. So again, this is, this is very similar to mogamelizumab. Um, this may or may not be available in the United States. Um, the, the development has primarily been done in Europe, so we'll see where, where this ends up going. Well, what about other kind of novel approaches? Uh, we're talking about, um, immune mechanisms and microenvironment, and that's very important now. Um, and this is, uh, one of the studies that was done earlier looking at CD47 antibody and CTCL. So, this is basically the macrophage activation eat me versus no eat me pathway. Um, it turns out that, uh, that, uh, that patients with MF, um, basically have evasion to macrophage activation. So this was a relevant microenvironment in which to try this. So, uh, this first study was actually done, um, using intralesional injections. So this was really a proof of Concept study. Uh, you can see patients with very bad, uh, disease. Uh, this patient with a foot, uh, had injections and then that actually got much better, um, after therapy. So it turns out that if you actually looked at, at the, um, the biomarker endpoints for this study, you can see a number of different things on the slide. Uh, that showed that, in fact, you were achieving the, uh, the expected, uh, goal here, uh, in that you were activating the macrophage, the increase in activation signature for the macrophages, um, and there were some other biomarkers showing CD8 cells increased in that microenvironment. Um, overall, everything was pointing toward the fact that this was an active, an activator of that microenvironment. So, unfortunately, that did not move forward, um, although we still think that this might be an active pathway for us in CTCL. Um, but the good news is that there's always another new molecule on the horizon. Um, and so, uh, this, uh, is a molecule that was actually developed, uh, by, uh, Electratherapeutics ELA 026. Uh, it's a humanized monoclonal antibody directed against SEF alpha beta 1, which is expressed on myeloid cells, and SERP gamma, which is expressed on T cells. Um, it kills by ADCC and it's a blocking antibody. So, it turns out that they actually developed this for HLH and they actually had this in clinical trials with, uh, in patients with HLH. Um, and it turns out that in those trials, a number of patients with HLH actually also have T-cell lymphoma. Um, and so they had some aggressive T-cell lymphoma patients and some CT cell patients. Um, and they were using this for HLH, but they noticed that the T-cell lymphoma seemed like it was getting better also. So, they then, um, started to look at this specifically in T-cell lymphoma, uh, and the current phase 12 clinical trial now is enrolling in CTCL. Um, and if you look at baseline, if you look at, uh, patients that were treated in the early trial, if you look at the, um, The immunostaining here, uh, at baseline and 4 weeks into the study, you can see, a very clear and very dramatic changes, um, uh, in, in terms of this therapy. Um, and so now we're, um, enrolling in that clinical trial and hopefully we'll have some data by, by Ash this year. Um, another molecule that's out there for T-cell lymphoma, um, that's actually not approved, but it's in the compendium listing for NCCN for T-cell lymphoma is duvalizib. So, duvalizib is a PI3 kinase inhibitor, uh, approved for CLL, uh, but we had done a clinical trial where, where we combined CTCL and PTCL, um, and we published that data. So, uh, this is just the CTCL data from that trial. Um, and you could see that we had 18 CTCL patients and we had some patients, uh, in that trial who did have a response with a, with a somewhat short response duration. So, uh, it was an interesting, it was interesting data, but we weren't terribly excited about it. Um, now, what has actually evolved from this is that, uh, the molecule is available. We can get insurance approval for it because it's Compendia listed. Um, and a number of us have actually used this now. It's oral. Um, it's something that our patients like, um, and we've had some very dramatic responses in CTCL. Some people with, uh, multiple. refractory chemo refractory disease have complete remissions with this. And so now there's renewed interest in looking at this, uh, and also looking at this in combination with Romodepsin. Um, so there is data with, uh, with this combination in aggressive T-cell lymphoma showing, uh, a much higher response rate with the combination versus single agent. Um, and we're now starting to segue our CTCL patients in that direction as well. Um, I'm not gonna talk at all about CAR T. Fortunately, I only had one slide. And, um, it's really just addressing the CD 70, uh, car study, which is the LOC study in CTCL that was multi-center study. Um, and I just want to show you in terms of the CTCL population, Uh, that we actually saw a pretty good response rate with this, albeit a short for many of our patients. Uh, you can see the PET scan on one of our patients who had a complete, uh, very, uh, virtually complete clinical response, um, and you can see that there was response in all different compartments, response in lymph nodes, skin, and blood. Um, and, um. The thing about CD70 is it's fairly widely expressed in patients. Over 90% of CTCL patients had expression of, of CD30 on their biopsy, and you can see some of these responses were fairly, uh, durable. Um, in, in the patients