CAR-T Revolution – Advancing Lymphoma Treatment with Precision & Innovation

Once you have relapsed refractory disease, only about 5% of the patients can actually be cured. The rest just go on to get second line, third line, fourth line. And with each line of therapy, the cancer becomes more and more aggressive.

I'm ron Najafi. I'm CEO of Emory Pharma. It's a pleasure introducing you to Dr. Priya Chowdhury. Dr. Chowdhury is a specialist in oncology, drug development and chemotherapeutic drugs. She's currently with Genentech, but will be moving very soon to Corcept Therapeutics as the Associate Director of Clinical Sciences. Dr. Chadhry did her PhD at the University University of Utah, and she spent a number of years as a postdoctoral fellow at Caltech and UCSF. So with this Dr. Chadhary, thank you so much.

Good afternoon, everyone. Thank you for calling me to present on this topic. I'm very excited to talk to you about the use of CAR Ts in lymphoma. These are very, very exciting new drugs that are really revolutionizing the treatment landscape. And so with all of that, I'm very excited to talk about it. And let me jump into the presentation. This is the general agenda for this presentation. I will initially start with introduction to lymphoma and DLBCL, how it is treated, then give an overview of CAR T cell therapy, then jump into specifically CD19, CAR TS and their use in lymphoma, and then talk more about their side effects and newly discovered items with CAR T's that we should take into consideration when prescribing them to patients. So let me start with lymphoma first. So lymphoma is a cancer of lymphocytes. Now, everyone must have heard of white blood cells, and these are our immune cell help us fight against infections and cancer and everything else. Now, these all arise from basically hematopoietic stem cells, and they can then give rise to either lymphoid cells, which I'm referring to as like the white blood cells, or myeloid cells. Now, when these lymphoid cells are immature, they are called BLAST cells. And when these blast cells give rise to or become cancerous, they can give rise to leukemia. However, once they differentiate, they can differentiate into T cells or B cells. T cells are the cells that help us fight directly against infection. You might have heard of CD4, CD8 T cells, and B cells are the ones that eventually give rise to plasma cells. And these plasma cells then help us make antibodies which again help us to fight against infections and parasites, etc. As I mentioned, when these blast cells give rise to or become cancerous, they can give rise to leukemia. And that leukemia can be called lymphocytic leukemia or myeloid leukemia based on which progenitor it gave rise to. Whereas when lymphocytes become cancerous, these give rise to lymphomas. So when the B cell becomes cancerous it gives rise to non Hodgkin's lymphoma. Or when T cells become cancerous, it can give rise to T cell lymphoma. And the one characteristic of lymphomas is that they do not give rise to malignant cells in your blood, whereas leukemias are notorious for being found in the peripheral blood. Now I'll jump into the classification of lymphoma. So there are a lot of lymphomas. In the previous slide I gave an overview of T cell lymphomas and B cell lymphomas. When we jump into their classification further, either genotypically or morphologically, they can be divided into multiple types. Don't worry, I will not walk you through this entire table. Just to give you an overview. As I mentioned, there are T cell and NK cell lymphomas and B cell lymphomas. Now B cell and both of these lymphomas can either be slow growing and in that case they are called indolent lymphomas or if they are fast growing they are called aggressive lymphomas. So among the aggressive class, the most common one is called diffuse large B cell lymphoma and that constitutes 31% of the B cell lymphoma population. Now jumping into DLBCL and I will just call it DLBCL for short. This is what it looks like. This as I mentioned is the most common non Hodgkin's lymphoma and making up 30 to 58% of NHL. It is characterized by masses of large B cells as shown in the figure over there. This is named after its wide diffuse pattern of growth. That's where the diffuse comes from. This one, as I showed before is actually a fast growing or aggressive lymphoma. This can be characterized into multiple different characteristics based on what method you're using if you are genotyping them. So molecular classification will be either ABC or gcb. If you can also classify it based on the clinical location. For example, is it found in the brain? So then it's CNS lymphoma or mediastinal etc. Cytogenetic. Again based on what rearrangements have occurred genetically and also it can be classified morphologically. The median survival for DLBCL is weeks to months if this is not treated. Because as I mentioned, this is a fast growing lymphoma so it can be quite aggressive and deadly. Now I will jump to the treatment landscape. So before I jump into this slide, just giving you an overview of treatment in general for any cancer. The first time it is discovered and treated, you would call it first line treatment. However, as you might might have heard from many patients, relatives, et cetera, is that the cancer can initially respond to treatment, go away and then come back. So that is called relapsed and sometimes it doesn't even respond to treatment and that is when it is called refractory. So this slide is talking about the first time you actually treat lymphoma. Next I will jump into the next slide when it is either relapsed, that it is, that means when it goes away and then comes back, or refractory that it did not respond to the initial treatment. Both of these, either frontline or relapsed refractory are treated differently in the frontline treatment. The most common way, and that's why it's called the standard of care is R CHOP and it stands for these chemicals. One of them is a biologic. So this is an antibody, again CD20 as shown in the figure over here. And this is just showing that this antibody, rituximab binds to the CD20 receptor on a B cell and can be killed by multiple mechanisms. The rest of them that I'm calling chop CHOP stand for different kill chemicals. And these are drugs and they attack the cancer cells in different methods. For example, hydroxydonomycin actually inhibits DNA synthesis. Oncovin is an antimitotic agent. And so this is a chemotherapy that has been present for a very long time. R chop, the combination of rituximab with chop was, was approved 20 years back. This is with Frontline. Now I will explain how a patient might be relapsed or refractory and why there is more of a need, unmet need in the relapsed refractory space compared to the frontline space. As I mentioned, when a patient first gets lymphoma, it would basically be treated first with R chop. Pretty much wherever you are, whichever country, this has now become the standard of care. So 80 to 85% of the patients will respond to this