A CAR T Revolution: Allogene is Bringing Lifesaving Cancer Treatment to More Patients

00:00:00
Speaker 1: This episode is brought to you by Allogen, a company redefining how we fight cancer and autoimmune disease. By pushing the boundaries of cartes cell therapy. Allogen is creating next generation off the shelf treatments designed to reach more people. Learn more at allogen dot com. Hi everyone. Cancer treatment has come such a long way from the blunt tools of chemo to today's precision immunotherapies like cart or chimeric antigen receptor T cell therapy. Our partner, Allogen Therapeutics, is helping lead that transformation. Cart is amazing. It reprograms your own immune cells to find and destroy cancer, and because it's targeted, it does it without some of the most brutal side effects of say, chemotherapy. But access has been a real challenge. That's where Allergen comes in developing truly off the shelf CARTI treatments made from healthy donor cells and ready when patients need them most. Who better to understand these exciting developments and Alergen's chief medical Officer, Doctor Zach Roberts. We talked about how cancer outsmart some of its fiercest opponents, but how CARTE therapy is changing the face of the disease, but first I wanted to know what drew him to cancer research in the first place. Doctor Zachary Roberts. So nice to meet you. I admire people like you so much who are cancer scientists who are trying to come up with better treatments to save people's lives or to at least manage their disease. I'm curious how did you get interested in cancer research? And by the way, thank you that I appreciate that you did well.

00:01:51
Speaker 2: Thanks Katie. This is absolutely lovely to be here with you today. I have to say that I was interested from a very very young age. I grew up wanting to be a scientist, wanting to be a doctor. I became quite fascinated with how cells kind of went wrong. There are a normal cell one day and then there are cancer cell the next, and so really understanding what genes were in play, what went wrong, what switches got turned on, which ones got turned off, all of that was so fascinating to me as a youngster.

00:02:23
Speaker 1: How old were you when you became interested in that?

00:02:25
Speaker 2: Oh it's probably seven eight really? Yeah?

00:02:29
Speaker 1: Wow?

00:02:29
Speaker 2: Yeah. But what I was really interested in was how the immune system interacts with cancer.

00:02:35
Speaker 1: Immunotherapy used to be kind of mocked in the medical establishment, right, and now it seems to hold the key to dealing with a lot of cancers. But I want to go back, if I could for a minute, to talk about how cancer treatment has changed and how immunotherapy has been embraced. My husband was diagnosed with stage four colon cancer in nineteen ninety seven. He was just forty one years old, and of course, back then, may I call you Zach, of course I did a lot of research. I was just desperate to figure out if there was any way we could treat and save my husband's life. And back then these approaches were just starting to gain a little speed. But for the most part, everything was treated with chemotherapy. Chemotherapy obviously was a great development in cancer treatment, but there are a lot of things wrong with chemo. Can you talk about that and talk about how you've seen cancer therapies evolve in the year since.

00:03:48
Speaker 2: Absolutely, so, You're right, chemotherapy is very much a double edged sword. And if you go back a leave it even a little further than your husband's diagnosis, maybe another fifty years. Let's say cancer was uniformally fatal at that time, and no matter what cancer you had, it was just a matter of time before you would succumb. In the middle of the twentieth century was when through serendipitous and lots of hard work, we discovered that these class of medicines chemotherapy could kill very rapidly dividing cells.

00:04:23
Speaker 1: And we should just mention the double edged sword of it is that it kills a lot of healthy cells too. It's indiscriminate. I used to call it the scorch body therapy, right because it just kills everything, and that while the healthy cells grow back, it's pretty ravaging.

00:04:42
Speaker 2: Yes body. I mean, the way that chemotherapy works is it has a slightly more toxic effect on cells that are rapidly dividing. So in your body, you've got cells that are very very slowly dividing maybe once a year, and then you've got cells that are dividing every day. You've got cancer cells that are dividing multiple times per day. So what we try to do with chemotherapy is just tune it so we get the cells that are dividing the most rapidly. But your hair cells, the lining of your stomach, and your GI tract, those are all rapidly dividing cells. So absolutely super super toxic, But the targeted therapies were not. They were very well tolerated by and large and these patients could go back to their normal lives. And this is coming back to the first question you asked me, the biology of cancer. In the intrinsic biology of a cell, we know that there are certain genes that in some cancers are activated in a way that gives rise to the cancer in that cell. That the ability it gives the ability of that cell to become tumorous. And if we could design a drug that targets that specific gene, we can arrest the cancer.

00:05:53
Speaker 1: It's so amazing to me how challenging cancer is as a disease. I used to you know, I think a lot of people think of cancer one disease, but it's thousands of diseases in thousands of different biologies. In other words, I got cancer, Zach. Even if it's the same kind of cancer. If we both got a certain cancer, the way my body reacts to it and the way your body reacts to it could be totally different.

00:06:20
Speaker 2: Right, Absolutely, that's a most people, You're absolute right, do not they think of cancer as a monolithic disease. But you're right, it's thousands of diseases. I mean, there are hundreds of phlymphomas.

00:06:30
Speaker 1: So when you think of targeted therapies, is immunotherapy a subset of targeted therapy.

