Jesus Berdeja, MD
Sarah Cannon Research Institute
Interview Date: June 27, 2022

CAR T therapy is both FDA approved and continues to be in development in clininical trials. While the Abecma and CARVYKTI products used commercially are autologous (meaning they use a patients' own T cells), a whole new set of CAR T products in developmnet are allogeneic, or "off-the-shelf." These allogeneic CAR T options could provide faster access, less bridging therapy and better availability. Learn more from CAR T myeloma expert Jesus Berdeja, MD about this class of new myeloma treatments in this important show.

Thanks to our episode sponsor

 

 

Jenny: Welcome to today's episode of the HealthTree Podcast for Multiple Myeloma, a show that connects patients with myeloma researchers. I’m your host, Jenny Ahlstrom. We'd like to thank our episode sponsor, Takeda Oncology, for their support of this program.

Today is the first program with a new name, changing the program name from Myeloma Crowd Radio to HealthTree Podcast for Multiple Myeloma. We'll be making a more broad announcement about name changes coming soon as we move our program names over to the HealthTree names. We're doing this just to simplify everything because I think we've thoroughly confused everyone, between Myeloma Crowd and our HealthTree products.

Now before we get started on today's show, I want to mention that we will be launching a three-year CAR T study relatively soon. If you have received CAR T therapy and you want to join that study to share your experience with others and see what we can learn together, you can get started by creating a HealthTree Cure Hub account today. Our team can help gather your records and put your myeloma history into a single place. This is a very helpful way for you to track your myeloma where we can help you collect your information from multiple treatment centers. There are also additional benefits that you get by using HealthTree Cure Hub.

Once you have that in place, when we're ready to share the CAR T survey questions, we’ll notify everybody by email, and you can share your experience in that survey. We want to do this because we're curious to answer important questions for patients, like who benefits the most from CAR T therapy? What's done pre and post-treatment to make it more effective? Are there genetic markers or patients that respond better to CAR T therapy? What was your experience like in the process, or your caregivers'? What side effects did you have and how severe were they? As CAR T becomes a key treatment of myeloma, these are very important answers we all need to have. You can get started today and go to healthtree.org/myeloma and click on Cure Hub in the top left, green menu bar.

Now on to our show. As we all know, CAR T treatments are becoming more widely used and more popular, having truly unprecedented response rates for highly relapsed patients. The two approaches that are FDA-approved today include Abecma made by BMS and CARVYKTI made by Janssen Oncology. These two CAR T products target BCMA and are both called autologous CAR T therapies, meaning that you use your own T-cells to make these treatments.

Many new autologous CAR T options, including Abecma and CARVYKTI, are currently in clinical trials to see how they can be used in earlier lines of therapy for high-risk patients and so on, but a new host of allogeneic CAR T cell products (and I’m going to have Dr. Berdeja to explain that later) are now in development. For today's show, we have CAR T myeloma expert, Jesus Berdeja of the Sarah Cannon Research Institute. Dr. Berdeja, welcome to the program.

Dr. Berdeja: Thank you, Jenny. It’s always a pleasure to talk to you and to the HealthTree family. 

Jenny: Thank you so much for joining. Let me give an introduction for you before we get started. Jesus Berdeja is the Director of Multiple Myeloma Research Program and senior investigator of Hematologic Malignancies Research at the Sarah Cannon Research Institute. He is a partner at Tennessee Oncology as well. He is chair of the Myeloma Working Group at Sarah Cannon and is a member of the Medical Informatics Committee, Myeloma Intergroup Committee and Clinical Trials Network, member of the Plasma Cell Working Group with CIBMTR, steering committee member on the Takeda Insight Study, a member of the International Myeloma Working Group, and a member of the CAR T Working Group. He's also the myeloma co-chair of the Via Pathways Multiple Myeloma Medical Oncology Committee, and member of committees for both ASH and ASCO.

He has provided peer review on many publications for over 15 major journals in blood cancers, and has published extensively on myeloma topics, and in the last decade, has been a key principal investigator for myeloma trials with a special early focus on CAR T technologies. I think you were one of the first to run some of these CAR T trials, so I know your experience is deep and wide. Dr. Berdeja, maybe we want to start by having you explain the difference between autologous CAR T therapies and allogeneic CAR T therapies.

Dr. Berdeja: Yes, I think that's actually a good start. An autologous CAR T requires that we collect the T-cells from the person who can receive the CAR T themselves. It's very similar to the process of going through an autologous stem cell transplant where you have to go collect cells first before you go through the procedure. The same thing here with the CAR T where you undergo leukepheresis to collect your T-cells, then those T-cells are taken back, and the CAR Ts are manufactured out of those T-cells. That process takes several weeks and then the product will be given back to the patient. That's the autologous process.

The allogeneic CAR T, on the other hand, does not require that the patient undergo leukepheresis. The allogeneic product actually is manufactured from volunteers who donated their T-cells who presumably are healthy and has no cancer, had not had chemotherapy, et cetera, so presumably, a relatively intact T-cell source. By doing so, those T-cells are taken from the donor, and several products can be manufactured from that one donor. The allogeneic CAR T product is actually available off-the-shelf, very much like bispecific antibodies or other drugs would be. Theoretically, if a patient's undergoing allogeneic CAR T, the time to receive the therapy would be much faster than the time it would take to actually receive an autologous CAR T product.

