Hey, everyone. I think we're going to ask those of you here in the room to please take your seats, and we're going to get started. Welcome to Caribou Biosciences KOL Panel at ASH 2025. My name is Rachel Haurwitz. I'm the President and CEO of Caribou, and it's my great pleasure to welcome you here, both the people here in the room with us in Orlando today, as well as the many who are listening online to our webcast. As we dive in, I would like to advance the slides. There we go. As we dive in, I would like to acknowledge that this presentation includes important information as well as forward-looking statements. Our speakers have several disclosures, which are summarized here.
We are so grateful to be joined today by four physicians who are going to bring their unique perspectives on the unmet need faced by their patients and the role that Vispa-cel could play in bringing the benefit of cell therapy to more lymphoma patients. Today, we're going to focus on Vispa-cel , Caribou's off-the-shelf CAR T- cell therapy targeting CD19 for large B-cell lymphoma. Our team recently shared clinical data demonstrating that Vispa-cel drives outcomes on par with auto CAR Ts, and we'll dig into some of those details in a few minutes. We also shared data demonstrating that Vispa-cel has a generally well-tolerated safety profile, unlocking the opportunity to deliver Vispa-cel outpatient and, importantly, in the community setting. You hear our team talk an awful lot about the 75% of second-line large B-cell lymphoma patients who do not benefit from autologous CAR T-cell therapy.
We're going to focus in particular today on these patients and the viewpoints of our physician colleagues on how best to address the unmet need faced by this patient population and the role that Vispa-cel could play. In the United States, approximately 38,000 patients are newly diagnosed with large B-cell lymphoma each year. This ultimately works out to about 12,000 second-line patients being treated annually. Our plan for the pivotal study for Vispa-cel is to run a randomized controlled trial in second-line large B-cell lymphoma patients and to focus in particular on a very high unmet need patient population who are ineligible both for auto CAR T and ineligible for auto stem cell transplant.
Research quite recently conducted by a third party has shown that approximately 60% of the entire second-line large B-cell lymphoma patient population is dual ineligible, and this is due to a combination of clinical and real-world barriers to access. This includes, for example, clinical status, rapid progression, referral challenges, distance between where the patient lives and where cell therapies are available, and, importantly, the challenge of wait times to receiving auto CAR T-cell therapy. I'm so grateful that we have these four physicians here today to represent both the voice of community doctors as well as doctors at academic institutions to share with you their experience treating these patients today and why they believe Vispa-cel could be part of solving this problem for the broader access issue for this patient population.
I would now like to hand the floor to my colleague, Dr. Tina Albertson, Caribou's Chief Medical Officer. Tina has been in the world of CAR T-cell therapy development for about a decade. At Juno, Celgene, BMS, she played the role of clinical development lead of what is now Breyanzi, from pre-IND to BLA filing. I am so grateful that we have her and her expertise here at Caribou. And, Tina, over to you. Thank you.
Thank you, Rachel. It really is exciting to be talking about bringing an off-the-shelf CAR T to patients. And you're going to hear today from our physician panel just how hard it has been to get auto CAR T to all the patients that need it. So I'm going to start with introductions. I'm going to start with Dr. Ormsby, and we'll move down the panel and finish with Dr. Thomas. If you can introduce yourself, say a little bit about your background, maybe where you trained, where you currently practice, and whether you have any CAR T experience at this point.
Sure. My name is Dr. Wayne Ormsby. I'm the Heme Malignancy Director for Utah Cancer Specialists. We are the largest independent, non-hospital-affiliated oncology group in the Intermountain West. We have a catchment area of about 450 mi north to south, stretching up into Idaho, Wyoming, and the majority of Utah, and a catchment area about the same east to west, going from eastern Nevada all the way to the edge of Utah. I did my residency and chief residency in upstate New York. I did my fellowship training at Mayo Clinic, where my area of focus was multiple myeloma, and I was very, very blessed to train under S. Vincent Rajkumar and Shaji Kumar. I have started a purely outpatient community bispecific program with Utah Cancer Specialists.
We did our first ramp up about a year ago and have continued to successfully go forward with the program, now engaging in clinical trials like TEC-7 and TEC-9 with J&J. We are not currently doing auto CAR T. We have two large centers in close proximity to us, but we are very excited about the idea of allo-CAR T and the opportunities it would provide to some of our patients who are either unable or unwilling to go to these centers.
Thank you. Dr. McGuirk?
I'm Joe McGuirk. I serve as Division Director of Hematologic Malignancies and Cellular Therapeutics at the University of Kansas. I did my residency at Yale, my fellowship at Memorial Sloan Kettering, and then went back to Yale, where I eventually became the Director of their stem cell transplant program. I'm a Midwesterner, grew up in St. Louis, and wanted to come back to the Midwest, so I moved to University of Kansas 26 years ago, and we've grown, basically from the ground up, one of the largest stem cell and cell therapy programs in the nation. We also have a remarkably wide catchment area. It's 10 hours out to the Colorado border from where we are in eastern Kansas, and we serve patients in Nebraska, Iowa, half of Missouri, Arkansas, Oklahoma, and then, of course, the entire state of Kansas.