that I treated, we were actually retreating them after a month. So there were several patients who, uh, had a partial response to their first dose of drug, um, and then we went back and. a second dose of the car, uh, and then the response continued to evolve. So, um, I don't think this molecule is actually moving forward. There's a newer version of it that I think is moving forward. Uh, I'm not sure where that clinical trial is right now. Um, and the only thing that I have to say about immune engagers, the only actual clinical, multi-center clinical trial, uh, is this one with PD1CD3. Um, this is, uh, sponsored by Ono Pharmaceuticals. Um, and if you actually kind of look at the relevance of, of PD1 as the, as the target on the tumor cell, uh, you can see that in CTCL Susory syndrome and MF, in Susy syndrome, uh, uh, 70% or more express PD1, whereas in MF it might be slightly lower. And if you look at those aggressive T-cell lymphomas, you can see, certainly, uh, AITL and PTCL NOS have. Expression of, of PD1. So, PD1 is the target on the tumor cell to bring, uh, the T cell engaged, uh, into the tumor. And, um, we do actually have patients, um, with Cesory syndrome on this trial. I have a couple of patients who have not responded, but they also have a couple of patients that are on it now for about 8 or 9 months who are continuing to actually do very well. Um, and actually some of these responses are evolving interestingly late, uh, after patients are on drug for at least 4 months. And then I'll just close with, um, two slides about allogeneic transplant in CTCL. So, um, there aren't that many patients with CTCL. There's not that much data out there, uh, and no center has a lot of data. So we put together this meta-analysis looking, uh, across all published papers, of which there were 14, as well as, uh, the registry studies of which there were 2, looking, um, at all patients with CTCL who underwent alloe transplant. Uh, and what we saw is the, uh, the overall survival at 1 in 3 years was 51 and 40% respectively, with progression-free survival of 39%, um, and a relapse rate of about 46%. Um, and then, um, taking that data in hand, we decided that we needed to try to make some recommendations on, on actually what, how you implement allogeneic transplant and CTCL. So, we got, uh, a group of, of people together, including radiation oncologists, dermatologists, transplanters, and medical oncologists. Uh, and we came out with these guidelines that were recently published, um, Um, in the, uh, the journal, the, uh, the, uh, ASBMT journal, um, as well as in the Durham literature. Um, at this very same time, the EBMT also came up with their recommendations. So I just kind of put them side by side to show you that we pretty much have agreement. Um, and the bottom line in terms of who should be transplanted would be, uh, consideration for transplant would be patients with tumor stage disease and refractory disease who continue to progress on therapy or relapse after at least two lines of systemic therapy. Um, patients with multifocal or generalized tumor stage disease or large cell transformation are the ones that we really should focus on. Um, as well as patients, uh, with nodal disease who have basically effaced lymph nodes and visceral involvement. Obviously, those are bad patients. Um, and the, uh, EBMT pretty much agreed with us there. Uh, and then in terms of extension of that, what we recommended, um, that patients should be in complete remission, but, however, that's, that's a dream for many of our CTCL patients, but we recommended that if they're not in complete remission, we should have at least a PR in the different compartments of disease, and we should not have a progression, a progression or PD in any one of those compartments. Um, we also recommend low-intensity transplant, which is what most of us do anyway. Uh, we also incorporate Great total skin electron beam radiation if it's available immediately prior to the transplant, a short course of radiation, skin radiation, which helps to keep the disease under control. Um, and then we also, um, had, had put in some caveats for agents like mogammalizumab or any checkpoint inhibitors because we know that if they're given, uh, too close in conjunction to the transplant, we can have accelerated graft versus host disease. So, um, those recommendations are now, are now published. With that, I'd like to thank you, um, for listening, and I'd just like to tell you that, you know, of course, Yale is one reason why, you know, people think about Connecticut. It's a small state. It's between Boston and New York, but this year was a banner year for us, like many years where 6 times our Connecticut Huskies, our basketball team, both men and women have both made the Final Four. And unfortunately, this year, we didn't make it. We didn't make it, uh, we didn't win, but hopefully next year we will. So, thank you. Nice of you. So I would like to welcome the third speaker of this session. Uh, it's a pleasure to welcome Doctor Chelsea Peterson. She's an attending physician at Russell Park, you know, transplant Service and lymphoma. Chelsea, come. She's gonna talk about T cell lymphoma systemic treatments. Thank you very much. So it's going to be tough to follow Doctor Emmons and Doctor Voss, um, but thankfully, a lot of what I'm going to talk about has already been covered. So