Jenny: That would be a major advantage, I would think. Do you want to explain fundamentally how the allo CAR T therapies work? I know it might be similar to how current CAR T-cell therapies work, but maybe walk through that process for those of us who may not be that familiar with CAR T.

Dr. Berdeja: Yes, certainly. It's actually, theoretically, it's very similar, but there are actually quite a few challenges. When you take your own T-cells and you manufacture CAR Ts and then those T-cells are getting back to you, your body knows those T-cells. It sees them as self, so those T-cells don't necessarily get destroyed. At the same time, those T-cells are not going to cause any damage to your body because they know it as self and really just go in and do what they have to do with this new CAR antibody that basically sends them directly to your myeloma cells and destroys. When you're using an allogeneic T-cell, it means that the T-cell is coming from a different donor.

Just to put it in perspective, when we do transplants and we do allogeneic transplants using a different donor, one of the challenges is finding that donor to match the patient. The reason you have to match is because if you get T-cells from a different donor to a patient and those are not matched, those T-cells will actually see the patient as foreign and can actually attack and cause this very severe side effect called graft-versus-host disease which can be lethal. At the same time, the patient's own immune system may not recognize those T-cells and actually go after them and destroy the T-cells themselves.

Because of that, in this case, we're not typing the donor. The T-cells that are being used for allogeneic CAR Ts are actually not typed. You have to basically do further manipulations to those T-cells in order to prevent the two processes that I just mentioned, which can be catastrophic. Because of that, the allogeneic products undergo much further manipulation. Aside from putting in the CAR, most products can remove also the T-cell receptor which is what mediates the graft-versus-host potential. Then you actually then have to do and manipulate a different entity which is the HRA moiety or CD52 which potentially prevents your own T-cells from destroying the CAR T product. Because of that, there's a lot more that has to be done to this.

Jenny: That's interesting information about how they're processed because you're not trying to, like what you're saying, you're not trying to match based on patient. You're just trying to make the product work for everybody.

Dr. Berdeja: Yes, because imagine if you had to match, then it becomes very similar to an autologous product. You have to wait, and you have to do all these exra steps. Whereas the process not matching is that you can have one donor and make hundreds of products which is really nice. That’s the difference.

Jenny: How do they pick the donors? 

Dr. Berdeja: Usually these are the people who volunteer and then they're vetted in terms of make sure they're healthy and that they can undergo leukepheresis. I suspect you know that different sponsors have different incentives for people. They might get compensated in some way for their time. It's really not too dissimilar from when someone donates blood or is willing to sign up to donate bone marrow. I guess it’s that same approach to the volunteer/donor.

Jenny: I know for allo stem cell transplants, I had an investigator talk about how they're trying to use younger donors because if you're trying to find even the sibling match, a younger donor might be actually better than an older sibling match. Hopefully they're choosing younger donors with very healthy T-cells.

Dr. Berdeja: Yes. It is. Also, from a donor standpoint, usually young males are preferred to females, especially if they've been pregnant. Because whenever you become pregnant, obviously you get exposed to a foreigner, that's the baby, and you actually can make antibodies against the baby. Because of that, female donors tend to have more antibodies potentially that could lead to more rejection. Usually, ideally, you pick a young male healthy volunteer.

Jenny: That's interesting. Once they're made, how are they stored? How long can you keep them? What's the shelf-life? 

Dr. Berdeja: That's a great question. Luckily, the allogeneic T-cell is no different than the autologous T-cell from that standpoint, and all the stem cell products. These cells can be frozen,  preserved and can be stored for many years. The FDA will always put a shelf life or an expiration date. The truth is that it's necessary, but there's no reason why a product that's older than what the FDA says, can't be given. Similar to if you go through a second transplant, for example, and you had your stem cells stored many, many years prior, those stem cells are fully functional. They can last many years.

Jenny: Interesting. In general, do you want to -- we’ll talk about dosing a little bit later -- do you want to give an overview of what you see are the potential advantages and disadvantages of autologous CAR T versus allo CAR T? You talked about having an off-the-shelf option which is faster. In general, how are you looking at it as a myeloma investigator?

Dr. Berdeja: Just to back up a little bit, I think most of you who are listening probably have seen data coming out, obviously with the autologous CAR T that Jenny mentioned earlier, but then you probably also heard of bispecific antibodies. The bispecific antibodies are similar in that they're also causing T-cells redirection to kill the myeloma cells. These are off-the-shelf products.

One of the benefits of the bispecifics is that they’re off-the-shelf. They’re available. They're not manufactured. The patients identified can get them faster. One of the disadvantages though, with the bispecifics is that these are antibodies that have to be given, continuously given. You move away from the one-and-done potential of the CAR T, to now having to undergo treatment every week, every two weeks, every three weeks, depending on the product. The allogeneic CAR T, in my mind, if it works as well as the autologous CAR T, takes the best of both worlds. It becomes that one-and-done product like the autologous CAR T, but it's also off-the-shelf, and it's readily available.