We're doing currently about 250-275 cell therapies on a yearly basis. I think that it's been an exciting time. We've been fortunate to contribute significantly to registrational trials for CAR T-cell therapy, co-authored four manuscripts in the New England Journal of Medicine, and we're a lead enrolling site on JULIET in the third line and on both BELINDA and ZUMA-7 in the second line versus autologous stem cell transplant. I think it's an extraordinarily remarkable therapy and is associated with statistically significant improvements in overall survival for patients, progression-free survival on multiple fronts in multiple studies. Our major challenge, although important issues such as CRS, ICANS, cytopenias-associated infectious complications, the fact that not everybody responds, not everybody who responds stays in remission, are important challenges, but I will discuss further. They're not the greatest challenge. The greatest challenge is the majority of patients who might receive these curative therapies never get referred.
Dr. Hamadani.
Hi. Good morning. Thank you for having me here. So I'm Mehdi Hamadani. I'm a transplant lymphoma and cell therapy physician at the Medical College of Wisconsin. At MCW, I lead our hematological malignancy program. In our cancer center, I'm the Associate Director of Clinical Research. Now, over nearly two decades of experience in transplant, cell therapy, clinical trial development. MCW is a big transplant and cell therapy program. We do about a little over 400 transplant and cell therapy procedures, both in the inpatient space, outpatient space. Our catchment area is essentially Wisconsin, northern Illinois, upper peninsula of Michigan. In MCW, for nearly a decade now, we have been involved in homegrown tabletop manufacturing of cell therapies. That's how we developed our cell therapy program. My passion, from a clinical research perspective, is to take trials to where patients live, take therapies to where patients live.
So in my role as the AD of our clinical research, I've been working for the last three years to open most of our clinical trials, not in the big city, but take those patients and those trials to where the patients live. And that's what really excites me about your strategy in Caribou, right? Like, patients have to come to big centers to get cell therapies, but guess what? They don't like traveling, right? Like, patients who come, I'm sure, to Kansas, patients who come to Milwaukee, they don't like driving in Milwaukee. They don't like staying away from their home for a couple of months. So taking the treatment to where the patient is is exceedingly important. So I'm very excited about your approach.
Great. And Dr. Thomas.
You bet. Thank you for having me. I'm Justin Thomas, medical oncologist here in Bozeman, Montana. I grew up in Helena, Montana, and one of my goals was always to come back and serve the community of Montana and make sure that everybody gets the exact same care here as we get anywhere in the academic centers. I was admitted to the University of Washington, where I did my school of medicine. I went to University of Utah thereafter to do my internal medicine training and then stayed at the Huntsman Cancer Institute and stayed there for three years and then came back, and I've been practicing in Montana since 2011. It's so important, I think, for us to continue to bring these novel therapies and having an allo-CAR T-cell therapy to be able to be done here in Montana is such a big deal.
We'll talk about those barriers to care. I teach at the University of Washington right now. I'm a representative at the biannual ECOG conferences, and we continue to cooperate with industry to sponsor other clinical trials here. We have over 20 other industry-sponsored trials. Again, my goal would be to make sure that everybody in Montana can get the exact same care here over the long term and not have to leave the state. We have a huge catchment area as well, most of Montana and certainly southwestern Montana. For myself, I subspecialize in hematological malignancies and classical Hodgkin's lymphoma, non-Hodgkin's lymphoma, and multiple myeloma. I'm excited for this product.
Thank you all. Let's dig into some of these topics. I'm going to start with the two of you that are CAR T-cell referrers at this point that you both have vocalized how excited you are to get allo-CAR T off the shelf into your own centers. But can you talk a little bit right now about the unmet need? What percentage of the patients that you would like to refer make it to actually receive CAR T-cells? And, Dr. Ormsby, let's start with you.
Sure. So in preparation for this, I went and did a chart review over the course of the last 12 months on patients we see at Utah Cancer Specialists. And I specifically focused on the ICD codes that are associated with diffuse large B-cell lymphoma, so not including transformed follicular, et cetera. And looking at everything, when we see the patients that are potentially or should be referred and would benefit from CAR T therapy, we still have about 10% to maybe 20% of eligible patients who are not going and are receiving second, third, fourth-line therapy, which would be considered significantly inferior to CAR T therapy at this point.
And when we look at what are the reasons for that, interestingly, just kind of following on what both of you said, I get a lot of patients who say, I don't want to go into the big city. And for me, believe it or not, that might even be patients who live 10-50 mi from Salt Lake City. So not a big difference or not a big distance, but still patients who refuse based upon that.
Great, and Dr. Thomas, do you want to speak about the referral challenges and percent that you get into the big centers from Montana?
You bet. I'm similar to all of the other challenges that all the other doctors have. We probably have maybe even more so because of the distance. The geography is such a big deal. A lot of patients, too, in Montana, again, don't want to go to the big city. I think for us, instead of it being 10%-20%, I think it's actually more 50%-60% of our patients that don't want to present to go to an allo-CAR T-cell or potentially even transition to an academic center. I think there is a bunch of barriers to the care. I think the geography is part of it. I think the socioeconomic piece of it is an issue where they financially get hit. There's a security of being at home.
It's always so nice to be home with your friends, with your family, with your dog, with your pillow that you need, and then having the nutrition that you require to be able to continue to heal as well as you can, and then I think we could talk about complications to bridging and all these other different things and time associated with collection that people just aren't as interested in, so having something be able to be done in our community is going to be a big deal, and I'm excited about it.
Dr. Thomas, can you give us an example, perhaps, that might personalize what this looks like of a patient that you really wish could have gone on to get a potentially curative allo-CAR T, but either for medical reasons or access issues could not?