00:06:38
Speaker 2: So I would say, no, it's different ball of whax. That's a different ball of wax. So in my mind, I kind of the way I organize it, there's sort of three pillars of cancer care. There's pillar one, which is chemo, which still has a big role to play, yes, you know, for better or worse.

00:06:53
Speaker 1: And by the way, I don't mean to dump all over chemo because it's so lightly.

00:06:57
Speaker 2: You're not gonna hurt my feelings.

00:06:58
Speaker 1: No, but you know what I mean. And I think a lot of people benefit so much from chemo therapy.

00:07:03
Speaker 2: It absolutely can prolong people's lives. And and one thing that has really improved in the last twenty years is the supportive care element of this.

00:07:13
Speaker 1: So you have fewer side effects.

00:07:14
Speaker 2: Fewer side effects, so you know, we've got growth factors to manage low blood counts, so you feel stronger between cycles. We've got very powerful anti nausea medicines now so and in a way interestingly that's actually made chemo even a little more effective because it means we can push the dose a little bit higher and the patients are able to to manage it. So, yes, chemo still it gets a bad rap, but it still has a pretty big role to play. So that's pillar one. Pillar two, I think is this targeted therapy, which is looking for specific regulators of cancer and targeting those directly. And then pillar three I would put as the imminotherapy in of things, and that targets a pathway in T cells, which are really kind of the field generals of the immune system. It targets what is often called the immunological break of those cells.

00:08:13
Speaker 1: Let's go back and talk about T cells because they sort of are, as you mentioned, the warriors of immunotherapy, right, Are there other cells other than T cells that can act like warriors against cancer.

00:08:28
Speaker 2: Absolutely so, even though it's a little cliched, I think kind of the army sort of analogy really works for the immune system because you actually have many different kinds of cells. Each of them has one or several very important roles to play. There's a lot of cooperation, there's a lot of crosstalk between the cells. So the cells will actually talk to each other, obviously not with voices, yeah, but with molecules that they secrete, and a T cell will secrete molecule that a B cell will take in, and that B cell, with that message will act now differently, it'll take a sort of an order from the T cell.

00:09:09
Speaker 1: Is the T cell the general I like to.

00:09:11
Speaker 2: Think of them as the general Now I call them field generals, though, which is the term I may have made up, but it means that they actually are doing some of the work themselves. They're not sort of sitting in a back office somewhere. They're actually on the front lines because they have Without getting too far into the weeds here, as I said, I'm an aemynologist, which is really my passion.

00:09:29
Speaker 1: Well, I'm really into this, so go ahead.

00:09:32
Speaker 2: The T cells have, in addition to their ability to send messages to many different other cell types B cells, macrophages, dendritic cells, they also have a very specific molecule on their surface called the T cell receptor, and the T cell receptor is unique to that T cell. So let's say you've got a billion T cells, and more likely you've got one hundred billion T cells in your body each one has its own unique T cell receptor, and bodies have evolved in that way so that you can in any infection that you encounter. Right when you're born. It's not like you're just given a set of instructions of all the infections that you could ever see or all the allergens. Right you are born with a truly naive immune system, and so you have to have this ability to create diversity in your in your T cell population so that you can attack anything that comes in. So the T cell receptors have an ability to recognize infections, and some of them have an ability to recognize tumors.

00:10:31
Speaker 1: As a T sell in a car T sell the same thing.

00:10:34
Speaker 2: Great question, so and great transition. So as as our ability to understand the function of T cells grew over the nineteen eighties, the nineteen nineties, and then into the two thousands. And it's really rather recent that we started to really tease all this apart. Many Nobel prizes were involved in this whole story in the early nineties. Someone, well, let me fill in one other little gap here, So I mentioned B cells as another member of this little army. B cells are famous because, like T cells, they've each got their own specificity. Right, there's billions upon billions of B cells, and each one has its own special specificity that is unique to whatever infection that you may get or may never get. When that little molecule that's on the surface of the B cells gets cut off and floats around your body by itself, we call it an antibody. So B cells make the antibodies.

00:11:30
Speaker 1: We love B cells.

00:11:31
Speaker 2: We love B cells. We love antibodies. They're good for a lot of things. They're a huge part of the immune response. And we've known how antibodies work for a little longer than we've known how T cell receptors work. And so One Suite began to realize the potency of T cells and their ability to kill target cells, including cancer sometimes. And we can do this in the lab. We can get them to kill cancer cells in the lab, but we couldn't really figure out how to do it in people until we started to use the checkpoint blockers in twenty eleven.

00:12:03
Speaker 1: And the checkpoint blockers basically they basically allow the T cells to kill the cancer cells without being told to back off. They're like, screw you, cancer, We're coming in. There's nothing you can do to stop us.

00:12:21
Speaker 2: That's right, it's taking the break off. The checkpoint is another term for the break. So if you block the checkpoint, the immune checkpoint, the T cells will just go on and kill. So in the early nineties, an Israeli scientist named Zella Geshar got this idea that if he took an antibody and actually stuck it onto a T cell, an antibody of known specificity, so we know what this antibody is targeting, and we actually put it into a T cell.

00:12:54
Speaker 1: Give me an example of an antibody like a specific one.