The autologous CAR T, the biggest benefit, is that we know it works, and it works incredibly well. We've seen an excess, in some products even, an excess of 90% response rates that are looking very, very durable, which responses and duration that we haven't seen in patients who are very refractory. That's the plus. The minus is that there are several roadblocks to get to it. One of them is, first of all, you have to collect the T-cells. Unfortunately, some people get certain treatments right before their T-cells are collected. That could potentially damage their T-cells so not enough T-cells may be circulating to be able to manufacture the product. Or the T-cells don't function as well because of all these pilot therapies that have been given. That's one of the drawbacks of autologous CAR T.

The other is that once you collect the T-cells, the CAR Ts now have to be manufactured. That manufacturing process takes some time, but as we're seeing with, especially with some of the commercial products, is that you require these viral vectors to make the CAR Ts. Those actually were back order, and there were a lot of delays in the manufacturing of the product because of it. You're dependent because it's on demand. When the patient gets identified, then the product is made. The product is made available for the patient then. While you're waiting for your CAR T, there's a potential that your myeloma can progress, can get worse. If it hurts certain organs, it might make you ineligible to receive that CAR T later on. These delays are not just annoying, they're actually potentially dangerous. That's the downside.

The further downside is that the autologous CAR Ts, well, it's a plus and a minus, expand so well inside the patient that we see very high rates of cytokine-release syndrome and then some rates of neurotoxicity, which are obviously side effects that we can deal with, but can pose a problem for some patients.

The plus of the allogeneic product, from my standpoint, is that it's not on demand. It's available off-the-shelf. If the patient needs it, it can be given. I think with the initial clinical data we saw from ALLO-715, I think it was five days from signing consent to receive, to when they received their allo CAR T product, so, very quick. That's nice. There's no need for any bridging therapy which you often need for autologous CAR Ts. Again, you can actually manufacture lots of product well before and stock it, so you're not dependent on whether we have enough of the substrates or whether we have any kind of manufacturer glitches that happened as we've seen with some of the autologous CAR T, so, less likely to be affected by the viral transduction production issues.

One of the other things that's interesting, so far, what we've seen is that the CRS and neurotoxicity seems to be less, compared to the autologous CAR T. The question becomes of course is that because we're not seeing the same expansion, which is possible, or it's just seems to be a lesser aggressive product. For some reason, the toxicity looks quite good from that standpoint. Then there's that potential that you could potentially dose multiple times. With autologous CAR T, that is a potential, but obviously, there's a limit in how much you can redose because of the T-cell collection and how much was collected. Whereas with allogeneic products, in theory, you could give multiple doses. Some products are actually already doing that, where they're actually giving doses several times to see if they can actually improve on the duration of those remissions. There are several reasons why allogeneic CAR T potentially could be better than an autologous CAR T, but it still has to be proven.

Jenny: Right. I think, as I said earlier, the two are already FDA-approved, so they're a little bit ahead of the game, compared to the allos in clinical trials. Maybe we should talk about that. Can you outline the different CAR T products that are in development? I think Poseida has one. Allogene Therapeutics has one or multiple maybe. I don't understand the differences between those.

Dr. Berdeja: Yes. There are actually several, but probably the one that's furthest ahead is the Allogene 715 product. Allogene does have two CAR Ts, but the one that's furthest ahead is ALLO-715. Just to back up a little bit, like I said before, the allogeneic products have to be manipulated a lot more than the autologous products. It's not just transducing the new DNA to create this CAR, but you actually have to go and disrupt the genes and the T-cells to remove things like the T-cell receptor. A lot of these allogeneic products use different technologies to do so. You'll hear a lot about things like CRISPR and Talon, which are probably the two most dominant ways to basically knock out different genes and putting new genetic information. Those are the technologies that are used the most.

The ALLO-715 product uses the Talon technology to remove the T-cell receptor, which again, that will prevent or minimize graft-versus-host disease. They also knock out CD52. CD52, it's important because it's one of the conduits for T-cell rejection, so trying to prevent your own immune system from preventing the T-cells.

The other thing it does is that CD52 is expressed on all T-cells, and so they have another antibody which they call ALLO-647. That's why it's confusing. ALLO-647 is not a CAR T. It's an antibody against CD52. We have an antibody to CD52 called Campath that was in the market for certain T-cell lymphomas and for CLL. That's still available. This is their own anti-CD52 antibodies. The reason that's important is they can get this antibody to basically deplete, to augment the lymphodepletion, deplete the patient's own T-cells, but it doesn't kill the CAR T because the CAR T doesn't express CD52. In the Allogene product, they're giving the fludarabine and cyclophosphamide like we usually get for the autologous CAR T's, prior to giving the CAR T, but they're also given this antibody for ALLO-647. I just realized that.