Yes. Again, about 50% of our patients end up not wanting to go. I have had patients with relapsed diffuse large B-cell lymphoma that are ranchers here. And even just saying, Gosh, there is a potentially amazing strategy at an academic center, and they're like, Hold on, where's that? And I'm like, Well, you either got to go to Salt Lake or you got to go to Seattle. And right away, I'm not doing that. I'll do anything else that I need to do, and I'm going to do it here. If you have something here for me, I'm going to do that with you. I feel like I trust in your team, trust in the team here, but going out of state or into a big city is something that I'm just not willing to do, even though they know that the potential data, as Dr. Ormsby said, looks better for some of those other therapies that they could receive elsewhere. So it does happen quite often.
Great. And, Dr. Ormsby, back to you before we move on topics. Do you have any examples of patients? You're actually a little bit closer to the big academic centers, but patients who actually can't wait for an allo-CAR T or you think can't manufacture that you're probably starting to give bispecifics to now, but really would maybe prefer a one-and-done off-the-shelf allo-CAR T. Can you explain to this audience maybe what that kind of patient might look like?
I can give you an example of a patient I'm going to start on therapy on Monday. Part of the reason I'm not staying at ASH, so I have a gentleman in his 50s with early relapsed diffuse large B-cell lymphoma with the disease behaving very, very aggressively who was seen at one of our allo-CAR T centers. We were able to get him in on just a couple of days ago. But because of the expected four-to-six weeks, we really don't have the option of delaying initiation of therapy. So he will be starting treatment with either glofitamab or epcoritamab. I will find out, hopefully, very soon which one we have approval for with GemOx. Whereas for this patient, I would have preferred CAR T therapy for him.
So, having an off-the-shelf CAR T where we could have very, very rapidly implemented therapy would have been a fantastic thing, because by the fact that I'm having to start him on an aggressive therapy, these two could address it to a better degree, but that would cause significant problems, if not impossibility, collecting T-cells for CAR T, but he doesn't have time to wait.
Thank you. I'm going to move on to speak with Dr. McGuirk. Dr. McGuirk already alluded to this, but he really has been a champion, not just in Kansas, but nationally for the access to CAR T-cells. He's part of the CAR T vision and here at ASH has an abstract entitled Real-World Treatment Patterns and Survival Outcomes in the Second- and Third-Line Settings in Large B-Cell Lymphoma. Could you share with us the study you conducted and what are the major barriers to patients receiving allo-CAR T that you found?
Certainly. We looked at a Flatiron research database, patient-level data in 10,000 patients from 2011 when CAR T was not available until it became available in 2018 initially, subsequently in the second line in 2021, and looked at those patients in the period prior to CAR T, and actually, quite remarkably, there were a significant percentage of patients who were fit, had good ECOG scores, were less than 70 years of age, who were not receiving any second-line therapy and dying within one year, so about 14% of that fit patient population. During the time that CAR T has been available, we saw in the database in 500 patients that only 25% of patients in the second line were receiving CAR T who were clearly fit for CAR T.
Even those patients who were borderline, so had ECOGs of two or three, those patients had a 7% chance of accessing CAR T. In the third line, it was 35%. It appears to have plateaued. There's a huge unmet need nationally. We present data demonstrating that CAR T, those patients who received CAR T versus alternative therapies through that same database, the time-to-next treatment, progression-free survival were highly statistically significantly better if you'd gotten CAR T versus bispecifics or chemotherapy or were on a clinical trial studying other therapy other than CAR T therapy in that setting. I think, as I mentioned previously, this really represents a major egregious issue when we consider that both in the third line, about 30% of patients are cured at five years follow-up in the two major prospective trials.
In the second line, we have an overall survival advantage with axicabtagene in those patients who went to CAR T versus autologous stem cell transplant. That allowed for a crossover, yet there was an overall survival advantage relatively early. I think that CAR T-cell therapy as a potentially curative therapy represents the standard of care in this nation. We have to get it out to the centers. We have randomized trials coming up by a couple of sponsors who are at the meeting here of different CAR Ts in the second line versus each other. As Dr. Hamadani and I were discussing earlier, that's not going to increase referral patterns. That's just going to take the patients we're already treating and have us put them on clinical trials. We have a great deal of work to do to improve this access issue.
I think Caribou, when we look at the safety profile, the efficacy profile, greatly lends itself to this outreach strategy. We, as you know, have formed a network of centers in our region that are greatly interested. The docs out in practice want to do these therapies. Of course, they want to make sure that it's safe and that they have a safety net 24/7 so that if somebody has advanced toxicities, we can get our hands on them quickly at a tertiary center such as ours.
Thank you, Dr. McGuirk. Can you also speak to why at your center you may also, what are the kinds of patients that may benefit from an off-the-shelf therapy at your large center, even though you have access to allo-CAR T?
I think patients who have rapidly progressive disease. I sent out a text to my good friend Tanya last night. I have a patient who was to receive commercial CAR T. And I got a call yesterday afternoon from the manufacturer. Failed, completely failed to process. And we're weeks into this, and he has progressive disease. And so now we have to start. They have more sample over, so we are restarting the manufacturing. It's going to be another three to four weeks. I've been holding off on bridging therapy. I can't. Say uncle now. I have to start him on bridging therapy. And we've published data showing that if you require bridging therapy, your outcomes are compromised thereafter after CAR T-cell therapy.