we will get caught back up on our time here. So just a little bit of outline of my talk. First, I'm gonna talk a little bit about the background of T-cell lymphomas. Um, the frontline management of peripheral T-cell lymphomas, and we're going to focus mostly on nodal T-cell lymphomas. Then we're going to talk about the treatment paradigm for relapsed refractory PTCLs and specifically dive into updates from the ASH 2025 conference. And then we'll talk a little bit about future directions for T-cell lymphoma. So, a little bit of background, um, T-cell lymphomas are a disease of post-thymic T cells. They affect males slightly more predominantly than females at a ratio of 1.5 to 1. Median age of diagnosis is about 50 to 60 years old. Um, PTCL makes up about 5 to 10% of non-Hodgkin's lymphomas in Western countries and about 15% globally. Um, and there is variation geographically in terms of the types of T-cell lymphomas that predominate, as Doctor Edmonds alluded to in his talk, and as evidenced by this map on the right-hand side of the slide here, you can see that PTCLNOS is the most common pretty much worldwide. Um, especially in the United States and then in Asia, you see more of the AITL, um, hepatosplenic T-cell lymphomas, um, and just different than what we typically see here. There are over 30 subtypes of mature T-cell lymphomas. Um, and so, I'm going to tailor my talk into what we see the most frequently and what there's kind of been the most, um, data that was presented at ASH, and most of that's going to be PTCL, AITL, um, or, um, anaplastic large cell lymphoma. This is just a nice little pie chart that again shows the breakdown of the subtypes of T cell lymphomas, and mostly this is just to show you how many subtypes there are, um, because as I mentioned, there are 30, and some of them are very rare. Um, some of them are more common. For example, PTCL NOS makes up about 20% of the T cell lymphomas. Mycosis fungoides is the most common at 25%. Um, ATLL we don't see as often. Um, and then CTCLNOS, um, also makes up a good chunk of T-cell lymphomas. So the current frontline management of peripheral T-cell lymphomas and nodal T-cell lymphomas specifically has not changed much at all over the years. Um, so this was an interesting talk to talk about clinical practice changes in the management of systemic T cell lymphoma because there haven't been many, but I will do my best. Um, so CHOP has kind of been our standard of care in intensive induction chemoimmunotherapy for PTCLs since 1993. And that was based on the SWA study, which compared CHOP to other intensive chemoimmunotherapy regimens for all non-Hodgkin's lymphomas. And this was before the era of subtyping. So we weren't even specifying whether these were B cell lymphomas or T-cell lymphomas. These were all non-Hodgkin's lymphomas. Um. And basically what the study showed is that CHO compared to a. Myriad of other regimens which we don't even use now, um, had a similar efficacy with decreased toxicity and so CHOP became standard of care. We see that there's about a 37.5% 5-year overall survival with CHOP and CHOP-like regimens for frontline management of peripheral T-cell lymphoma. So that's not great. The addition of ata aside to CHOPP has been studied and has not really shown consistent significant improvements in overall survival, PFS or overall response rates for the first line, um. Uh, treatment of peripheral T cell lymphomas, and it has shown considerable risk of toxicity, which therefore leads to treatment delays, dose reductions, etc. So it's not commonly used in the frontline setting, except for in patients that are younger than 60 years of age and deemed to be fit to tolerate the addition of opposide, in which case, it has been shown to show some improvement in, um, event-free survival. Um, as my colleagues have already mentioned, Echelon 2 introduced the role of rituximabvidotin to the T-cell lymphoma therapeutic repertoire. That was in 2022, and that has been probably the biggest update in the frontline management of T-cell lymphomas, um, at least since I've been born. Um, and so that was initially shown, initially showed therapeutic benefit in people with ELK positive ALCL, um, specifically due to the CD30 expression seen in that subtype, and now we do use it, um, even in people with CD30 low disease. And then autologous stem cell transplant in first CR, um, as Doctor Edmonds alluded to, um. That's kind of touchy. That's a, that's a whole topic of its own, but in some patients with high risk disease and first CR that is standard of care. This is, um, a diagram that I actually took from the ESMO clinical Practice guidelines from 2025. Um, and it kind of just summarizes the past couple of slides nicely, um, for nodal peripheral T-cell lymphoma, as you can see front. regimen is pretty much always going to be BVCHP, CHOP, or CHOOP, um, and then depending on response and stage of disease, if they have high-risk disease, and you do get them into a CR autologous stem cell transplant for consolidation. So, now talking about relapse PTCL because as I mentioned, only about 37% overall survival of 5 years with frontline, um, CHOP. Obviously, these people are going to relapse. So, average response rates to first-line treatment are about 53 to 55%. Um, and as I mentioned, 5-year overall survival varies. Um, it's about 31% for PTCLNOS and much higher for ELK positive anaplastic large cell lymphoma. We have better options and, um, 2nd and 3rd line treatment options for ELK positive disease. So, 5-year overall survival for that subtype is about 79%. 