therapy. And that's why I'm calling it either complete response or partial response. However, some of them will eventually progress. Out of these 80%, 20 to 25% will then not respond or the cancer will come back. And that's what I'm calling relapse refractory. Out of the responders, only about like 60% of the patients are cured. However, the non responders, There are some 10 to 15 that don't respond and another 20 to 25% from the responders that then become, that are relapsed or refractory. And so total around 40% of the lymphoma patients would be relapsed refractory. And here the median survival without treatment is only three to four months. So that is very, very aggressive and we definitely need them to be treated. The standard of care for treatment for this relapsed refractory population is to get transplants, and that is hematopoietic stem cell transplants from either other patients or, or mostly other patients, actually. So if these patients are eligible, they can get transplant, but a lot of them turn out not to be eligible because of other comorbidities, etc. In order to get transplant, then what you need is to get salvage treatment, which basically will reduce the bulk of the tumor so that it's smaller and so that the stem cells, the hematopoietic stem cells from another patient or a healthy person can actually engraft into the bone marrow and take over and actually help you fight the cancer. However, this treatment itself sometimes doesn't work, so another 10% of the patients are then not able to get therapy. And then from the patients who actually do respond to salvage therapy and are able to get transplant, they eventually progress. Overall, once you have relapsed refractory disease, only about 5% of the patients can actually be cured. The rest just go on to get second line, third line, fourth line. And with each line of therapy, the cancer becomes more and more aggressive and your overall survival decreases. I've seen patients who as soon as they get or they can't even get to the first treatment because while you're doing all the blood tests and just eligibility to get on clinical trials, meanwhile the patient has already progressed and stays eligible for the clinical trial. There is a huge unmet need for the relapsedrefactory population. Thankfully, lot of research has been going on and a lot of novel therapeutic agents have been developed recently. These include antibodies. This is an antibody drug, conjugate, another antibody, and bispecific antibodies, also small molecules which block specific pathways like the BTK pathway or the pi3 kinase or block BCL2 and this basically blocks this leads to apoptosis. I won't go into detail for all of them. Just wanted to show you that some of these newer therapies have been approved and have been added to the guidelines for treatment. So I have highlighted the newer therapies in red here or as I showed in the previous slide, this is ADC which is an antibody drug conjugate. So that's an antibody which is basically conjugated to a drug that blocks mitosis. This has been approved at the first line therapy. It has also been approved as a bridging therapy. Then to bring your attention to the main topic for this presentation is CAR T cell therapy. And these have now been approved as second line therapies. These are really, really strong because as I mentioned, only 5% of second line patients are actually cured. But by car T is 20% of them can be cured. So that is a four times improvement over other chemotherapies. So I will jump into CAR T cells now. These have been like a buzzword for a very long time now, for the last at least 10 years or more. Just wanted to give you a brief introduction in case you don't have not heard of what or don't know exactly what they are. So it's a cell therapy but it basically is super efficient because it, even though it is relying on our own immune system, it is bypassing all the slow steps of the immune system and the immune system activation and can immediately lead to strong responses. So in general this is our normal immune response. We where this is the cancer cell and this is your T cell here. And basically any epitope from the cancer cell has to be processed internally and then presented by our MHC molecules to the T cell receptor on the T cell. Then there are several co stimulatory molecules also needed on the side and this whole big complex needs to be assembled in order to activate the T cells. This takes a long time and takes meanwhile the cancer cells are still growing and there are other pathways by which they can also be inhibited. And the CAR T cells basically completely bypasses this because there is no need for the epitope to actually be processed by the MHC system. What they have done is basically generate antibodies against the epitope and just use that antibody binding part, put it here, have a hinge and then have the signaling domain from the T cell receptor here. So this whole system, you don't need for it to get activated as soon as this T cell binds to the epitope, it will immediately get activated and will not need all of these steps of assembly and CO stimulation. That's the simplest form that was the first generation. The second generation and third generation basically have added more CO stimulatory molecules, which makes the activation even stronger. And they have shown basically vigorous T cell activation as well as powerful responses. What is happening then is that you can either get T cells from the patient itself or, and in this case it will be called autologous T cells, or you can get it from a donor in which it will be called allogenic T cells. You take, wipe cells from these patients, flow, sort them to get the T cells, stimulate them with different cytokines, and then use gene therapy basically to input that whole CAR T construct that I showed you in the previous slide. And once these T cells have the construct integrated inside you, expand the T cells and do some QC and put it back into the patient. And now these activated T cells, which are already in high numbers, like you're basically injecting millions of them into the patient, can now go and attack the cancer cells and mediate response. The treatment is basically similar across whether you are using the CAR T cells for multiple myeloma or lymphoma or whatever. What you do is basically have the leukopheresis, as I mentioned, that's taking out all the cells from the patient from their blood, have some bridging chemotherapy. And the goal here is to basically debug the tumor or to slow it down. Then there is a conditioning chemotherapy step. And here you basically think of it as emptying out the bone marrow of a patient. That's where the hematopoietic stem cells reside. And so basically you're making space for the CAR T cel cells to go and engraft and expand further. And then you, after that you can infuse your CAR T cell product. And this is a single infusion, so a single treatment, one time treatment that can then basically cure the patient. As you can imagine, this is such a