00:12:58
Speaker 2: So remember what the first one he actually did. But let's say let's say her too. I'm going to make this up, right, this is making up. Her two is a famous breast cancer marker. It's the drug trans twos amab her septin. Her targets her two. So her two is on the surface of breast cancer. So let's say we had an antibody to her too, and there are many, herceptin is one of them.

00:13:25
Speaker 1: Thank you, Denny Slayman.

00:13:26
Speaker 2: Yes, absolutely, Danny Slayman. So let's say let's say I wanted to make a car te cell with her sceptin. So this going back to the early nineties. Let's say I have got this antibody that is un that is targets the HER two antibody hertoo molecule, and I put that into a T cell. And I do that by actually creating the genetic sequence that is used to make the antibody. Because everything comes from DNA, so the DNA is like the blueprint. So you take that piece of DNA, you stick it into the T cell. So the T cell's none the wiser and it sees this piece of DNA and it says, oh, I need to take an antibody now. So the antibody goes to the surface of the T cell.

00:14:03
Speaker 1: It doesn't reject it. It says welcome.

00:14:05
Speaker 2: It says welcome. It's just DNA. And so they are. They are appliable in a way. We can modify them using genetic techniques.

00:14:15
Speaker 1: Which brings us to allogenic therapy because I'm like, how do you do that?

00:14:19
Speaker 2: So the basic biology is you have to modify the T cell, right, because as I said, right, you've got billions of T cells, they are all unique. Right, that's not going to help you if you need to kill a kilogram of tumor, right, you need a lot of T cells that are all focused on the same thing. The easiest way to do that is to modify the T cells. Now it's not easy, it's hard to do that, but if you can do it successfully and get them all to see the same thing and react in the same way, suddenly you've got an entire army that you can deploy to eradicate this tumor. So the CAR T cells are just that. So we take in the early days, it was an antibody put in the T cell, and suddenly the T cell became specific for her too. In our example, which was itself a massive breakthrough. It took another twenty years. We talked about Carl June before we get started, and he was one of the pioneers in this. It really we really had to incorporate a lot of what we had learned about how T cells themselves work before we do anything to them to then design a perfect CAR. And CAR stands for chimerican, chimeric anigen receptor chimeric because it's part T cell receptor, part antibody, so it's a chimera and it's an anigen, which anigen is a fancy word for the molecule that this receptor sees. So the anogen is on the tumor cell and the receptor sees theanogen, so chimeric anigen receptor. And so once we designed an effective CAR we put that into T cells using the same general techniques we can talk about that. It's actually quite interesting. We use modified HIV virus to do that, and we drop this DNA into the T cells. The T cells again are none the wiser, and suddenly you now you've got a population of T cells with uniform specificity. They all see the same thing in this case, her too in our example. So if you've got a patient and there's no CART cells, effective cart cells for her too. But we'll come back to you know, the real situation in a moment when when the analogy is done. If you've got a breast cancer patient who's got a very her too positive tumor, and many do, and you put the car T cells in them into the patients, suddenly you've got billions of car T cells that are all finding her too on the on the breast cancer cells and they'll kill the breast cancer cells. So it's remarkable how well this works in solid tumors. It's been a little tricky. Allergen actually has has some great data in solid tumors, but it works really well in blood cancers. Lymphoma's leukemia is multiple myeloma.

00:17:01
Speaker 1: Why you know, I always have a hard time, just because my experience with my husband was calling cancer. My sister pancreatic I was diagnosed with early stage breast cancer three years ago. I always have a hard time envisioning how cancer acts in the blood. Can you explain that.

00:17:19
Speaker 2: To me, picularly blood cancer.

00:17:21
Speaker 1: Yeah, Like, well, my mom had lymphoma, yes, so that was a blood cancer, right, yes, But how I have a hard time envisioning in the blood stream how blood cancers were. Can you explain that to me?

00:17:36
Speaker 2: Sure? So it's probably helpful to go back and realize that all cancers start with one cell more or less, and we give the name to the cancer depending on which cell became the cancer. So in pancreatic cancer, it was a pancreas cell. In blood cancers, it's often cells of the immune system. So T cells, B cells both can can give rise to cancer.

00:18:08
Speaker 1: Wait a second, I thought they were fighting cancer.

00:18:11
Speaker 2: They are, they are, but they are they are subject to the same molecular malfunctions as any other cell in your body, So lymphoma, non Hoskins lymphoma, almost all of those are come from B cells. So your mom had mantle cell. Correct, mantle cell comes from a from a B cell. Most leukemias that are that are lymphoid in nature come from B cells. There are some T cell leukemias as well. Most leukemias that we think of actually come from a different blood cell that are give rise to macrophages and other immune cells. But they all they're all start in the marrow or in the lymph nodes. So you've got thousands of lymph nodes in your body. This is where all of the immune system cells all come to congregate and form an immune response to an infection. So if you get a cut in your arm, you get some bacteria. You've got a lot of lymph nodes in your arm, and as the bacteria make their way into your body, they find their way into the lymph nodes and that's where the TMB cells encounter them and.

00:19:19
Speaker 1: They eat it up.