10-year overall survival for relapse disease is about 40%. Majority of deaths are due to lymphoma, and the median overall survival for relapse refractory PTCL is a dismal 5.5.8 months. Salvage salvage options for T-cell lymphoma kind of depend on the treatment intent. So if you, if you have a young fit patient that you're intending to take to alloe transplant, um, you have more. Um, intensive regimens such as Dhab, GDP, bendamustine, ICE, rituximab, if it wasn't used in the first line. And then, um, we also have ballinostat, pralatrexate, Romodepsin, Daveliib, and azacitidine. Um, limited data available to guide kind of what you use in that relapsed refractory setting. And then this is just, again, kind of the algorithm for relapsed refractory disease. Um, you can see all kind of culminates in an alloe transplant. So if your patient is a transplant candidate, that's what you're trying to get them to. You're trying to get them into a deep CR so that they can move forward with an aloe. So All that being said, the bulk of what was presented at Ash this past year was in patients with relapsed and refractory PTCLs. Um, so the first abstract that I'm going to talk about are the final results of the phase 2 primo trial. So this was a phase 2 open label, single-arm trial evaluating Duveliib monotherapy and relapsed refractory PTCL. People had to have at least 1 standard line of therapy prior to enrolling. Um, and this was the dose expansion phase. So they received 75 mg PO BID of Duveliib for two cycles. And then once they had undergone that debulking for the first two cycles, then they decreased to 25 mg BID until progression of disease or toxicity. The primary endpoint was overall response rate, and it was assessed by PET CT, um, after every two cycles. There were 123 patients enrolled. The median age was 65, and the age range was pretty impressive to me, 21 all the way up to 92 years old. Median prior lines of therapy was 2 with a range of 1 to 9. Most of these people were PTCL NOS, um, but then we also had 37 AITLs and 20 ALCLs. Median follow-up of the PRMO trial was 11.5 months, and they found an overall response rate of 48% with a complete response rate of 33%, median duration of response of 7.9 months, median progression-free survival of 3.4 months, and a median overall survival of 12.4 months. So if you remember a couple of slides back, I mentioned that the median overall survival for relapse refractory PTCL is 5.8 months. So that's pretty promising data. Um, What's more interesting is that when they broke it down by the subgroups by histology, um, they actually found that specifically AITL subgroup, uh, performed really well. Um, so you can see that the, the AITL, which is angio angioimunoblastic T-cell lymphoma subgroup depicted in the red. Um, and then the PRO EP is the expansion phase. So that's the whole cohort is black. PTCLNOS is green, and ALCL is in blue. Um, so superior, you know, PFS and overall survival in, um, the AITL subgroup with a, with a median overall survival in the AITL subgroup of 18 months. Um, in terms of safety, out of the 123 patients that were enrolled, 63 received greater than 2 cycles of treatment. 25 patients received over 6 cycles of treatment. The most common side effects were neutropenia, AST and ALT elevation, thrombocytopenia, fatigue, diarrhea, and the most common grade greater than or equal to 3, toxicities were, again, cytopenia, rash, diarrhea, hypokalemia, and hypoxia. So, what they've concluded, um, from the, these findings were that Duveliib monotherapy is safe and effective. And they also found, interestingly, that people with heavily treated disease actually still had a good response to Duveliib and people that, um, had, I believe it was greater than 3 lines of therapy still had about a 44% response rate. Um, AITL patients responded particularly favorably. And so based on that finding, the sponsor initiated the phase 3 Turzo trial. Um, which I've provided the schema for here. So, this is currently enrolling, I believe. It's a, um, Open label phase 3 randomized controlled controlled trial of Duveliib versus either bendamustine or gemcitabine in patients with relapsed refractory, um, nodal T lympho nodal T cell lymphoma with a T- follicular helper phenotype. And again, that was based off those findings from the AITL subgroup. The next study, we're gonna kind of shift gears here. The next abstract that was presented at Ash that I want to talk about is the final results of a phase one trial with socholitinib. So we've talked a lot about kind of the role of T cells in the immune system, the formation of cancers, and their role in helping to treat cancers. So. This was an interesting study. Um, and basically what they did, they had socoliib is an oral covalent inhibitor of ITK, which is IL-2 inducible T-cell kinase. Um, so it was a phase one trial and treatment of relapsed refractory T-cell lymphomas. And the pictures on the slide show kind of how socolitiib has its effects. So it suppresses the TH2 response via reduced GTA 3 expression. So you can see that if you have a naive CD4 positive T cell, by blocking ITK you skew the T cells to Kind of go down that