strong therapy as compared to 8 or 10 cycles of chemotherapy over and over every few months, that or month that you're going into the clinic, repeated visits and all the side effects that happen with chemotherapy. So if you could bypass all of that and basically get cured with one treatment, that is why, you know, there's such a buzz around it and everybody wants it. So many CAR T cell therapies have been approved by fda and this one gives a list. And so as you can see, Some of them are against multiple myeloma, but a bunch of them are against lymphoma. And you can see all of these are targeted against CD19, which is a receptor on B cells. That is why I chose this to take a deep dive. But you can basically take the learnings from here and apply them to most car T cell therapies. As I mentioned, these are the advantages. It's a single treatment. It elicits a powerful anti tumor response. As this slide shows 60% reduction in risk of lymphoma progression, death or need for new therapy. Also in addition, you see very long response remission time. As I mentioned, 20% are cured in second line therapy. In addition, you can also get T cell memory, which means that if the cancer ever comes back, you don't have to reinfuse the cells. There are memory T cells that stay in the patient and they will just get activated and elicit a second response in the patient. Obviously right now as you can see has mostly been used for lymphomas and multiple myelomas, so cancer. But right now there are also many companies are developing it for other diseases which have been treatment resistance, for example hiv, fibrosis, autoimmune. There is newer paper showing that tissue resident B cells can also be targeted and that is an advantage that B cell targeting therapies like biologics, antibodies, etc don't have. Because T cells can do this while others can't. Yeah, and I will jump into DLBCL that I've already talked. That is a high unmet need in second line dlbcl. However, this also comes with challenges and these include the cost. So for example, Kimraya was only $475,000. I don't have that kind of money in my bank. I don't know how many. This definitely is a big hurdle and that's where lots of policy comes into play. Whether insurance companies will cover it or not, et cetera, which geographic location you're at. So availability is also a huge thing. Another problem is the complex logistics because as I showed in the previous slide, basically when you're doing autologous T cell therapy, we're taking cells out of your own body and then expanding them, genetically manipulating them. All of this can take four weeks. Meanwhile the patient can still progress get worse and you want to minimize the amount of time that is needed. But think of all the shipping that's required and then making sure that the cells stay alive and are kept at the right temperature. And you're basically shipping them all across and bringing them back to the patient. So it is quite complex also access. So you can't just go to your primary care to get this, you have to go to big institutions like UCSF which have access to this, where the PIs are trained in dealing with it, how to get it all set up and also to treat the toxicity that comes with CAR T's and all the bridging therapy and salvage therapy that I talked about before, because these are very, very strong therapies that are added on before. And also some patients just get excluded even before infusion, so they might not be eligible. Or as I mentioned, you might have disease progression even before you can get the therapy or they might, you might not even be able to collect enough T cells in order to generate more, or there might be a manufacturing failure, etc. So it's definitely very high intensive therapy, but also very high reward. So in addition, there are also some safety events that are associated with CAR T therapy which we don't see with other therapies. I shouldn't say that because bispecifics also have some of them, but they do add on another consideration to your choice of therapy. So what happens here is basically as I said, the car Ts or bispecifics basically activate the T cells and they can activate all of the T cells or all the T cells that have been injected. So as I said, we are injecting 1 million T cells and they all get activated all at the same time. And they can lead to so many pro inflammatory cytokines released all at the same time. And this big onslaught basically can then lead to activation of other cel, can secrete more cytokines and this whole thing basically acts as a vicious cycle and everything gets activated. So that is cytokine release syndrome. And this can be at higher grades, can be very, very hard to manage and can also lead to death. So this needs to be managed very very well. And in addition another one is called ican, so it's stands for immune effector cell associated neurotoxicity syndrome. And here it's a similar thing except that the cytokines then penetrate the blood brain barrier and enter the brain and can lead to encephalopathy, aphasia, delirium, et cetera. So however, these are now expected to happen. And so that timing has gone been studied so well that basically institutions can regulate that, hey, you need to be hospitalized from day two to day three because all of this will happen. And they can monitor the patient very, very well and can manage it pretty well. So basically it has not been an issue in clinical trials because as I mentioned they have led to approvals and has been done pretty well. And so as knowledge spreads people know how to treat, it can actually expand to more as well. So all right, I will now jump into specifically the CD19 car T products because as I mentioned those were the majority of the ones that have been approved by fda. So I will give you these are the main ones. One is Escarta and I'll be talking more about this this. So all of these are directed against CD 19 and they just happen to have differences between the actual epitope on CD 19 as well as the COSTA minatory domains that have been added on the CAR T design. And so this one, yes, Carta is by Kite and Gilead. Brianzi called Lysocell is from BMS and Kypria is from Novartis. And I will jump into specific studies for two of them. So I will start first with the Escarta. This is the construct basically against anti cd20 cd19 and they also had two co stimulatory domains for cd28 which formed the hinge domain and the signaling domain was CD38. So they used large B cell lymphoma patients, 359 patients and they were randomized. One is to to the AXI cell therapy or the standard of care. The standard of care here was basically platinum based therapy from these patients who received standard of care. Either if they showed response to the therapy, they were called responders and they proceeded to get your hematopoietic stem cell transplant which is also the standard of care. However if they did not respond to this therapy they actually went off. Several of them ended up getting some either Axisl itself or some other CD19 car T