00:19:20
Speaker 2: They eat it, they kill it, they tell their friends about it. The friends then get deployed and go and get inflammation in the cut. So often B in T cell lymphomas will start in a lymph node because there's such an explosive proliferation of those cells in response to an infection. But this is where those T cells and B cell lives. So if you have lymphoma, it's not so much circulating in the blood as it is in the lymph nodes. And so you'll see patients come in with very just enlarged lymph nodes throughout their body. You do a PET scan and you'll see lymph nodes even in their abdomen and their chest. So throughout leukemias, on the other hand, they are often circulating. Mantle cell lymphoma is an example that is a also has a circulating phase. So you can actually draw blood in these leukemia patients and find tumor cells in the blood.

00:20:11
Speaker 1: But what you're saying is the T cells in the B cells are basically not doing their jobs in the blood cancer and that's what's creating the opportunity for blood cancer.

00:20:22
Speaker 2: Or it just takes one. So you might have you might have ninety nine point nine to nine percent of your B cells might be doing the right thing, and your T cells might be doing the right thing. You've just got one bad apple in there.

00:20:40
Speaker 1: This episode is brought to you by Allogen, a company redefining how we fight cancer and autoimmune disease. By pushing the boundaries of car T cell therapy. Allogen is creating next generation off the shelf treatments designed to reach more people. Learn more at allogen dot com. So clearly, an approach to killing cancer is to make these T cells or turn them into car T sells, right, which give them the ability to attack specific cancer cells. Right, How do you do that?

00:21:26
Speaker 2: So the approved therapies that are on the market already for blood cancers all start with the patient's T cells themselves, and so the procedure works as follows. You. The patient who's got the lymphoma goes and sits down for several hours in as procedure called aphoresis, and that is it's kind of like an enhanced blood donation where we where we take out billions and billions and billions of circulating normal T cells from that patient. That becomes the manufacturing star material. We take that bag of T cells and that's a literal bag of T cells, and then we bring it to the lab and that's when we do our genetic modification. We use that that that special HIV virus to deliver this genetic material into the T cells. The T cells then become car T cells. We wash them and purify them and put them in a different bag, and then they get frozen and sent back to the hospital where the patient is receiving their care, their thought at the bedside, and they're infused into the patient.

00:22:31
Speaker 1: It is amazing.

00:22:32
Speaker 2: It's amazing. It's amazing that it works as well as it does.

00:22:35
Speaker 1: So what happens when they get an infusion of their modified car T cells, right, or their T cells that are modified and turned into car T cells.

00:22:45
Speaker 2: Yeah, okay, we often just saying it, you're nailing it. We we often just say car T cells. They get their cart cell infusion. So so the infusion itself, and I've seen many is sort of little anti climactic. It takes about five minutes. Cells just go into a normal IV and then what happens next can be exciting. The patients can get quite sick with the side effects of these cart cells because, as you'd imagine, they're on overdrive. They're on overdrive, and they all have the same specificity, so they're all seeing the same thing at the same exact time, within minutes of being infused, and.

00:23:25
Speaker 1: It's like swarming. This the swarming, right.

00:23:27
Speaker 2: And they're also dividing, so they can actually divide in the body ten thousandfold, and so you get this massive immune response. You feel like you have the flu. Sometimes that can become quite serious. We learned in the early days how to manage this pretty effectively. But once you get through that first week or two where the toxicities can be the side effects can be a little you know, difficult. Once you get through that, then you begin to see the effects of these cart cells on the tumor. And these patients will come in often one month after their infusion, before their infusion, you know, they're just loaded with cancer on a scan, and they come in one month later in a complete remission. Every visible tumor is gone.

00:24:15
Speaker 1: So I was just going to ask you what is the success rate for this kind of therapy and specifically in blood cancers.

00:24:22
Speaker 2: Yeah, so in blood cancers it works really, really well in the best cases. You know, there's a lot of different trials out there, but you can see remissions like this eighty ninety plus percent of the time, depending on the patient. The disease and the car T cell that you're using that applies to leukemia, lymphoma, and myeloma. Myeloma is a very common blood cancer, famously and curable, and just earlier this year we saw data that was five years out from the first trial using a Carte cell for mioloma, patient's still incomplete re mission. So really astonishing efficacy. Not only high response rates but durable. These patients can and they're leading normal lives after a single infusion.

00:25:11
Speaker 1: And what about recurrence? Is it just too early to say.

00:25:17
Speaker 2: So with blood cancers, they tend to come back quickly, usually within most most of the time within one year. But certainly if you're beyond two years out, you generally are in a good place. So there may be a few relapses after two years. So if you can, you know, certainly for leukemium film, if you're two years out with no recurrence, you know, as on Collegist Animals has to say it, but you're probably cured at that point.

00:25:43
Speaker 1: The problem with this, I mean, it's extraordinary and so exciting, but the process itself is is is a lot, right, That's a lot. And I know that access has been a problem talk about out the people who can benefit from this and the people who aren't able to access this kind of therapy, which is always so upsetting to me.

00:26:09
Speaker 2: That's an absolutely topical question, Katie, because ten years ago, when I was doing all of this work with the Carte cells and we were seeing these remissions, you know, as I just described, it was a revolution. We had never seen anything like this before, and it was so exciting to be doing this every single day. But what became very clear is that it was very very few patients who are actually able to receive this procedure.