TH1 differentiation pathway, um, which are going to be your cells that are cytotoxic and help play a role in elimination of virus, viruses and, and cancer. Um, so by skewing that pathway, then you kind of reduce the, the differentiation to the TH2 and TH 17 pathways. Um They enrolled 75 patients in this trial, 28 were in the dose escalation, um, arm, and then 47 in dose expansion. Uh, median age was 62. Median prior lines of therapy was 3 with a wide range from 1 to 19. Histologies were varied. Again, PTCLNOS is pretty much uniformly the most common subtype. Um, and then in terms of their outcomes, they found an overall response rate of 39% in patients who had received less than or equal to 3 prior lines of therapy, 6 CRs, 3 PRs, and median progression-free survival of 6.2 months with the median overall survival. For PTCL of 28.1 months. Now, notably, they did not see any responses in patients that had received greater than 3 lines of therapy. So, if you have a heavily pre-treated patient, this is not a good option for them. Um, interestingly, the graphs on the right-hand side show the effects on the different T cell subsets. So at the top, we see the frequency of TH1 and TH 17 CD4 cells in the blood. And you can see that by day 22 after treatment initiation, this TH17 cells have bottomed out and the TH1 cells, um, Are the predominant subset. So again, just kind of demonstrating the effects of ITK inhibition on TH one skewing. Um, just below that, you can see that they also were able to do paired banking with, um, blood and tissue and tumor tissue samples. So you can see that the TH1 affector cells were seen in both the blood and the tumor specimens during treatment. So we're seeing that there is TH1 infiltration into the tumor cells. And then at the bottom, you can see the effects on eosinophils and serum IL-5. Um, again, those dropped after initiation of treatment, which just supports that, um, we are inhibiting the TH2 and TH17 differentiation of the, uh, CD4 T cells. And then in the box and whisker plots, you can see increased expression of Tibet and interferon gamma, which further supports, uh, this TH1 skewing. So with silquelitinib, there were grade greater than or equal to 3 side effects in 29% of the patients. Pruritus and anemia were the most common toxicities. Uh, and as I've mentioned, the other outcomes that they studied were the increase in TH1 and T effector memory cells and a reduction in T cell exhaustion markers, LAG 3 and TIM 3. So in conclusion, it was a phase one dose escalation and expansion study of soquelitinib, which is an oral ITK inhibitor. In relapse and refractory PTCL they found a dose of 200 mg BID to achieve full target occupancy. So that was what was used in the dose expansion cohort. Durable responses were seen in patients that received less than or equal to 3 lines of therapy, and patients that had received greater than 3 did not have any response. And there's currently a randomized phase 3 trial underway that is comparing soquelitinib to Belinostat and pralatrexate, which is currently enrolling. Um, So, kind of shifting gears now and talking more about, um, epigenetic regulators and their role in T-cell lymphomas. Again, Doctor Emmons alluded to this earlier, but mutations and epigenetic regulators such as TET2, IDH2, and DNMT3A are frequently implicated in peripheral T-cell lymphomas. And thus HDAC inhibitors and DNA methyltranrase inhibitor combinations have shown promising results with response rates of 60% and CR rates of upwards of 43%. The specific study that was presented at AS, um, looked at the safety and efficacy of an anti-PD1 monoclonal antibody in combination with lenalidomide and azacitidine. And so they enrolled 31 patients, um, 18 of which were male, the rest were female. Median age was 67, which is pretty typical. Um, histology breakdown is shown, median lines of therapy was 2, and median follow-up time in the study was 15.8 months. And they actually found a pretty surprising overall response rate of 62% with a CR rate of almost 40%, 37.9. With a 2-year PFS of 67 and a 2-year overall survival of 73%. Uh, so it's pretty, pretty exciting data. They did have NGS available for 17 out of the, um, 17 of the patients that they had enrolled, and they found that 14 out of the 17 that they had data for had at least one mutation greater than or equal to one mutation. In TE 2, row A, or DNMT 3A. Um, and in those patients specifically, the response rate was 70%. In terms of toxicities, grade greater than or equal to 3, neutropenia was the most common, followed by thrombocytopenia, um, and anemia, and then some other organ dysfunctions, which were less common. Doctor Emmons already talked about this, but this is the, um, first in human phase one dose finding study of the dual population autologous CD5 deleted anti-CD5 CAR T and relapsed refractory T-cell lymphomas. So I will kind of go kind of quickly through these last few slides just for sake of time, but it was the VIPR 101 trial, um, which was An autologous gene edited dual population CAR T5 product where they use CRISPR-Cass 9 to knock out CD5. Um, and as he mentioned, they use the Sens of platform which allowed them to have rapid 5-day manufacturing of the CAR T cells. This was an open label dose finding phase one study, um, with a single infusion. Their primary endpoint was safety and the recommended phase 