One of the things that happens when you give CD52 however is you get this very profound lymphodepletion. One of the reasons Campath was originally removed from the market or taken back was it induced such a profound lymphodepletion of acid for so long that people started having lots and lots of infectious complications. That's one of the constraints about using this kind of lymphodepletion that a lot of us are shy about, gun-shy especially in myeloma patients because now you're really knocking out the T-cells for a much longer time than the therapy does by itself with the auto CAR Ts.

For example. I think the important part here is going to be looking for whether they see any increase in infections or unusual infections, but that's their strategy to allow their CAR Ts to expand. CRISPR Therapeutics also has an allogeneic CAR T using CRISPR technology that actually was in clinical trials, but that actually has been halted. We'll see why that was, but presumably they were not seeing the results they wanted to see.

You mentioned Poseida. Poseida has this allogeneic CAR T as well. What's very interesting about Poseida - you might have heard about Poseida because they had an autologous BCMA CAR T - they're the only product that uses a non-viral method to transduce their CAR T. They actually use this method, this piggyback technology that uses transposons to actually introduce the new genetic information to the T-cell side. That's actually nice. They’re not dependent on just viral transduction, potentially bypass some of these issues some of the auto CAR Ts have had.

We'll see. This is very early on. Clinical work was just starting. The autologous CAR T, the data we have from that looked interesting. There was expansion. There were some responses, but the responses didn't seem durable. They abandoned their autologous CAR T to go more with an allogeneic product. We’ll see if their technology lends itself better to an allogeneic product. Those are the more dominant products out there. There are definitely others, especially that target different, something other than BCMA as well. 

Jenny: The two that are FDA-approved right now are both targeting BCMA, but you've got other CAR Ts going after, like, CD19 or MCS1 or other targets like that. Then the bispecifics are adding even more targets like GPRC5D and other targets like that. Are all the allos right now targeting BCMA? Or do you see that changing in the future, that they might add some new targets? 

Dr. Berdeja: Actually, there's really an allo that is going after a different target, and I think there'll be more. UCARTCS1A is an allogeneic CAR T that targets CS1 which is the same target as elotuzumab or EMPLICITI. That's actually in clinical trials now, so we'll see. Because I agree, I think we need new targets. The autologous CAR Ts now, we have some targeting GPRC5D as well. To my knowledge, there's no allo product going after GPRC5D, but I suspect that that's coming as well. As you know, the target itself is important, but I think what's also becoming important is, how do we maximize the options for patients? Can we continue to just give BCMA products, or do we have to go to different targets? I think it's important that we continue to explore and improve on the BCMA-targeted therapies, but also to come up with new products, new targets that hopefully can be complementary to each other and can be used potentially sequentially or even concurrently.

Jenny: Can you weigh in a little bit, and maybe this is both for auto and allo CAR T, on dual targets, like trying to build a CAR T that goes after maybe CD19 and BCMA or CS1 and BCMA.  Are you seeing a lot of development in that area? Do you think that's promising, or do you not?

Dr. Berdeja: I think that's very promising. Right now, there are dual-targeted CAR Ts. Originally, what we started seeing was people were using two different CAR T products, to go to different targets. That's different from an actual dual-targeted CAR T that is one CAR T product that just happens to have two CARs on it, and two different targets. The one that's most advanced, it was just presented at ASCO this year, from China, where they actually target both BCMA and CD19.

CD19 is the target that is used a lot in lymphomas and in B-cell ALL because those cells express CD19. CD19 is not really expressed in myeloma cells, but it is thought to be expressed in terms of early myeloma cells and maybe even the myeloma stem cells. That's why it's the rationale for using the CD19 CAR is that the BCMA could potentially debulk the tumor and then maybe the CD19 can go and eradicate those cells which are bringing back the myeloma, which will be great. That's the idea behind that.

There's definitely potential in CAR Ts, they're starting to look at going after two different, like BCMA and CD38, for example, or BCMA and GPRC5D at the same time. The idea being that perhaps the expression of the antigens may be different in any one cell. The cells that are surviving either have down-regulated BCMA, for example, or they just don't express it enough that they were bypassed. Whereas if you actually had a different target, that different target would then go after those cells. It’s similar to what we do with using triplets or quadruplets where we want to have different mechanisms of targeting the cells and go after them in various ways.

If we're talking about the allogeneic products, actually the one that's the most intriguing to me from that standpoint is the Poseida product. Part of the problem with it is as you add more and more CARs, and I told you all these manipulations that have to be done, you start becoming genetically unstable. There's more potential for error, and there may not be enough room for some of these viral transfer methods to do or to carry out that well. Whereas, take that method with the transposons, they actually have shown that they can actually put up to five targets into their CAR with this method. Theoretically, the Poseida technology may lend itself best to these dual or triple-targeted CAR Ts. They haven’t done it yet, so we’ll have to see.

Jenny: That'd be amazing, but then you'd probably have to test them one at a time for safety. You keep adding ones, over and over again. That's interesting. Can I ask you about CS1 as a target for CAR T in general also? Because I know there are some for both auto and allo. You look elotuzumab and by itself, targeting CS1, it's really not that effective. They always combine it with lenalidomide or other products. Do you see the same thing happening for a CS1 CAR T, or it's just as good as a BCMA target? I guess you need data.