product. Then tumor was assessed after three cycles here or also after day 100, day 150 and later assessments. The primary endpoint was EFS and key secondary endpoints were ORR and OS and PFS etc. This showed great response. As I was saying, basically it improved ORR EFS overall survival as well as progression free survival. This graph on the left shows event free survival. As you can see here, the axis cell arm basically had a median EFS of 8.3 compared to 2 in the standard of care arm. That again is a four times improvement over the standard of care. This was published in 2022. In addition this graph shows the overall survival. The red colored line is basically the standard of care and as you can see the median overall survival in this arm was 31 months, whereas for the blue, which is the AXI cell arm, it has not been reached. One other thing I wanted to point out that in previous historical studies with the same standard of care, the overall survival has actually been 10 months, not 31 months. So this has already. This is longer, mostly because about 57% of that arm that the patients in that arm went on to receive cellular immunotherapy. Anyway. The fact that half of them, even half of them received cellular therapy and reached that increased the OS from 10 months to 31 months. And this arm, where 100% of them received it is already beyond 60 months, just shows how much of an improvement it would be. Because even if you just assume that overall survival becomes 60, which it's clearly not at this stage compared to 10 months in the standard of care, that is already improved by several years, which really shows the durability of response and how good it is. However, as I mentioned, it does come with several side effects and I already mentioned cytokine release syndrome and icans and you can see that they predominantly occur in the access cell arm and not in the standard of care arm. But they could be managed pretty well because you can see only a low percentage actually reach grade three, whereas most of them were low grade, low grade one or grade two. The other thing to point out is progressive disease in the axis cell arm, only 30% of the patients then went on to progress, whereas 42% went on to progress in the standard of care arm. So overall, based on the efficacy and safety data, this CAR T was basically approved by FDA in second line treatment. And again, to give you another example, this is a second CD19 product called LysoCell and this is the transform study. And similar to the other study, basically you had randomization into two arms. In this study though, basically patients received two or three cycles of chemotherapy and instead of then going on to getting autologous stem cell transplant, they directly went on to this arm if they if they progressed. So here more number of patients basically ended up getting Lysocell. And if the patients did respond to two or three cycles of chemotherapy, which means they had a complete response or partial response, they went on to then get stem cell transplant. Here the primary endpoint was EFS and the secondary endpoints were cr, PFS and os. Again you can see a huge improvement between the standard of care, which is your stem cell transplants are 2.3 months versus 10 months and PFS was 5.7 months versus 14.8 months. So this is like almost five times and this is almost three times. So yeah, overall both of these showed great results and have been approved by fda. And this also led to basically changes in the guidelines for treatment. So if you remember, the guidelines previously said if you are second line patients, you have to get your salvage therapy and then autologous stem cell transplant. But now they're saying basically they've updated it to see if your second line therapy is occurring in less than one year and you're eligible to get CAR ts. Just go ahead and get CAR ts. It's only if your second line. So your progress, you progress more than one year after the first line therapy and you're eligible for stem cell transplant. Only then do you, you go ahead and get stem cell transplant. But if you're eligible for Car TS, you should go ahead and get Car Ts. And again to point out that the projected cure is 20% versus 5%. And just to go on CAR T therapies are still quite new and we are still finding new adverse events and still figuring out really what is going on. But so many patients are being treated that we actually have high enough numbers to make decisions. So this for example, this is a paper that just came out in July of 20, so now this month basically in Nature Medicine and they did a meta analysis of patients who received CAR T cells. And basically what I wanted to point out here is that they said patients who basically died from icans or CRS represented only a minority of the non relapse deaths Deaths, so only 11.5. What they believe is a bigger problem is basically death from, from infections. So they basically did this whole analysis from 7,604 patients across 18 clinical trials and 28 real world studies and basically looked into the patients who were dying from not progression, so all other causes of death other than progression. And they showed basically that 50% of them were basically attributed to infections. So as you can imagine, T cells piping out your B cells. So B cells are the ones that then generate antibodies and are key to basically fighting infections. So again those patients should then be treated very carefully and make sure that they can't get infections or reduce the risk of catching infections or the would be very hard to do during like a COVID pandemic. Right. Because again infection or any other infection that's going on, maybe you could time it so that you don't get it during flu season, etc. So just needs to be looked into more carefully as we get more and more data. Another significant publication that happened and this one actually happened earlier this, this year is when FDA required, basically they found again, out of 34,000 patients treated with CAR TS there were 19 cases that developed a secondary malignancy. So basically they develop leukemia or lymphoma. And again, you can think, because you're basically taking your T cells, genetically manipulating them and putting them back into your body, they can actually start proliferating and become cancerous. So that's always a possibility. And they found that, yes, looking at the numbers, it is a 5% possibility. And so now they have added that to the label for cancers. For sure, you're already at especially aggressive cancers where you believe it's a life and death situation. These are, are something that you know, these possibilities you will jump over or it's a risk that you're willing to take. However, CAR T cells are now being looked at in autoimmune diseases, fibrosis, a bunch of other indications where it is not a life and death situation. So there you have to be very careful about whether should we take this or not. So just food for thought. And that's where I wanted to end. And here I'm happy to take any questions.