2 dose with secondary endpoints of manufacturing feasibility, in vivo expansion, tissue trafficking, T-cell plasia mitigation, response rate and CR rate. Um, so at the time that this was presented at Ash, 6 patients had manufactured, 5 had infused. Um, only 4 patients were valuable for safety and 3 for efficacy at the time of their analysis. Um, treatment-related adverse events, they saw grades 1 to 2. CRS in 100% of patients, as well as transient cytopenias and gastrointestinal toxicities. Um, infections were quite common at 75%. Uh, and they didn't go into too much detail about the nature of those infections or the severity. Um, one patient at higher, at a higher dose of the cell product, um. Developed a severe infection that they deemed was not related to the CAR T. They did confirm CAR T trafficking to the disease sites, um, on biopsy. And they found robust in vivo expansion in all patients, and by day 28, all had demonstrated reconstitution of CD5 negative, CAR negative T cells. Um, overall response rate was 100% of all in all patients achieved a CR. Again, that was only 3 patients available for efficacy at the time of this analysis, though. And then again, um, as Doctor Emmons mentioned earlier too, the MB 105 was another CD5 CAR T trial, um, that was presented at Ash this past year. This was a multi-center three-part phase two study. Um, this product was a little bit different and they didn't have the CRISPR Cas 9 CD5 knockout, but they had a self, um, The product resisted self-targeting and fratricide by rapid degradation of CD5 on the CAR T cells. Uh, similar inclusion criteria, patients had to have failed at least one prior line of systemic therapy. They also included CTCL patients on this trial. They had to have CD5 positive disease, um, and adequate KPS and no recent transplant or cell therapy. Uh, median vein to vein time for this product was 29 days. So, again, they're not using the same manufacturing platform. Um, as the VIPper trial. 7 patients received infusion and 5 were valuable for, for response at the time of this analysis. 4 of the patients had PTCL, 3 had CTCL. Prior treatment regimens ranged from 2 to 8. Um, CD5 was greater than or equal to 50% in all except for one patient that had CD5 low disease and was not deemed, um, not included in the efficacy analysis. Um, so out of the 4 patients that were included in the efficacy analysis, 100, there was a 100% response rate with 3 CRs and 1 PR in 1 patient pending response assessment at the time of the presentation. Peak expansion of the cells was seen at day + 14. In terms of safety, they had 50% grade 1 CRS, no neurotox. Um, again, frequent cytopenias, um, nothing that persisted beyond day plus 42. Viral reactivations were seen in 2 out of six patients, however, with BK, CMV, and EBV being seen. And there were two deaths, one due to progression of disease and a CD5, uh, which was CD5 negative, and one due to EBV positive B cell lymphoma. So, shifting into kind of where future directions for T-cell lymphoma, um, I think that where we're headed are, we need better frontline options because we know these patients relapse, and when they do relapse, it's not good and we have a really hard time getting them back into remission. Um, the Golden study is currently, is a, is a trial that's currently underway. It's a phase two single center, single arm study evaluating golidecitiib plus CHOPP in newly diagnosed PTCL. I probably butchered that, but tried my best. And then the Alliance trial, which is looking at CHOP versus CHOP plus duveliib versus CHOP plus CC 486, which is oral azacitidine. Um, so really looking at different combinations in the frontline setting, adding to that CHOP backbone, looking at using, um, things that target these, these mutations in the epigenetic modifiers, which we see frequently in T-cell lymphomas. Um, additionally, we see more CAR T cells in the pipeline, um, CD30 T cells, CD4s. Doctor Emmons has, um, group has been looking into CD7 and CCR4s, as Doctor Foss alluded to, uh, future combinations for relapsed PTCL. So there's a trial currently looking at Pembroke plus BV, um, and retreatment with previously treated BV. There's Herzotri, which we talked about, and then combinations with soquilitinib, which was the oral ITK inhibitor. Um, additionally, we have newer targeted therapies and bites such as 0104685, which again, Doctor Foss discussed is a bi-specific targeted against PD1 and CD3. In summary, systemic T-cell lymphomas are a rare entity that have not seen much progress, at least in the past 30-something years, um, especially in terms of frontline treatment. Outcomes are often dismal with frequent relapse and short overall survival, especially in the relapse setting. There are not many large randomized trials that have been done to move the needle, largely because the disease is so rare, and there's a lot of geographic variation in terms of what subtypes we're seeing in what regions of the world. Um, recent discoveries have led to some practice changes, including the histologic subtyping of peripheral T-cell lymphoma. So we now understand the importance of putting a name on the T-cell lymphoma, whether it's not just ELK positive or ELK negative, but, um, T- follicular helper, angioimmunoblastic T-cell lymphoma, um, as well as, you know, checking that next generation sequencing and, and molecular mutations