Dr. Berdeja: No, it's a great question. You have to remember that the difference here though is that when you're talking about a monoclonal antibody, so, Darzalex, Empliciti, Sarclisa -  those are antibodies. They bind to the target, but then they're dependent on your own immune system to go after and kill the cells via that antibody. As opposed to CAR Ts where the CAR itself, basically you think of it as the antibody, that’s the binding site is the antibody, but it is now fused with this down-signaling that activates that T-cell. It doesn't require a different part of the immune system to come and kill the antibody. The T-cell already, as soon as it's engaged, is activated and kills the myeloma cell.

There's a lot of questions as to why Empliciti doesn't work better than it does by itself. We know that CS1 is expressed on different NK cells and T-cells. The idea is that perhaps the binding of all these different parts of the immune system almost cancels each other out, in a way. Presumably, the CAR T shouldn't have the same issue because it's going to go after our cells that express CS1. What UCAR Ts have done is that they actually removed the CS1 expression on the CAR T so that their CAR can actually go and almost like lympho-deplete for them because T-cells that normally would come after it would potentially be a target for this CAR, as well as myeloma. It'll be interesting to see. The targeting and the mechanism of action are so different that it's hard to really know whether, just because an antibody doesn't work, doesn't mean that CAR T won't work. 

Jenny: That's a great answer. Thank you so much. Because I think that's a question that some patients might be interested in knowing. When you're thinking about using these different therapies or joining a clinical trial, the question is always like, if I use something that's already targeting BCMA, even an antibody drug conjugate like Blenrep or maybe a prior CAR T targeting, can I go ahead… Is it going to be effective if I try to use an allo product later? Could you fail or progress on Abecma and then use this? Or could you use Blenrep and then use this? Do they even have that open in the trials? Is that even a possibility right now in some of those trials? 

Dr. Berdeja: Those are great, great questions that unfortunately we don't have answers for. Some trials are starting to allow prior BCMA, but a lot still don't. I think you have to look at it two ways. One is, when you're trying to develop a new product, you want to maximize the chances that it's actually as effective. I think from that standpoint, I can see why a new sponsor that's just discovered this BCMA-targeting product doesn't want to enroll just patients who have regressed on a BCMA product because we don't know why that patient regressed. We know that there are different mechanisms of resistance. Most patients don't or most patients, myeloma doesn't seem to lose expression of BCMA, but we know that it can happen. That's the minority of people or so, but it definitely can happen. If you lose BCMA, you now lost your target. This product is not going to be effective. That's one of them.

The other is we don't know, again, was it that the T-cell -- let's say, you got a bispecific like teclistamab against BCMA. You had a response, and you progressed. The question becomes, are you progressing because you've exhausted all the T-cells so then when you go and collect those T-cells, are they not going to function anymore because they're exhausted for an autologous product? That may not be the case for an allogeneic product, so perhaps this might work better. At the same time, if that's not the case or if that wasn't the reason the person progressed, it has more to do with the microenvironment, that regulation is certainly inhibitory molecules, that will also inhibit the allogeneic CAR T.

I think there's lots of reasons why a lot of these new products don't necessarily want to tackle that from the very beginning. The good news is that as more and more products are manufactured and different sponsors want to get a niche somewhere, we're starting to ask those questions. A lot of the products now allow at least a cohort of patients to have had prior BCMA exposure to test that theory, so it's always important to just ask the eligibility for all the trials. It seems like they're all the same, but they truly aren't. There are some specifics. You just want to ask that question in particular.

There was some very interesting data presented at ASCO this year with the real-world usage of Abecma. I don't know if you saw that. Basically, one of the concerns is, does the clinical trial translate to the real world? Several institutions pulled the data together. They had over 100 patients that had been treated with commercial Abecma. What's very interesting is that the response rates and the PFS that they saw were very similar to what we've seen in KarMMa, the KarMMa study, so that was reassuring. What's even further interesting is that I believe 70% of their patients would not have qualified for KarMMa because of various reasons. That was also very interesting and reassuring. What was a little bit, and it was very small number of patients, but when they looked at the patients who had prior BCMA therapies, including bispecifics on trial or Blenrep, their responses were less and the progression for survival was quite short. Again, this doesn't mean it doesn't work, but it leads you to believe that, should we be using these products if we have the option beforehand? Maybe until we find out more, I will try and stay away from them as much as possible.

Jenny: That means, for patients, they have to be very careful about what they pick, which clinical trial or which therapy. Maybe it's just a matter of access, which one you can get actually, because that's the problem for now.

Dr. Berdeja: Unfortunately, that is true. Sometimes you can choose, sometimes you can't, but I think it is a very important question. That's what I would take from this, because I don't want to scare people that they shouldn't be taking this or that, is that if they're being considered or considering a CAR T -- it's really probably the immediate prior therapy that's more important. I don't think if you had a BCMA therapy first line because you were one of those people that were in that first study ten years ago and got it then and then ten years later, you're requiring an autologous CAR T therapy. I don't think that applies.