So ultimately, if you can get your hands on therapy and get it into these patients in a very timely manner, like an off-the-shelf therapy, it's like a drug. You can get it within 24 hours, start your lymphodepletion right away. That really offers a significant potential advantage for us. And we've participated in some allogeneic CAR T clinical trials. And even in the context of clinical trial and some of the things that can delay getting there, we access those in the context of clinical trials much more quickly than we can access an autologous construct.
But we're also very attracted to the idea of a T-cell population from a young, healthy person that's not been exposed to chemotherapy and doesn't have dysfunctional T-cells that let them down in the first place and allowed the cancer to recur or to progress and not respond in the first place. So I think that we're big believers at the University of Kansas that allogeneic CAR T-cell therapy is the wave of the future.
Great. Thank you. I'm going to briefly review our data from ANTLER. And then, Dr. Hamadani, I'm going to ask you about some of the patients that you enrolled and have treated with Vispa-cel and why we think this strategy of going out into community centers, but also filling an unmet need at academic centers as well, is the right path forward for Vispa-cel , so the ANTLER study, we've just recently presented data on 84 patients. These are all patients with B-cell lymphoma, all treated with lymphodepletion of cyclophosphamide of 60 mg/kg/day for two days, followed by five days of fludarabine, and over the course of the trial, we started in diffuse types of B-cell lymphoma, but we quickly focused in on second-line large B-cell lymphoma.
The data I'll talk about today and that we presented and highlighted is in large B-cell lymphoma, predominantly in second-line. As you know, we also, over time in this study, have learned that HLA matching and the age of the donor cells that we manufacture Vispa-cel from play a large role in outcomes, and particularly in durable outcomes. We focused on two data sets. The confirmatory cohort was a prospectively enrolled cohort of 22 patients, second-line large B-cell lymphoma at our recommended phase two dose that we will be moving forward of 80 million CAR T-cells, and required four-plus HLA matching out of 12 alleles. This was a confirmation experiment after we saw preliminary data that HLA matching mattered. We required HLA matching for this cohort. Of these 22 patients, 20 were treated with young donor material.
As we followed patients from all of the dose escalation and this confirmatory cohort, we realized that the young donor material played a large role in durability of response. We actually stopped using Vispa-cel from old donors and exclusively started using young donor material. It turns out when we use young donor T-cells to make Vispa-cel, we can actually get the same durable responses with a lower level of HLA matching. The second cohort I'm going to talk to you about is what we're calling the optimized Vispa-cel cohort. 35 patients, large B-cell lymphoma, the majority were second line, treated at all dose levels. In this dose range, dose level did not seem to matter, and having two-plus HLA matching. Those patients, both of these cohorts we presented, you can see here high overall response rates, CR rates in the low to mid-60s.
And most excitingly for an allo-CAR T is this durability. The median PFS and median duration of response are not reached. And you can see in the PFS curves on the right this nice plateau that you see with CAR T-cells. We've seen patients out two and three years after Vispa-cel, which is really exciting for this potential curative type of therapy to be able to be made from allogeneic healthy donor T-cells. As Dr. McGuirk already mentioned, the safety profile is manageable. It's consistent with a safety profile that can be managed as an outpatient and certainly in community sites. We're seeing low rates of severe neurotoxicity and CRS, manageable severe rates of infection, and our prolonged cytopenias are manageable and actually recover quite quickly.
These safety outcomes are very similar to Liso-cel, which is already being given as an outpatient and has been shown to be able to be given in community centers. So we're very excited to have an off-the-shelf allogeneic CAR T-cell that has an efficacy that's on par with the auto-CAR T-cells that are already available and a safety profile that can allow us to get this product to the patients out at centers that do not have auto-CAR T at this time. As we work with the FDA, our pivotal approach is a randomized control pivotal phase III trial in second-line patients, as Rachel already mentioned. These would be in transplant and auto-CAR T ineligible patients.
What this allows us to do is randomize to a standard of care immunochemotherapy since there are no curative options available for these patients with a PFS endpoint and secondary endpoints of response, durability of response, overall survival, quality of life, and safety, so now I'd like to turn it to Dr. Hamadani. You've been a major part of the ANTLER study. Could you share why patients from your site were eligible for allo-CAR T like Vispa-cel , even though you have access to auto-CAR T?
Yeah, it's a good question, right? Because in our center, when a patient comes for an auto-CAR T consult, you have access to at least two FDA-approved products, Liso-cel, Axi-cel in second-line setting. You have three FDA-approved products in third-line setting and beyond. And then we have our internal manufacturing platforms, investigational. So when we approached our patients for an off-the-shelf therapy, there needs to be a reason, right? So I'm going to give you an example of a recent patient I saw, not enrolled on the ANTLER study. So that patient at the borderline age where we would comfortably consider CAR T-cell therapy in her mid-seventh decade, primary refractory disease, relapsed very early with explosive progression of disease. So this is a pathway of somebody who is on track for standard of care autologous CAR T.
From the time you make the decision to do CAR T till the time the patient actually gets CAR T, it's what a lot of people call not the vein-to-vein time, but the brain-to-vein time. In most centers, and I hope Joe will agree with me, that number rests at around six to eight weeks. It takes about two months from the time you think about CAR T for the patient to get CAR T. So you have to get insurance authorizations. You have to find a day the patient can get an apheresis line placed. In busy centers, you have to find a day you can have a bed available for apheresis to happen, then manufacturing, shipping back and forth. So this is a sad case where the patient was on track. I start lymphodepletion on the patient. Day two of lymphodepletion, patient has mental status changes.