that we're seeing. In the T-cell lymphomas to kind of help us determine who's going to respond to therapies and which therapies might work better for our patients. Um. And in conclusion, a lot more needs to be done for T cell lymphomas. Thank you. Thank you, Chelsea. We're gonna open this for questions. Hello, you have a question. I do. hello, it's me again, um, um, you know, in all seriousness, it's not every day that I, uh, have a captive audience of so many people smarter than me, so I, who have to answer my questions, uh, so, um, my, my question actually, um, all three of you touched a little bit on. Um, transplant, especially, uh, for consolidation and, uh, in the front line of these very high risk patients who when they relapse have very dismal outcomes and a question that comes up very frequently at our center, especially in these particularly high risk peripheral. T-cell lymphomas, you know, these AL negative DUSP 22 negative ALCLs, it's especially is if we get them into a remission after the front line, do we take them to autologous transplant? Do we take them to allogeneic transplant? Do we leave them alone, uh, in some cases, and there's some data that actually supports all three. And so I, I would be very curious to hear all three of your approaches to thinking about who you send for transplant at all in the front line and if so what type of transplant, uh, in, in these very, very high risk patients. You just stuck, OK, um. OK, so I mean there are certain histologies that you would take to an aloe like hepatosplenic, you know, and gamma delta T cell lymphomas, you would take them to an upfront aloe. Uh, most patients with the kind of garden variety, you would at least give them a chance with an auto transplant because the relapse rate after auto is greater than 50% for pretty much all these histologies. It's my practice to actually give a year of maintenance, so kind of adjuvant maintenance therapy. There are studies trying to address this issue right now. But, um, I, I, I think you certainly could be justified doing that in terms of like the bad histologies that you would take upfront that are the kind of garden variety ones. I mean, certainly there are people with very aggressive high IPI, um, PTCLNOS and AITL and ALK negative ALCL that in particular chemo, you know, not typically chemo sensitive require. You know, more than one regimen to get them into a remission. Those people are not gonna do well with an auto. They're, you know, not chemo sensitive. So I think definitely that group, um, whether you can then expand it to like very aggressive like stage 5 patients. I mean, I have done that in certain instances. I think it's a patient like specific decision, but we interestingly, so we are trying to address this very question now with another, uh, Delphi survey to try to. Get kind of community consensus opinion about which patients you take to Otto and which patients you take to Aloe. So those questionnaires are floating around and like we haven't really come to a consensus yet, but you might see that in the next year. So I try to keep it simpler. I, I guess, uh, and I certainly agree that we don't have the best data right now, but there's no question that the ALK positive anaplastic large cells that do well with chemotherapy, if they relapse, and Otto's clearly on the table. They're generally chemo sensitive. It's a good thing to do for that smaller subset of patients who relapse. For the anaplastic alk negatives, if you look at the largest registry trials, of which they're really not that large, but they're as good as we get, the ones that stand out. That do better with auto transplant are those of the nodal T cell lymphomas. The other ones really don't differ very much and they don't really respond very, very well to that. So we need other strategies there and that's where the question of aloe comes in, right? So that's the million dollar question with regard to response. So if we get very good responses with some of these therapies, especially if we do better with CART across the board. And especially again if we can make alloe transplant really safe. Remember that CD7 thing I showed you, the new sexy. I mean, that's amazing if you can just use a CD7 auto car. To put the disease into remission. Aloe ablate the patient to get in a new, you know, an an HLA matched transplant. No GVH prophylaxis. The aloe effect eliminates the auto car, of course, in the long term, so it sort of makes it go away, but it hangs around long enough to lympho deplete so that you don't need GVH prophylaxis. That's an incredible technology. I mean, if that carries forward for T cell lymphoma like it did in those AML patients. That's gonna be a paradigm shift in terms of how we do allo transplant across the board and especially for these T cell lymphomas. So, you know, I think we're tantalizingly close to sort of being able to answer that better, but I think the depth of remission is really important in these diseases. The other thing is, you know, of these 30 different lymphomas, there's a huge disparity in how they behave. There's some of these. Things that'll, you know, they're like MGUS and T cell lymphoma, right? They're gonna go on for years and years and years and never get the patient into trouble. So we need to be better in understanding the molecular and immunologic underpinnings of the disease to