The problem here is that most people, unfortunately, are getting these, all one after the other. I think that's actually potentially important. Again, I actually don't know the answer to that, but what I would urge people is to, if a CAR T is being contemplated, before they go onto their next line of therapy, they should be talking to the CAR T provider and work with their local doctor, if it's not the same person, to try and minimize the potential or maximize the potential for the best outcome possible. There are some things that perhaps maybe we should steer away if it looks like the next step is a CAR T.

Jenny: Yes, that's interesting.

Dr. Berdeja: I was just going to say that's where having different targets is helpful. I’ve had the luxury and my patients have had the luxury of having access to a lot of these clinical trials. I’ve had patients go from a BCMA CAR to a GPRC5D bispecific and another patient that went from a BCMA CAR to a GPRC5D CAR several years later. At least right now, maybe the data isn’t out there, but we're very encouraged by the activity of these non-BCMA products, even if it's the same or similar technology. Perhaps only towards different targets actually may obviate this question that we're asking right now because right now, the BCMAs are so far ahead. 

Jenny: Interesting. Do you want to talk about some of the data? You mentioned a little bit about it. For the allogene CAR T or some of the others, what is the data? I know comparisons are difficult. You don't usually like to compare studies to studies, but just in general, are you seeing the same response rates and progression-free survival and all those other things in the allo CAR T, compared to the auto CAR Ts?

Dr. Berdeja: I guess we could have started there. The truth is the clinical data that's been presented is pretty scant. We don't have very much data to go, and we definitely don't have any longer-term data. It's not too dissimilar. If you recall, we make fun sometimes of some of these sponsors that seem to present a three-month update with every single meeting. At the same time, it's nice to see that progression, to see those patients doing well. The allo CAR T is really in that infancy where they're just presenting, obviously, the only clinical data that is allo CAR T. To my knowledge, there are some NK data out there, but it's really the ALLO-715 product. They just showed us data from their dose escalation.

This is where just trying to find their dose, so, very few patients treated. I think it was like about 25 to 30 patients treated, but only about a dozen or so treated at what they consider to be active doses. Those patients, they reported response rates of about 60 to 70% which is actually quite good, but they are not fully the dose escalation, so, not too dissimilar from what we've seen with the bispecifics. We'll see with more numbers whether that actually looks better. I think it's similar to what we're seeing with Abecma, maybe not as good as what we’re seeing with some of these other things like Arcellx and CARVYKTI which are in the high 90 to 100% response rates, but I think reasonable response rates. We don't know anything about PFS. We don't know anything about the duration of that response. I think the 45 patient they had was seven or eight months or so, but most of them were within three months of therapy. We really don't know anything about that.

That’s the important part, in my mind, is whether these products are going to be less or the responses are going to last as long as what we see with the autologous CAR T. Just because with the bispecifics, obviously, you keep getting the product, and so if we don't see the same duration of the response, then the question or that potential for redosing becomes important. Perhaps maybe the allo CAR Ts have to be dosed every six months or something to that effect to keep that going. I guess, we'll see. 

Jenny: So interesting. I know that when they did redosing of some of the auto CAR Ts, it didn't seem to be that effective. This whole field is evolving so fast that maybe that’s going to be great.

Dr. Berdeja: You are correct that, at least with ide-cel and cilta-cel, so, Abecma and CARVYKTI, retreatment doesn't seem to be beneficial. Now one of the potentials there is that, let's see, Abecma is a mirroring chimera. That means that there's actually some mouse proteins in the CAR itself. CARVYKTI is what they call a camelid which is, it has some llama protein in the CAR. When the CARs are introduced into the patient, the patient actually can make antibodies against those foreign proteins. We know that with the autologous CAR Ts, there is an increase of these, what we call anti-CAR antibodies. One of the potential thoughts is that what happens is, if you give that CAR T again and you have these antibodies, these antibodies kill the CAR T very quickly and won’t allow it to expand.

With the allogeneic product, that could be the same thing, especially if they're using, again, mirroring chimeras. Most of them are humanized or actually synthetic products, so it's possible that we will not see that. The other thing is that it depends on when you give the CAR T. The retreatment for the autologous CAR Ts was at the time of progression. The thought would be, can you give a product before progression in a particular sequence that will allow you to maintain that remission? I think that's a different potential, but those are the caveats of pre-treatment. Yes, there is a potential that if you can pull them out, work with the other products.

Jenny: That makes a lot of sense that you would do it before you have a problem to deal with and keep the disease in check. I have a question about side effects. You mentioned that you seem to see lower side effect profile like for cytokine release syndrome or for some of the neurotoxicities. Is that the case? Then, are there any new side effects? Do you see the graft-versus-host disease or GVHD, like you do in allo transplant for these patients? Or because they did all the manufacturing enhancements ahead of time, you just don't see any of that?