Bad sign. I immediately do a lumbar puncture, do an MRI of her brain, and by this time, she has progression of her disease in CNS, leptomeningeal disease, intraperitoneal disease, a setting where I personally think CAR T-cell may not help a patient, so you have a completely different discussion with the patient. You stop therapy. The patient transitions to hospice, right, so this is a true real-world story of how even when you have access in a big academic medical center, that wait time can really impact a real-time case, so the cases that we considered on the ANTLER protocol, and I'm by nature investigationally very conservative, so I waited intentionally to see data from other centers to see if Vispa-cel is working because there have been other alloproducts in the market. I had concerns about durability.
Once I saw a nice initial signal, the very first patient I approached was a 78-year-old lady who showed up on our doorstep with circulating lymphoma cells in the blood. It's a relatively uncommon presentation, and her circulating T-cell count was zero. This is a scenario where your probability of manufacturing an autologous product is fairly low. Our institutional experience, because we manufacture CAR T in-house, if we see circulating large lymphoma cells, we have zero success rate of manufacturing CAR T-cells. That's the first patient we enrolled. Rapidly progressive disease. Within a matter of two weeks, she was starting her lymphodepletion. I believe this is one of your longest survival. This patient is now in remission, two years out, hopefully cured. Fingers crossed. Other settings.
One is if you identify a clinical marker that this patient may not manufacture autologous CAR T-cells successfully. There are certain markers of circulating disease, very low lymphocyte count because you're going to use the lymphocytes to manufacture the CAR T. Second scenario is certain social or insurance-related factors. The two next patients we enrolled were Wisconsin natives. One was a veteran. The second patient had an employer-driven insurance. The VA patient needed to go to Nashville or Seattle from Wisconsin. You're traveling long ways to get CAR T-cell therapy. Even if they go to Seattle or Nashville, you need to take a caregiver with you there for two months. The person who had employer-driven insurance had to go to Minnesota.
But he socioeconomically was not in a situation where you could travel out of state, take somebody with you out of state for CAR T-cell delivery. So then you have a very open conversation with the patient, right? You have to give patients all options. So you sit down with them and say, Hey, right now the standard of care is autologous CAR T. Because of insurance constraints, I can't deliver that therapy to you here. So one option is, I'm happy to refer you to the institutions which are within network for your insurance. Or this is an investigational approach. This is the data we have. This is how it works. It doesn't have, to be fair, as long of a follow-up available because it's an investigational product. And both of those patients opted to get the therapy in MCW.
One of those patients is now beyond a year in remission. Then I can quote one patient who had none of these barriers, right? He had no insurance constraints. He didn't have rapidly progressive disease. Then you sit down with that patient and you say, Hey, this is an investigational product. What are the benefits of this product? At least what we know for sure is that there is no apheresis. There is no figuring out whether there's going to be a manufacturing failure. Manufacturing failure still happens in 2%-5% of the patients. Not the biggest problem we deal with, but when it happens, it's a mess. Then you talk about the theoretical advantages. Vispa-cel has PD-1 gene knocked out. It can theoretically overcome T-cell exhaustion. These T-cells may be more fit.
That patient, even without any barriers, intellectually was stimulated with the concept of being on this trial, and that's why he participated. But within my center, these were the three different scenarios why we considered CB-010.
Thank you. I'd like to shift to the safety profile of CAR T, and particularly Vispa-cel. I'm going to stick with you, Dr. Hamadani, about another patient we know of that you treated on trial that was over 80 years of age, or at least 80, who by most measures would be transplant ineligible. This is a patient population we, as you saw, are going to be enrolling on our pivotal trial as well as auto-CAR T ineligible, and there's some skepticism, or I think lack of knowledge around this auto transplant population and whether they can tolerate something like Vispa-cel or CAR T-cells, and can you speak to the tolerability of Vispa-cel in your patient that was 80 years or older, or in other patients that have gotten CAR T over that age?
Yeah, so I think your safety profile, I'm going to break it down into sort of like the patient experience during the lymphodepletion portion and the patient experience once the CAR T is delivered, what are the CAR T associated toxicity. So the differences in terms of lymphodepletion, so there are two main differences between the fludarabine cyclophosphamide we give for autologous CAR T. It's lower dose. It's three days of lymphodepletion. What happens with Vispa-cel, to ensure that these allogeneic partially match CAR T-cells expand, you need a higher degree of immunosuppression. So these patients get lymphodepletion over a longer period of time. And the main feedback that I have heard is that the Cytoxan dose is clearly higher than what you would deliver.
And to those concerns, we are a big allogeneic transplant center where Joe will agree with me that now it is not unusual to transplant patients approaching the eighth decade. My transplant service is full of patients in their mid-70s who, by the way, get reduced intensity conditioning with fludarabine and busulfan. And after transplant, we give them exactly nearly the same dose of Cytoxan to prevent graft-versus-host disease. And they tolerate that drug. Now, I'm not arguing that any older patient walking through the door is going to tolerate 60 mg/kg of Cytoxan. Yeah, in most elderly patients with acceptable renal and hepatic function, liver and kidney function, I think they do well. You have to be careful about, like the protocol mentions, you give them mesna to prevent hemorrhagic cystitis. They get a little bit more mucositis on occasion.