00:26:37
Speaker 1: Why because of expense.

00:26:39
Speaker 2: Sometimes it's expensed. Sometimes it this whole thing with the blood collection and the manufacturing that can take a month or even two months, sometimes even longer. And so if you are a patient as often as the case, who's had a disease relapse, their cancer has come back, it is an emergency and it is sometimes you know, galloping along and growing very fast, and you become frankly too sick to even receive the car T cells if they come back. So and this bespoke manufacturing, one patient, one manufacturing process, one product, really has been a deep limitation to getting access. And it's only done in certain certain centers, large academic centers predominantly, So I knew from the from very early that we would need a new plan. And so you know, we've talked a little bit about this termalogenetic Allogenetic car T cell therapies are really a path to solving this access problem. And it sounds like a subtle difference between the regular car T cells, which are sometimes called autologous car T cells made from the same person, but it's actually quite different. It's we take the cells from a healthy donor, so the T cells don't come from the patient, they come from a healthy person, and we take those T cells and we make them into car T cells, and then we of that product to a patient. Right now, even ten plus years after the very first or close to ten years from the very first approvals of CARTI, only twenty percent of patients who are eligible are actually able to access this therapy. It's a lengthy process, it's complex, there's insurance issues, it's only given in certain centers. The majority of patients in our country don't get their care at those centers. So there is just multiple burials barriers that prevent a patient who could have their life saved and their cancer cured by car T cells, they just can't get them, which is a tragic situation. So after we figured out how to make car T cells in the very beginning, and we were doing it using patients material patients T cells and making the car T cells in the lab. During in that process, I described one of the companies that was at the forefront of that was a company called Kite Pharma. It was a company that was founded by Ari Beldergrim and David Chang, both of whom at the end of the Kite cycle went on to form Allogen. And the reason that Allergen came about was because even though we were working with these carte cells at Kite, and all three of us were working on this together, we very quickly realized that there was going to be significant limitations in our ability to scale this manufacturing process, and with our inability to scale, we were going to run into massive access problems. There just wasn't going to be the wherewithal of the ability the manpower that would be required to make products for all these patients that needed to receive them. So the vision at the time was, how can we take healthy donors and collect their T cells and then make dozens or hundreds of doses from a single manufacturing run instead of making one dose from a manufacturing run. And so that was really how allogen was born and the new field of allogenetic car T cells was launched.

00:30:04
Speaker 1: Wait a seconds, so all car T cells Zacher created equal Like, if you needed car T therapy, I could donate my T cells that would become car T cells that could be used in your body. It's not like a bone marrow donation.

00:30:22
Speaker 2: It is not like a bone marrow donator. Actually crazy, Yeah, And actually the question is a very interesting one, and it's partly why it's been so difficult to achieve this, to use a healthy, a healthy donor starting material to make these cart cells. The immunology is a challenge. Our bodies are able to recognize other people's immune systems as foreign, and those immune systems are able to recognize our body as foreign. Because we can use elegant gene editing technologies, we can actually solve that immunology. And so we can use universal donors. We can take a donor to use your example, Yes, your cells could work for my cancer. It's not actually how it works. We have there's a sort of an elaborate testing and we have to make sure that we're picking the dright donors.

00:31:11
Speaker 1: And it's there and I might be too old.

00:31:14
Speaker 2: There is an age limit. I don't know if it would apply to you or not, but yes, those sorts of attributes are are minded and therefore we can make from a single donation. We can make up to one thousand doses of Carte cells from a single donation.

00:31:28
Speaker 1: Are we talking about a thousand patients?

00:31:30
Speaker 2: A thousand patients? Wow? Yeah, the donation piece is not the limitter for us because we can make so many doses from a single donation. We have many many doses frozen away. What I think the barrier that we need to solve is we need to find better ways to administer these products at the place where patients get their care.

00:31:51
Speaker 1: Instead of just a few or academic centers all across the country. They have to be in rural hospitals and places low income areas, right.

00:32:01
Speaker 2: I mean even yes, absolutely, but even large suburban areas. I mean, you would be surprised at how reluctant patients are to leave their primary oncologists to get a referral into, you know, across town to you know, the gigantic building and the nurses who name I don't know, right.

00:32:19
Speaker 1: Can't the Cartie cells be shipped to various places.

00:32:23
Speaker 2: In the context of the autologous, the the yes, kartas, and all the ones that come from the patient them cells, that whole apparatus to collect the T cells, to manage the to and fro. That actually is pretty rigorous, and there are accrediting bodies who make sure that that's done all right, because you have to track the cells back and forth. You can't get lost in the case of an off the shelf analogeneic another word is off the shelf. We could it's just we just send the product to the patient.

00:32:55
Speaker 1: And aligenetic just means it doesn't have to come from your body, comes from somebody else, right, somebody else's T cells, right, correct, So go ahead, I'm sorry.