Dr. Berdeja: We'll start with the easy questions or the easy answers. GVHD is not being seen, so that's good because, again, that would be catastrophic. They were very good at removing that TCR receptors, so we're not seeing that. The cytokine release syndrome and neurotoxicity is interesting. With all of these allogeneic products both in myeloma and in lymphoma, but actually it's a little more ahead of us, where we're using allogeneic, either NK cells or allogeneic T-cells, the rates of cytokine release syndrome are actually quite low. With ALLO-715, I think it was 40%. It's even lower in some other products. All are grade one, very few grade twos, no grade threes or fours, and really no neurotoxicity. The question of course immediately becomes, is it because the cells are not expanding to the same degree that autologous T-cells can expand and/or the cells are just not persisting as long and they very quickly get removed by the patient's own immune system? Because we know that those side effects of cytokine release and neurotoxicity correspond to the expansion of T-cells.

The patients that get the largest expansions and who may actually then have persistent, their CAR T at high levels, tend to be the ones that have the most toxicity as well. It's one or the other. The hope is that the expansion is sufficient to see activity, and the persistence is sufficient to see that activity because it's still unclear whether you have to persist to maintain your remission. Hopefully that's not the case because I think that's what's going to happen with the allo products. We'll see less expansion and decrease persistence. The idea is that hopefully you get such a deep immediate response that you don't need to persist. If it's not, if it’s not a sufficient response and the cells are being removed quickly, then that can lead to less effective responses with autologous CAR Ts.

Again, we just refer to the data, but yes definitely the cytokin release and neurotoxicity seems to be less with the allo products. Infection is something to keep an eye on, like I said before, especially because the efforts to try and really suppress the patient's immune system so that it doesn't destroy the allogeneic CAR Ts, a lot of these allo products are using lymphodepletion that's much more aggressive than obviously autologous CAR Ts, which can have its own consequences as well. We'll have to see if we can find the fine line of when is too much too much or not enough. 

Jenny: Great. Well, I want to give a little time to caller questions. If we don't have caller questions, I have several more questions for you. If you want to ask Dr. Berdeja a question, you can call 347-637-2631 and press “1” on your keypad. While we're waiting to see if we have any questions, well, you mentioned, one of my questions was about the time frame, but you already addressed that. Go ahead with your question.

Caller: All right. Thank you. I’m just wondering why you need lymphodepleting chemo before a CAR T?

Dr. Berdeja: That's a great question. When you get a CAR T, there's only so many T-cells that you’re giving back, so you have a lot more T-cells in your body. The idea here is that T-cells are always going to be competing against each other. You give them lymphodepleting chemo to decrease the number of T-cells in your body that are circulating so that when you give the CAR Ts, they're not competing against each other to go after the myeloma. Because you want these CAR Ts to see the myeloma, go after it and expand. That's the reason for the lymphodepletion. There actually are some studies, CAR Ts originally were done without lymphodepletion or with a different lymphodepletion that was not as aggressive, and the expansion of the CAR Ts was much less. They were not as effective. Unfortunately, right now, we do need the lymphodepletion, but we're all trying to figure out how to minimize or how to improve on the lymphodepletion so it doesn't have some of the potential longer term side effects that we're seeing in some people where blood counts stay suppressed for a long time and infections. Yes, great question.

Caller: All right. Thank you. That makes sense.

Jenny: Thanks for the question. I guess a follow-up question on that is, you mentioned that these allo CAR Ts are engineered to knock out the CD52. Do you use the same dose of the fludarabine and the cytoxan and all that, or they're probably just going to learn over time maybe, if it goes into being too much?

Dr. Berdeja: Right now, we are using the same dose. That's because the first dose levels on the use of fludarabine and cytoxan, it would seem that the expansion was not what was hoped for. That's why the antibody, the ALLO-647, was added. It was just added to lymphodepletion. It wasn’t instead of. That's an excellent question. Is the antibody sufficient that maybe you don’t need CAR T therapy at all? I think it's going to be one of those things where you're just going to have to try to attenuate, but it's hard I think for a CAR T product to test because that requires testing a whole bunch of new patients and dose levels if you make too many changes. Sometimes, unfortunately, once you start with something and it's working, it's stays until a separate study or somebody else decides to tackle that on.

Jenny: That makes sense. There's a lot that goes into this clinical trial design development, so much. Go ahead.

Dr. Berdeja: I was going to say, lymphodepletion, that's one of the reasons why, because patients often ask why can't they get a CAR T because their kidneys are not working, and one of the reasons for that is that the fludarabine is excreted through the kidneys. If your kidney function is too poor, we can't give the fludarabine. We don't know what it means to, whether the cells will expand without fludarabine. Just realize that sometimes some of the exclusions are for a reason. Unfortunately, sometimes the reason is we just don't know.

Jenny: Great.  Go ahead with your question.

Caller: Hi. Thanks for taking my question. This has been a fascinating presentation. You mentioned that the CAR T uses viral vectors. Are there availability issues for the allo CAR Ts in addition to the auto CAR Ts?

Dr. Berdeja: Are there availability issues? Is that what you said?

Caller: Yes, availability issues for the allo CAR Ts in addition to the auto CAR Ts.