But I think the lymphodepletion part, I think once you do it, and we have done all our lymphodepletions outpatient, every single patient, right? And even this patient, 78 years old, was she when we lymphodepleted her, did fine. Now, the other part that I'm more interested in, and we should highlight it, is the post-CAR toxicity signal, right? So in autologous CAR T, we struggle with three things. And I'm going to start with one thing that people don't focus on is cytopenias, right? So about 20% of autologous CAR T-cell recipients have prolonged cytopenias, and they have prolonged growth factor requirement or blood product requirement. The data to that with Vispa-cel, despite an augmented lymphodepletion, a higher dose lymphodepletion, looks numerically better. Or worst case scenario, it's about the same.
The second thing, the CRS signal is about the same as what you see with an autologous CAR T. In fact, all the patients I treated, if I remember well, none of the patients got tocilizumab for treatment of CRS, or maybe one patient did. The third thing, which is very important, is when my go-to autologous CAR T is Axi-cel. Axi-cel has nearly 20%-25% rate of grade 3 or higher ICANS. When you develop higher grade ICANS, you get a slug of steroids. When you give a high-dose steroid to somebody in their 70s, the age unmasks very quickly. I think Joe will agree with me when an elderly patient gets ICANS, you treat it with dexamethasone for about a week. Those patients don't go home after the ICANS resolve. They 99% of the time go to a rehab facility getting rehabbed.
So what I really pay attention to is the ICANS rate in your study. And so far in the confirmatory cohort and in the optimized cohort, the grade 3 or higher ICANS rate is zero. I'm not saying it's going to stay zero when you have 250 patients on a trial. You'll see that. But I don't think it's going to approach the rates we see with Axi-cel. So I think it's in an elderly population, this toxicity profile, we need to keep an eye on that. I think that makes me comfortable delivering that therapy.
Wonderful. Thank you. I'm going to go back to Dr. Thomas and Dr. Ormsby out in these community centers. There's some skepticism about this lymphodepletion regimen, as we just heard from Dr. Hamadani. This is higher intensity than what we use with auto, but actually compared to other chemotherapy agents for other malignancies or for transplant, it's well within the range of what most oncologists can give. Based on the data you've seen with ANTLER, Dr. Ormsby, I'll start with you. How comfortable are you giving this lymphodepletion regimen at this intensity to your center? And are there similar intensity regimens your team is comfortable giving?
Sure. I feel very comfortable doing it, actually. So I think it's a misnomer, as you said, that community oncology programs can't give intensive chemotherapy regimen. If you look at standard sarcoma regimens, or you look at complex lymphoma regimens, for example, like a Burkitt regimen, or if you look at acute leukemia regimens, which many community centers are doing, these are highly intensive chemotherapy regimens that we have done, our staff has done, and we feel comfortable with. One of our initial challenges was the concept of a seven-day in the outpatient setting. But all it requires is buy-in. So my partners have been wonderful in allowing me to start our bispecific program. And with the bispecific program, we've established a seven-day, 24/7 outpatient capability to evaluate our patients. We manage the vast majority of our toxicity in the outpatient setting.
If you look at the data for CRS and ICANS for Vispa-cel, it's not dissimilar from many of the bispecific therapies when you look at the percentage occurrence rates, which is something we've gotten very comfortable with managing.
Great. And Dr. Thomas, can you speak to your experience?
I would mirror Dr. Ormsby exactly what he was saying. I always think there's a misnomer about what community oncologists can actually handle. Again, we are trained at these academic centers, and we come back and we're little mini-me's of all the attendings that we learned from. So having these regimens in, like you were saying, aggressive Burkitt's lymphoma with hyper-CVAD or something similar to that is very, very normal for us. Cytopenias, mucositis, diarrhea, all these things are completely normal for us. And so the idea of that, plus us having already implemented a bispecific program that has very similar side effect profiles to this allo CAR T, I think it's a perfect time to jump into something different because people are feeling a lot more comfortable with CRS.
People are feeling a lot more comfortable with ICANS and bringing this as an outpatient and having the rest of the hospital continue to feel very comfortable with it, including the nurses, the pharmacy team, the team, the pulmonologists, the infectious disease team, so the emergency department team. I think it's exciting that it's kind of dovetailing what's already going on in the bispecific programs that we feel comfortable with.
Wonderful. And I guess just kind of one step deeper into that is you see the Vispa-cel safety profile, your experience with bispecifics. Can you describe why you'd be comfortable either running this pivotal trial, infusing the CAR T-cells, and monitoring your patients? Is there anything else you would plan to implement, or do you feel like the resources you have at this point will make that something that's an easy next step?
For me, I think this would be an easy next step. I think that we've already implemented the bispecific program. We've had multiple patients already go through the induction therapy. I think this would be very, very similar, and I don't think it'd be tough to get it implemented into a community oncology clinic.
Great. And Dr. Ormsby, just a similar question. Looking at our safety profile, are you comfortable that your team is already ready for a product like this? Are there other steps you might need to take prior to implementing an allo CAR T like Vispa-cel ?
Sure. So agreeing with Dr. Thomas, having already established a bispecific program, it's huge. If we hadn't already developed our bispecific program, I'd say we need to actively do a lot of things. Now, that's not to say we're constantly trying to expand and improve and be better implementing nurse navigator programs, training more nursing staff, working with our community hospital partners in order to make sure that they're up to date with training, establishing close relationships with critical care, pulmonology, neurology, infectious disease in the community. So those will all be ongoing and will require continuing medical education, but I certainly feel comfortable doing this.
Great. We're going to wrap up with just two last future-looking questions that I would love to have each of you answer, the first one, and then the last one's just going to be a one-word answer, but let's start down the road. I'll start again with you, Dr. Ormsby. We'll just go in order. How do you think Vispa-cel would fit into how would it impact the practice and treatment choices for your large-cell patients in the future if it were to be approved?