So are there any, I guess, biomarkers that are being explored to be like sort of predictors for the patient success or responsiveness to any cartel treatments?

Definitely they are collecting. So firstly, none of these trials were held at the company I used to work at, Genentech, So this is all public data that I'm presenting. I do know that from those trials biopsies were collected from patients and they're doing some exploratory analysis. None of the, as far as I'm aware, biomarker data has not been published or they might be out there, but I haven't looked at it deeply. Definitely that is something patient they're investigating because as I mentioned, it's not just CAR T's. Bispecifics are another modality that has come out and is showing an equally durable response. And they have the advantage over Car Ts is that they can. It's almost like any IV drug that can be given like any other antibody. So you don't need to go to specialized centers. They do have the side effects of CRS as well. So that does need to be managed. So you do need to go to centers who know how to handle those adverse events. However, they skip the whole manufacturing and collection and reinfusion step because it's basically can be abundantly available. You're generating, making a monoclonal antibody almost right. There is a Lot of debate in the community right now of whether to use bispecifics or car Ts or use bispecifics first and then use car Ts or use car Ts first and then use bispecifics. So. So I'm sure more biomarker data is definitely being investigated to figure this question out. I just am not aware of it. This might be a little outside the scope of this, but what are the unique regulatory considerations that you guys have.