Dr. Berdeja: Theoretically, there are, except that, like we discussed a little bit before, the autologous CAR Ts are on-demand. If you were getting an autologous CAR T, I collect the T-cells and then they have to be manufactured. You need to have that vector available to create those CAR Ts. With the allogeneic CAR Ts, the donor is separate from the patient. You can actually take one donor and manufacture hundreds of products. They're frozen, and they're ready to go, so when you need your CAR T, that's already made. Because you don't have that on-demand feature, they're not as susceptible to availability of the viral inspection process, so, less so but, yes, theoretically, they could be. 

Caller: That makes sense. Thank you. 

Jenny: Thanks for the question. I think this whole viral vector issue is interesting because all these COVID vaccines use these viral vectors, so maybe that’s why there's this big global shortage, I think. I don't know. All this supply stuff and everything affects us as well. There's a lot of shortages in medicines and so forth. I’m not surprised the viral vectors are being affected as well.

Jenny: Interesting. Well, last question. One of a few questions and you can pick which one you answer. Where is CAR T headed, in your opinion, to extend remissions? You were talking earlier about some of your patients using bispecifics before or after, or using them in earlier lines of therapy or these new allo therapy options or using maintenance. Where do you see the field headed in general? Then, just if you have any CAR T open trials that you want to mention.

Dr. Berdeja: Great question. I think we're all very interested in taking the CAR Ts in early lines of therapy because we know most myeloma therapies work better earlier in the course than later. It makes sense that this would happen, especially with autologous CAR Ts. We're worried about certain therapies impacting the T-cell function, so the less heavily pre-treated the patient, perhaps the better. A lot of studies are already ongoing, looking at CAR Ts given in first line and then one, two, three four lines. We're going to have some data actually, potentially, with at least one of the randomized trials in one, two, three, four lines of therapy using CAR T against standard of care, for example. That’s coming our way.

Personally, I think CAR Ts are so powerful. We don't know, but I believe that they're so powerful that they actually can detect very minimal residual disease. In my mind, I would like to see CAR T being tested and used in the minimal residual disease setting, trying to use them as a means to really wipe out that residual disease. The other advantage of that is that we know that patients with high tumor burden get the CAR Ts, often are the ones that have the most toxicity. Theoretically, in that setting, that would be much less toxic. That's what I would like to see. There are some studies now looking at the post-transplant setting or after induction, for patients under control, given the CAR T. Those are the ones I’m most intrigued by.

In terms of trials, obviously we have quite a few trials. We have a lot of these trials with Abecma and CARVYKTI, early lines of therapy, including frontline in high-risk patients, and actually as consolidation after transplantation. Keep an eye out for those. There's also a couple of autologous CAR T products that are looking very impressive. One is CTO53. The other one is the product from Arcellx which showed 100% response rate. Those two are surely the next two autologous BCMA CAR Ts coming down. They differ in that CTO53 is human, so it doesn't have mouse or llama. We talked about the antibodies. Potentially they would have decreased potential for that in terms of destroying the CAR Ts. Arcellx actually uses completely synthetic binding sites, so theoretically, it’s non-immunogenic as well. Those are available in the relapsed/refractory setting with us. Then we have several CAR T trials with allogeneic CARS, including ALLO-715, ALLO-605 trials, so lots of CAR Ts.

Jenny: You've been prolific in running these CAR T studies. This show has been so enlightening on the allo product idea, in general, but also just in CAR T in general. I think what you're saying is really important, about thinking ahead, getting on a waiting list, looking into clinical trial participation early and positioning yourself to take advantage of some of these newer therapies because it takes a long time for them to get approved. These allos are very early, like you mentioned. Sometimes there’s an availability issue, so it might be almost easier to get into the trial versus getting it as an approved therapy. I don't know.

Dr. Berdeja: Without a question I can tell you that my patients that we have on the waitlist for commercial products, we usually can get them into a clinical trial faster, so definitely continue to support with clinical trials. I’ll just put a plug that I still have a patient who was at the very first CRB-401 which is the phase one trial prior to KarMMa for Abecma, and who is still in remission about five and a half years now. She had access to it way before we even were dreaming that this would be a commercial product. 

Jenny: I agree. I think patients should consider CAR T at every stage and clinical trials at every stage of therapy. That's one of the tools that's in that HealthTree Cure Hub product that I talked about as a clinical trial finder that you can find personalized things.  Dr. Berdeja, thank you so much for everything you do for CAR T and for myeloma patients in general. I know you're running many more studies beyond just CAR T. Thank you for being a leader in this field. We just appreciate you so much.

Dr. Berdeja: You're welcome. I appreciate all of you. Yes, please reach out to your local docs, to your transplanters, to your research sites or to me, to whoever you can. Obviously, the Myeloma Crowd has such great resources for you. Definitely seek out those clinical trials because that opens up significant avenues for you for treatment. Thank you so much for having me. I always enjoy talking to HealthTree.

Jenny: Thank you so much for joining. We really appreciate you so much. We thank our listeners for listening to this new HealthTree Podcast for Multiple Myeloma. Join us next time to learn more about what's happening in myeloma research and what it means for you.