I feel it would be profoundly beneficial. I gave the example of a patient where if we had Vispa-cel , I would be treating that patient with Vispa-cel as opposed to bispecific in combination with chemotherapy. And while I am blessed to be close to two transplant centers, as I mentioned, we do have a percentage of patients which, when you look at our overall volumes, 10%-20% is actually not a small number of patients where these patients could very actively be treated with potentially curative therapy as opposed to therapies that are either, well, that are in all cases right now show lower progression-free survival and overall survival and are far more burdensome on patients in terms of ongoing frequent therapy, whether that's weekly, biweekly, monthly, depending on which part of the bispecific therapy they're in. Or I'm sorry, bi-monthly.
Dr. McGuirk.
Undoubtedly, the success of Vispa-cel in community centers would represent a national paradigm shift and save countless numbers of lives as representing, as I mentioned previously, a potentially curative therapy. This is critically important, and it paves the way for the future of other cellular therapeutics that will surely come to the forefront, not just in blood cancers, but in solid tumors as well. Simply, academic centers won't be able to handle the volumes and shouldn't be in the business of handling all of those volumes. We have highly trained experts like Dr. Thomas and Ormsby who are out in the community, and we need to partner with them and get these therapies out to patients to contend with the number one problem with CAR T-cell therapy, and that is access.
Dr. Hamadani?
I think one point that Dr. McGuirk just made very subtly is very important, right? 85%-80% of oncology care happens in community, right? We keep talking about that 70%-75% of patients who can get CAR T do not get CAR T, right? The focus of the academic centers is to get them to academic centers. But what we forget is that if you fix that problem and these patients show up, you're not ready to take care of that volume, right? Like I can barely take care of the 400 transplants I do. My center is not geared to take care of 800 patients. I hope in future, if this study is positive, I think the uptake is going to increase that same concept. You need to take the treatment to where the patient lives, right?
So I think that concept is important. But I also think that even in the academic medical centers, it's going to have an impact on our practice. So if this trial is hopefully positive, even in academic medical centers, you will see an uptake in use because I struggle to apherese our patients. It's not fun dealing with manufacturing failure when it happens 2%-5% of the time. So I actually foresee a scenario where even us physicians sometimes bend the label a little bit, right? So I think it's not going to just have an impact in community practices. I think it will have an impact on our practice and the teaching hospitals, the academic sites as well.
Great. And Dr. Thomas?
Yeah. Same. I'm mirroring everybody else. I think it would have a profound impact for us. And I'm excited about the opportunity to potentially have something that, like you said before, is a one-and-done therapy where Dr. Ormsby mentioned it as well, that all the other therapies typically at this point would be second or third line, even in bispecifics or a maintenance program. So the patients continue to be hooked with the clinic. What we always want to do is have patients feel they just live their life and not see us. We're trying to see them as least amount as possible so they can have a life in between. And having something that would be off the shelf, allo CAR T, that potentially is a curable disease with this particular treatment would be a big deal for all these community centers. So we're really excited about it.
And then potentially opening up the opportunities for other indications for therapy and potentially even solid tumors would be exciting.
Excellent. I'm going to end there since you all answered the last question, which is, would you use Vispa-cel if it approved? So thank you very much. We're actually going to open up the floor to questions.
Just two questions. In terms of the usage of allo versus auto, assuming Vispa-cel is approved and it has all the features and properties of the data that we've already seen, would there be an argument for allo CAR T anymore or not? So I guess that's number one. And also, I'm just curious, in the current situation where patients relapse on allo CAR T and the allo was available, would you try allo in those relapsers or that wouldn't work? Thank you.
I can speak to the issue of. I think I'll make this a projection and then come back in 10 years and you guys, I can tell you all, I told you so. I think the allo CAR T are the future in the field. And if you had an allogeneic CAR T like Vispa-cel that had efficacy as good or better than what we have with autologous constructs, you got around all of the constraints and issues that we've been talking about today and had a very manageable toxicity profile and it could be given out in community centers, why would you do an autologous CAR T-cell therapy? I think that our work in academia is not to take on the volumes of patients who are in need.
Our job is to figure out what the next best step is to improve efficacy, to improve toxicity profiles for our patients. This is the beginning of a burgeoning approach to cellular therapeutics for very intuitive reasons. An allogeneic CAR T from a young college student or a young adult who's partially HLA-matched, who's never seen chemotherapy previously, these cells, and your ability to manufacture exactly what you want as a product, which we don't have the luxury of that. Stan Riddell, the Hutch, says, what are we giving to patients when we're giving them autologous CAR T-cells? We're giving them a mishmash of cells and hoping for the best. Here, there's so much more control that can be exerted. You can pick exactly the donors that you want to make CAR T for, for hundreds of patients from a single donor potentially.
I think it's the way to the future, and the constructs that we're going to be doing further modifications in and such are going to be these allogeneic CAR Ts that change the paradigm shift when we say, okay, this is the way we're going now. Now, how do we take that efficacy up to 100%? How do we get rid of all of the toxicity in these therapies, so I'm confident that that's the way we're going in the future, and I didn't get the second part, perhaps.
Dr. Hamadani, do you want to speak to whether you would use an allo after an auto or sequence CAR T? I think that was the second question.