00:33:03
Speaker 2: So we can actually send our products to the hospitals, the suburban, the rural hospitals where the patients receive their care. And in fact, in our Alpha three program where we're using this new technique of MRD to find patients who are very high risk of relapse, those patients are remaining with their local oncologists and they're completing their frontline care, they're getting this MRD test, they're found to be at high risk of relapse, and instead of being referred at that point to the big academic center maybe hundreds of miles away, we enroll them into the trial and we just shipped the cart cells right to that practice. And in fact, many of the clinicians on our trial are giving Carte cells for the very first time. They've decided at their practice to not invest in the infrastructure required for the autologous programs, but for an allergen off the shelf program, they have everything that they need ready to go. So these patients now are getting access to this life modality simply because we can just ship it right from our warehouse.

00:34:10
Speaker 1: What is the most important thing for patients and their doctors to know about this exciting new possible therapy for recurrence early in the game.

00:34:23
Speaker 2: So the most important thing I think for patients and doctors to know is that we have new techniques to assess disease at the end of treatment, not just pet scans and cat scans. We actually have this new class of blood tests called MRD tests that will really give you a much better prognosis of your likelihood of relapse. Right now, the only option for treatment is in the Alpha three clinical trial. So if you're a patient or you're a doctor who takes care of patients with diffuse large B celempoma, ask about the MRD test, Ask about the Alpha three clinical trial. Well, because we are really it's not widely available. We do believe it eventually will be wildly available, but we're really at the cutting edge here and we want to get these patients access to the clinical trial enrollment to again, hopefully if they're in that very high risk of relapse, that third of patients, we can find them and treat them when we have the best chance of care.

00:35:20
Speaker 1: And patients need to be aware of this so they can make sure their doctors give them this test.

00:35:24
Speaker 2: Oftentimes, it's remarkable, Katie, as you may know how important the patient's questions and opinions are in determining the care and walking in and saying to your doctor, Hey, you know I heard about this new MRD test that will tell me whether my disease is going to come back or not. What can you tell me, doc about this? Just that conversation that one question often will lead to a patient finding a way into the clinical trial?

00:35:51
Speaker 1: Is this only available to people who have a high risk of relapse. Let's say a patient comes in and they have I don't know, one of the blood cans you mentioned. Can they just go ahead and get the allogeneic therapy? Is there any advantage of using your own T cells over kind of what might be more widely available.

00:36:14
Speaker 2: So right now, the only time that you would get a product made from your own T cells is if your disease has come fully back, so in May.

00:36:24
Speaker 1: What about your very when you're initially diagnosed.

00:36:27
Speaker 2: So right now there is a couple of clinical trials testing whether the patient's own T cells made into car T cells can actually work in what we say are very high risk patients. So ones that we know are going to have a tough time. But for the most part, patients with blood cancers typically often are cured. In fact that the case of non Hodgin's lymphoma, two thirds of the patients are cured with standard frontline chemotherapy. And so when you get to the end of that, the issue is, right now we don't really know who's cured and who isn't. All we can do is wait and we just scan these patients every three months and wait for their tumor to come back. With this new test that we have, this ultra sensitive MRD test minimal residual disease, we can actually pick you know, if we've got two patients who both look in complete remission, one of them is MRD positive and one is MRD negative, we know that MRD positive patient, which means we're finding little traces of cancer DNA and that blood. That patient is at a very high risk of relapse, and so it could really benefit could really benefit court. So in that case, it's really tough. You can't really make the car T cells the way that we've done with the patients because the own car T cells they don't really have a lot of T cells. They've just finished their frontline therapy. Sometimes the disease can come back within a matter of weeks, so while the cells are being made, the tumor comes back. So this is really a great opportunity for an off the shelf product to just go. At the time that we get that MRD result, we send the car T cells that are made from healthy donor. They're all frozen in.

00:38:08
Speaker 1: Our fop residual disease.

00:38:10
Speaker 2: That's the term, they mop up the residual disease. So that is the clinical trial that we are running right now. So this is a very fascinating area of oncology because we are using these enhanced techniques like MRD to identify the patients who are likely to relapse. So far, we're only studying that in clinical trials, and so the Alpha three trial is the one that Alergen is running, and it's designed exactly that way. So if we find a patient who looks to be in remission based on scans and they feel great, but if they're MRD positive, we're pretty sure that patient's disease is going to come back, and it might come back in a matter of weeks or months. So we're treating those patients in our clinical trial right now with our off the shelf car te cells.

00:38:54
Speaker 1: This is potentially a life saving intervention because if you wait until the disease appears on a cat scan, sometimes it's too late and the car T therapy isn't as effective.

00:39:09
Speaker 2: That's exactly it. So if we were essentially bringing car T cells to the patient much sooner, when they stand a greater chance of benefiting, they probably will have fewer side effects because side effects are related to how much cancer is in the body at the time of infusion. And really the goal here is to cure these patients before they ever have to suffer that relapse. And that is what makes Alpha three such a revolutionary design.

00:39:34
Speaker 1: If someone's cancer has recurred and they do have evidence of disease, right, then they can source car T therapy.

00:39:45
Speaker 2: Now in that minority of cases right where there's about fifteen to twenty percent of patients who are fortunate enough to be have the stars aligned, yes, that would be the standard second line, right, but there are a lot.

00:39:56
Speaker 1: Of people who have this happen and they don't have access. And that's what you're trying to tackle.