predict earlier who needs to go for the aggressive therapy right away, hopefully before they become so resistant that it makes it really hard to get them in remission. But hopefully, you know, CCR4 car, you know, uh, in the CTCL and CD7, CD5. Those are great targets and they may get us over the hurdle in terms of getting these patients into deep remissions for successful hour. Yeah, I think the other thing to take into account is that aloes are not as scary as they used to be, and this is coming from a person that never did aloes back when they were really scary. So, um, take this with a grain of salt, but I think a lot of the data that we have for aloe transplant and T cell lymphomas predates post-transplant cyclophosphamide and a lot of the newer graft versus host disease medications that we have, so. Um, I wouldn't hesitate as much to, to use an aloe as a prelude to tomorrow, I'm just gonna mention in passing the aloe space is something that we need to revisit for a lot of these diseases now because, you know, for myeloma, yeah, OK, we're, we're getting the cell to cell down into good remissions, but the 5 year, you know, it's only about 25%, you know, a lot of these patients are not staying in long term remission. So the question is now in the modern age of therapy where we do such a good job getting these people into deep remission, can the aloe effect really cure these patients now? It's a different age than it used to be, so we need to revisit some of these older therapies for that reason too. Yeah, the other thing I just want to say is, um, you know, we always talk about CTCL as a chronic disease and we always tell people we're, we're never gonna cure you. But I think those days are gone too, so we have proven and others as well that we can definitely cure people with aloe. So our recent paper, I think we, we had 70% long term remission. We, we're curing people and I think it's important to know that because that's going to then trigger people to refer those patients earlier to consider an aloe. But Dr. Foss, in that, did you, did you prove that depth of remission mattered before they went to the aloe in that cohort? Um, interestingly, that wasn't the case in our series, but if you look at the Europeans, they felt that it was, but it's an open question. Uh, well, well, one question. So if, if we're gonna do car therapy for T cell lymphoma, I'm assuming we expect to have a prolonged T cell depletion. So are we supposed to consolidate the patient with a, uh, an aloe that would be the only, right, so, so it depends on the type of car, right? So if you use an aloe car that typically doesn't survive for as long, so you can get recapitulation. The auto car tend to last longer and then you're really asking the question. You know, should you do something like the CD7 car that's gonna be eliminated by the aloe effect just as the new alloe cells come in and, uh, automatically ablate what you've already put in to try to get the disease under control? That's the most elegant solution. But you know some centers are seeing over many months recapitulation and die off of the auto. So the devil's in the details here in terms of what the cell dose is. How competent the host's immune system is because that makes a big difference for the survival of these T cells as well. So it gets back to that original thing about, you know, thymic function and predicting exactly what the host brings to the table as well as what the car does as well, and we need to get better at understanding the host effects to to predict the survival of the car and therefore the long term toxicity against the immune system. Yeah, and I know like the one, the one study from ASH, the MB 105, they, they showed that 100% of the patients that, I mean it was like 4 patients, but they had immune reconstitution at I think 42 days, which then makes, but I don't know how they, they quantify. I didn't see how that was quantified, um, and then that also begs the question, are these gonna be long term responses if the cars aren't lasting or if they're. And the question about the CDC is like I know Linford is kind of coming up as a new potential treatment. Of course the schedule is a little bit challenging because it's like a 5 day dosing. If there's any role to maybe do less, like a 3 day dosing instead of 5 day dosing. Yeah, I think it's the same argument with Balinistat, right? Try to get a patient to come in 5 days in a row, every 3 weeks or whatever. So I, I think it's, it's an obstacle for sure. Um, they, the company has heard over and over again from all of us that we need a different schedule. I, I think once the drug is available, there'll be IITs to look at, you know, weekly dosing or 3 days every 3 weeks or just alternative dosing. We desperately need to readdress that issue of dosing. Whatever I know you did that trial a couple of years ago on tag CHOP and there's a role to revisit. Yeah, we did 3 days. We did, we, we already published a study combining it with CHOP showing that 3 days every 3 weeks was perfectly fine and maybe the same. We don't know if it's the same, but it was, it was in the study, yeah. Show. Good. Well, thank you much, everyone. Thank you. So let's take a break. So we're gonna take a 10 minute break and then we'll be back for the last session of the afternoon. Thank you.
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