So it's a good question, right? And I'm going to answer it in a different way, right? There are two autologous CAR Ts available in the second-line setting, right? Let's call it product A and B. I, by the way, use product A off-trial consistently, right? The product B more or less is exactly the same product. So even within our group, when we talk about, well, you use Axi-cel, why don't you use Liso-cel, right? With certain differences, those products are essentially interchangeable. It's the same collection process, same insurance authorization, same waiting, roughly same manufacturing failures now. So there is no reason to necessarily change. But if you have a scalable, and that's for Caribou to sort of deliver on post-approval, but if you have a scalable product available where you're logistically making the delivery of the product very easy, I think it will impact practice.
A good example is, let's look at a slightly different disease, myeloma, right? Myeloma, when the CAR T got approved because of scalability issues, there were patients waiting for months and months to get an apheresis slot. It's gotten better, of course, over the years, but for about a year, patients couldn't get the treatment. But when bispecifics got approved, that was the uptake, right? The drug is immediately available. So if I want to give my myeloma patient bispecific, post-insurance approval, it's going to be that week, sometimes next day. CAR T, still two months away. So I think that's the missing piece of puzzle that an off-the-shelf, readily available CAR T product can potentially fix. Now, you had a second part of your question that I forgot.
That was the.
That was the second part.
That was the second part? Okay.
That was the second part.
Okay. Thank you.
Yeah, sure.
Hey, Alec Stranahan, Bank of America. Thank you for the very interesting discussion this morning. Maybe dovetailing off that last point that was made, when you think about what efficacy Caribou's allo CAR T would need to show in a phase III or for uptake, are we thinking not inferior to auto CAR T? Are we thinking something in between a bispecific or an auto CAR T product? And as a follow-up to that, what are sort of the top three or four aspects of an allo CAR T that would be sort of ideal in your view for ease of use and patient experience? Thank you.
So I think this might be worth either Dr. Ormsby and Thomas talking about first, what efficacy might you at your type of center need, and then maybe one of you, Dr. McGuirk or Hamadani, could answer.
So ideally for me, non-inferiority would be ideal. That being said, if I have a patient who refuses to go to an academic center for a consultation, if I can see equivalency data with bispecific or ideally superiority data, especially with a one-and-done treatment approach versus I have to bring this patient in weekly, then every two weeks, then monthly, and if I've got them on epcoritamab, there's no end in sight, I'm going to prefer the allo CAR T.
Yep. I think the same thing. Dr. Ormsby and I thinking the same. If we could have somebody that would come in and be non-inferior, I think that would be enough. Hopefully, it's that or better, but if it was just non-inferior for me, that would be an opportunity for us to push.
You mean a non-inferior to the bispecifics?
Yes, exactly.
Yep. Great. And then anything else, Dr. Hamadani or Dr. McGuirk?
I think the way the trial is designed or the way this registration trial is going to be, it's comparing Vispa-cel in an autologous transplant CAR T ineligible patient setting, right? And it's designed as a superiority trial. So you're talking about a patient population where patients would not have gotten CAR T, and now they have an off-the-shelf CAR T available. If the study is positive for that patient population, it's immediately practice-changing. But I suspect in centers where you have both products available, in my center, let's say Vispa-cel is FDA-approved now, a few years down the road, and an autologous product is still available, which it will be, people will do what we are not supposed to do, do cross-trial comparisons.
So far, what we can say is that the CR rates with Vispa-cel are exactly numerically similar to what you get with Axi-cel, 65%, 64%. The one-year durability of response, the progression-free survival is identical. And I think once you get to a year time point in remission post-CAR T, the vast majority of those patients are cured, right? So people like me will do those comparisons, although there will be no prospective randomized comparison available. And then some people like me will potentially say, well, this is an easier thing logistically. I can just order it. My patient is going to get it next week, and they may change their practice. But physicians are also creatures of habit. I can't say every single person will change.
I think these products will coexist, but I think Vispa-cel will find its place, as I mentioned, in academic centers as well, hopefully in community sites.
Just in terms of the ideal profile of an allo, maybe Dr. McGuirk, if you have an idea of what you'd want to see in an allo product?
I think in the current state, if Vispa-cel fits the bill, it's readily available immediately overnight so we can start therapy immediately in patients. That's critically important. It has a, and I'm being redundant, but these are the features. It has an acceptable, manageable safety profile, and it has an excellent efficacy profile. And then the fourth I would add, because you asked for four, I think the fourth I would add is it lends itself to a platform for future further manipulation to improve those issues associated with taking that efficacy north more so, taking the toxicity profile, albeit already very favorable, south and making that better. So I love the platform, but I certainly like what we've been talking about this morning in terms of this construct specifically.
Great. Thank you very much. It's been a pleasure hearing from all of you, and of course, thank you for your time this morning. I think we're going to wrap up, and it's really been a wonderful panel. Thank you.
We're incredibly grateful. Thank you so much to all four of you, and thank you to all of you for being in the audience today. We really appreciate it. To close, you've heard us talk very enthusiastically about Vispa-cel for more than an hour. I want to also just take a moment to acknowledge the incredible work our team has been doing in multiple myeloma. We were very excited last month also to share initial clinical data on the first 48 patients treated with CB-011, which is our allogeneic CAR T targeting BCMA. For this patient population, we are beginning dose expansion work for CB-011 this quarter and plan to share dose expansion data for CB-011 next year, and so with that, I'd like to close with a tremendous thank you to the physicians here in the room and to Dr. Thomas on Zoom.
Thank you so much for your time today.