00:40:02
Speaker 2: That's one hundred percent what we're trying to tackle.

00:40:04
Speaker 1: So how are you trying? How are you tackling it? Are you can you go the seven to eleven and say, I like those card cells.

00:40:11
Speaker 2: No. So, this MRD story is developing across oncology, not just in blood cancers where we're studying with Alpha three, and so patients more and more are starting to ask for these tests. More tests are becoming available. So even in your community oncology practices, at the end of a treatment cycle. The oncologist will often order this MRD test to see how do we do did we get every last cell? You know, in a manner of speaking. And so if in the context of our clinical trial, they send this test, which is very sensitive, and they find that it is that there is residual tumor there, then that patient is potentially eligible to enroll in our study. And so what we're trying to see here is whether us treating the patient when they only have that molecular disease nothing on scan the MRD alone, if we treat with our car T cells at that moment, are we able to cure the patient and have the disease never come back.

00:41:09
Speaker 1: Car T therapy is really effective when there's residual disease? Is it also effective, Zach if your tumor comes back and you see something on a scan.

00:41:21
Speaker 2: So almost all the data that we have so far, including all the approvals for the car T cells, have been in that exact situation when your tumor has come fully back. So this would be a time when we would take a patient to a BOEM or transplant, for example, if you gave them car T cells instead. This is what has led to those miraculous outcomes that we discussed a little early when their tumoror has come back. But what we do know is that car T cells work better when you have very little disease. We've known that for a long long time. So what the Alpha three trial is designed to do is actually find the patients with the lowest imaginable amount of disease, just the microscopic disease.

00:42:03
Speaker 1: And what percentage of patients are those.

00:42:05
Speaker 2: So most likely ninety to probably close to one hundred percent of patients who eventually relapse will have an interval of time where they have MRD only disease, where you can only find it in the blood using a very specific molecular test. Relapse doesn't typically happen out of the clear blue sky. So if we time things well, as we're trying to do with Alpha three, the patients get the MRD test at the right time, their doctors order it. If it's found to be positive, we act on it. In this case, we enroll in our clinical trial. But eventually, if this trial is positive, we hope that this off the shelf car T cell will be available commercially, so this could become a standard of care.

00:42:50
Speaker 1: But you're hoping that if you're able to introduce CARTI therapy much earlier with the help of this test that will indicate your risk of relapse, that it is much more effective.

00:43:03
Speaker 2: That's one hundred percent. If we can find these folks when there are disease is at its weakest point and mop it up with the Carte cells at their local institution without a big onerous referral or blood collection, just take care of it right then and there. Does that improve long term cure? Does that improve outcomes and you prevent the horrific relapse. That's a terrible moment for everybody when you think you're cured of your lymphoma and then suddenly you go to a clinic one day and you get a scan and the doctor comes in and says that your cancers come back. What we're trying to do with this trial by deploying these Carte cells early, is to prevent that from ever happening and get those patients into a cured state. That is really what we're trying to do. If we are successful here, this will be the most impactful change to first line outcomes in almost thirty years. That's how hard it's been to improve outcomes in frontline non HODGKINSLM foma. So Alpha three is really potential to be revolutionary here.

00:44:12
Speaker 1: Most people are cured with the standard of care when you have these blood cancers, correct, correct, But there is a subset of people who relapse, and we don't know who they are, right and.

00:44:24
Speaker 2: It's about a third about a third of patients with the most common type of non HODGKINSLM foma that we're studying, it's a disease called diffuse large B cellmphoma, pretty common blood cancer. About ninety percent of these patients will achieve a remission to frontline care, which is the standard regimen that we've been given for thirty years, but a third of those patients will eventually have a relapse. And the standard of care right now is you get to the end and then you watch and wait. These patients will come back every three months for a clinic visit, they get scanned every three to six months, and essentially you're kind of on pins and needles waiting for this tumor to recur.

00:45:04
Speaker 1: Can you tell me a little bit, Zach, about how this specific trial that you're running came about.

00:45:12
Speaker 2: Certainly a very cutting edge trial and in fact, even just a few years ago, we wouldn't have been able to run this trial. There really needed to be a confluence of new technologies all coming to the four at roughly the same time. So the example first that I'll lead with is the MRD platform. This test and this class of tests is pretty new. It's only been around for a few years in this iteration that it is right now, and it's only recently begun to be used in patients with lymphoma. So that advent was something that was required. The next big thing was because we need to act so quickly on the MRD positive result. You know, we can't spend months referring patients to cartee centers having their products manufactured. We have to act really within days. We needed to have an aalogenetic off the shelf therapy ready to go.

00:46:07
Speaker 1: And when you say allogenetic, just remind people what that needs.

00:46:10
Speaker 2: That means it's coming from a healthy donor, but it means from a practical perspective, from a patient perspective, that it's off the shelf.

00:46:18
Speaker 1: And it's ready, it's ready to need.

00:46:19
Speaker 2: It when the patient needs it. It's ready to go. It can be there literally in days because time is of the time is of the essence. For these MRD positive patients, we know their disease could come back any day, and it actually can happen very very quickly within weeks, so we really have to act very rapidly on.