To keep in mind for CAR T cell approval?

Good question. To repeat the question, what are the regulatory considerations that need to be taken into account for CAR T cells? The I don't have it right now, but basically FDA has come out with a separate set of guidelines for CAR ts themselves and they're available on FDA website itself. And a lot of it, you know, is deals with manufacturing ability to manage the adverse events, a lot of other things. It's very, very detailed and consistency, of course, especially since the starting material is different because they're getting it separately for each patient.

So any cardio or neurotoxicity associated with this treatment?

Good question. The question is any cardiotoxicity or neurotoxicity associated with Car Ts? Yes. So ICANS, the one I talked about before is neurotoxicity. So that is an established adverse event with CAR T cells, immune effector cell associated neurotoxicity syndrome. So as I mentioned, basically the CAR T start attacking the tumor cells and that leads to release of several cytokines and activation of myeloid cells. These cytokines can then penetrate, go through the blood brain barrier and activate CAR T cells and myeloid cells and monocytes that are already resident in the brain. And this can lead to encephalopathies and tremors, seizures, delirium, et cetera. Cardiotoxicity, I don't believe I've seen that might be at a very low percentage, but I have seen overall the most common adverse events. And cardiotoxicity isn't one of those. Nephro A little bit, yes. If. Especially since they can start dying so very fast and the elimination can become a problem. But also I believe it was low grade, but don't quote me on that. I. I'll have to look up the data to be sure.

Any study has done in combination with this CAR T cell with antioxidant or something to reduce this neurotoxicity, right?

Yes. So management does include prophylaxis and so prophylaxis is basically some drugs that you can give ahead of time. So like either some cytokines. For example, for neutropenia, you can give colony stimulating factor before you give your treatment, and that is called prophylaxis, because basically the growth colony stimulating factor basically will increase the number of neutrophils, knowing that the treatment will lead to neutropenia. So similar to that, there is prophylaxis for cytokine release syndrome and icans, since, you know, sort of exactly the timing of when CRS and ICANS will happen. Patients are typically admitted in the hospital at that time. They're all being monitored, and as soon as the very first symptoms start occurring, they start treating them right away. And then generally, steroids, interleukin antibodies, and JAK inhibitors are definitely getting given for this. Thank you so much. Thanks for the opportunity to present. Really appreciate it.