00:46:38
Speaker 1: That is the reason a trial like this hasn't been done before, because all these technologies didn't exist and all the pieces of the puzzle weren't there yet.

00:46:49
Speaker 2: That is essentially it. We needed enough time for these technologies independently to mature to a point where we could combine them into what is really a very cutting edge and revolutionary design. To be able to act upon a disease before you can see it on a scan. That is kind of a new concept, but it makes a lot of sense because drugs and cart cells tend to work better when there's not very much cancer around.

00:47:18
Speaker 1: Let's talk about the patients that will benefit from this right now. Is it a specific lymphoma patient you're looking for to participate in this trial? Is it people with leukemia who are you looking for?

00:47:33
Speaker 2: Yes? So, in the Alpha three trial, it is for a group of patients with non Hodgkins lymphoma, and it's actually the greatest or most prevalent non Hodginson foma, which is a disease called diffuse large diffuse large B cell lymphoma or DLBCL. So that is the main type of cancer that is eligible for Alpha three. There are a couple other non Hodginson foma which are less common, but that's the majority of patients that we're looking for at DLBCL patients.

00:48:03
Speaker 1: What is the standard of care right now for people with diffuse large B cellomphoma.

00:48:12
Speaker 2: So everyone gets the same treatment. It's a five drug regimen that's chemotherapy our CHOP, and it's given every three weeks. Those five drugs are given together, all on the same day, six times three weeks apart, and at the end of that six cycles of our CHOP, you undergo a cat scan to see whether your disease has gone into remission or whether it hasn't. The majority of patients will have entered or remission, and about two thirds of them are cured. They never need another drop of treatment ever again in their lives and they're not going to hear from their lymphoma again. There is a third of patients, however, who will eventually have their disease come back and right now. The problem is with our PET scans and our cat scans, the way we measure disease activity is we can't distinguish who's who right when they complete treatment.

00:49:09
Speaker 1: So will this expand to other blood cancers do you think, in other words, leukemia patients or other people who might need it.

00:49:19
Speaker 2: Absolutely so. If the Alpha three trial is successful and we are able to show that preventing relapse leads to cures, I think it would make a lot of sense for Allergen or other drug developers to start to replicate this study in other settings like B cell leukemias, like other types of lymphoma. It is such a revolutionary way to look at treating cancer, preventing relapse before it occurs, and using this MRD test to really segregate patients who are very high risk versus those who are probably cured and you don't need to worry about them as much anymore.

00:50:00
Speaker 1: What about beyond oncology, do you see this therapy as efficacious for other diseases?

00:50:10
Speaker 2: So we have seen the last three years an explosion of work into treating autoimmune disorders with cart cells. So diseases like lupus and systemic sclerosis are scleroderma and others multiple sclerosis, for example, there's been some proof of concept there. So these same products that have demonstrated such power in oncology are now bringing to patients with refractory autoimmune disease for the first time in many years, an opportunity for a drug free remission. These patients are entering remissions, their disease activity is going significantly down, if not all the way down to zero, and they're able to come off of their drugs that they've been on for in some cases decades. This is poised to become yet another revolution in car just like we saw in oncology, and so I think that it's a very exciting moment here. There's hundreds upon hundreds of thousands of patients who could potentially benefit from this intervention, and so companies like Allergeen are trying to come up with ways that are tailored to this patient segment that is oncology patients are different rheumatology patients, and trying to meet the needs of those individuals directly through our product design and study design.

00:51:30
Speaker 1: Well, it's really thanks to scientists like you who work tirelessly trying to figure out how to help patients so on, behalf of so many people who I'm sure might be listening to this and really being grateful for your work. I'd like to say thank you first and foremost. And where can people go to find more information that could potentially really help them in the future or right now?

00:52:01
Speaker 2: Certainly so, We've put together website Alpha threetrial dot com that has a lot of different resources for both patients and for physicians to learn about the trial and all the various technologies that we're using in the study.

00:52:12
Speaker 1: Doctor Zachary Roberts, thank you so much for the work you're doing for sharing this potentially life saving information with the public. I really appreciate it.

00:52:21
Speaker 2: Thank you, Katie, It's been a pleasure.

00:52:26
Speaker 1: Thanks for listening. Everyone. If you have a question for me, a subject you want us to cover, or you want to share your thoughts about how you navigate this crazy world, reach out send me a DM on Instagram. I would love to hear from you. Next Question is a production of iHeartMedia and Katie Kuric Media. The executive producers are Me, Katie Kuric, and Courtney Ltz. Our supervising producer is Ryan Martz, and our producers are Adriana Fazio and Meredith Barnes. Julian Weller composed our theme music. For more information about today's episode, or to sign up for my newsletter, wake Up Call, go to the description in the podcast app, or visit us at Katiecuric dot com. You can also find me on Instagram and all my social media channels. For more podcasts from iHeartRadio, visit the iHeartRadio app, Apple Podcasts, or wherever you listen to your favorite shows. This episode is brought to you by Alogen, a company redefining how we fight cancer and autoimmune disease. By pushing the boundaries of cartes cell therapy. Allogen is creating next generation off the shelf treatments designed to reach more people. Learn more at allogen dot com.