CAR T-cell Therapy for Patients with Lymphoma: Who Benefits?

Transcript of Presentation:

(00:00): Michala O'Brien: Introduction. Welcome to the workshop, CAR T-cell Therapy for Patients with Lymphoma: Who Benefits. My name is Michala O'Brien, and I will be your moderator for this workshop.

(00:12): Before we begin, I'd like to thank Kite, a Gilead company, and Bristol-Myers Squibb, whose support help make this workshop possible.

(00:19): It's my pleasure to introduce today's speaker, Dr. Jay Spiegel. Dr. Spiegel is an assistant professor at the Miami Miller School of Medicine and a hematologist in the Transplant and Cellular Therapy division of the University of Miami Sylvester Comprehensive Cancer Center in Miami, Florida. He is a translational researcher working to improve Chimeric Antigen Receptor T-cell (CAR T) outcomes for B-cell malignancies such as lymphoma. He led first in human clinical trials of novel CAR T-cell therapies and investigator-initiated trials testing CAR T in combination with targeted therapies. Please join me in welcoming Dr. Spiegel.

(01:05): Dr. Jay Spiegel: Overview of Talk. Thank you for that kind introduction. I'm very happy to talk today about CAR T-cell therapy for patients with lymphoma and who benefits.

(01:17): We'll first start with an introduction to lymphoma. I'd like to take kind of a 30,000-foot view, and then hone in. We'll talk about the science of CAR T-cell therapy. Then will talk about the CAR journey, both logistical and then the patient experience.

(01:33): The immune system consists of numerous types of cells that ideally protect us from disease. This is a graphic of how your blood system is made, and I think it's most relevant to patients when they're getting a complete blood count. So, what are really the main things we look at when patients get a CBC?

(01:48): First, the red blood cells, they provide oxygen to your tissues, give you energy. Your platelets, which clot your blood, prevent you from bleeding, and then the rest are really your white blood cells.

(01:59): And on the left here, we have your myeloid cells, the main ones being the neutrophils. They are the most numerous white blood cell, and they're very important for preventing bacterial infection.

(02:12): For those of you who have undergone any sort of chemotherapy, you may have received the growth factor, filgrastim. You might know it by brand names like Neulasta. And they're given during chemotherapy to boost your neutrophils to prevent any bacterial infections during therapy.

(02:30): Now, on the right side here, is your adaptive immune system, made up of the lymphoid cells, primarily the B-cells, which produce antibodies to prevent infection. So, if you get a vaccine, like the tetanus vaccine, the antibodies will be made by B-cells.

(02:46): T-cells are crucial to preventing or eliminating cancer in the body. And then you have your T-cells, which fight viruses but also work to prevent cancer. We'll come back to how this is leveraged in CAR T-cell therapy, but it's important to know that T-cells are what prevent everybody from having cancer. So, the reason why people might be walking around cancer-free is that their T-cells are going around surveilling all the cells in their body and eliminating cells that might turn into a problem.

(03:07): Now, if we talk about what lymphoma is, a lymphoma is a cancer of these lymphoid cells. And you can break lymphoma down in different categories, Hodgkin lymphoma versus non-Hodgkin lymphoma, T-cell lymphoma versus B-cell lymphoma, and for the purposes of what CAR T is approved for, those are all non-Hodgkin B-cell lymphomas at the moment.

(03:30): You can further subdivide these into either aggressive or indolent lymphomas. Aggressive lymphomas grow fast, can be life-threatening, but are curable in a proportion of patients, the primary example being diffuse large B-cell lymphoma.

(03:45): The indolent cancers are slow growing. You don't usually have to treat them right away, you can wait until there's some concern for organ compromise or the like, but they are generally thought of as incurable, so treatment is something like whack-a-mole. You'll wait, treat the disease, have a period of remission, then the disease will come back again and eventually necessitate treatment. And the most common indolent lymphoma is follicular lymphoma.

(04:10): It's important to note that indolent lymphomas can transform into aggressive lymphomas at a rate of about 1% per year, which is a cumulative risk. So if you have indolent lymphoma for 20 years, you're obviously at increased risk for transformation over time.

(04:26): And the one cancer that I also didn't mention in the lymphoma categories is Mantle cell lymphoma, which sort of straddles these two categories. It has features of both aggressive and indolent lymphomas, is generally considered incurable, but can certainly act very aggressively and require urgent treatment.

(04:41): Now, there are a fair bit of new treatments that have been approved for B-cell cancers in the recent years, and they, in large part, are leveraging the markers that are on the B-cell itself. You can see here, CD19, CD20, and CD79-B are three B-cell surface markers that have been targeted by approved therapies for lymphomas.

(05:08): Drugs to treat B-cell lymphoma include antibodies, antibody drug conjugates, and bispecific antibodies. On the left, you can see there are different drugs in these categories. First, we have the antibodies, which are the oldest in this sort of targeted therapies, with rituximab (Rituxan) being approved in the early 1990s. Essentially, an antibody labels the cancer for the immune system to come and clear it.

(05:26): Next, we have your antibody drug conjugates, which in theory, provide targeted drug delivery. So the chemotherapy is supposed to be targeted just to the cancer. Polatuzumab (Polivy) targets CD79-B, and Loncastuximab (Zylonta) targets CD19.

(05:41): And then the last of these is the bispecific antibodies, which are essentially two antibody arms stuck together, bringing the cancer and the T-calls close to each other to allow the T-cells to do their work. The examples that I listed here, Glofitamab (Columvi), Epcoritamab (Epkinly), and Mosunetuzumab (Lunsumio). I saw somebody on Twitter describe this as a Tinder for the immune system, just to give you a sense of how you might think of bi-specific antibodies.

(06:08): CAR T therapy removes T-cells, modifies them to fight cancer, and returns them to the body. But a CAR T sort of operates, I'd say, maybe a step above that, in terms of the science behind it, in that it takes a T-cell and actually modifies it to be able to kill cancer. So we talked a little bit about how a normal T-cell interacts with a tumor in a very restricted fashion to identify it and clear it, and evasion of this mechanism is one of the hallmarks of cancer formation. This is very tightly regulated because if you have unregulated T-cells in your body, you might get something like autoimmune disease, for example. So what a CAR T does is, it says "Let's just put a protein into the T-cell that will allow us to interact with the tumor without this restriction."

(06:47): CAR T has the additional benefit of being living cells, so they grow after you put them in the body. They localize to the tumor and carry out tumor killing, and then they can persist in the body to provide ongoing immune surveillance to prevent relapse.

(07:01): Now, why is it called a chimeric antigen receptor? On the right is the figure from Greek mythology. A chimera is an animal with three different animal heads. So sort of like that, a CAR has different fragments from different parts of the immune system. The targeting fragment on the outside of the CAR, outside of the cell, is a B-cell fragment that can bind to the target. And then on the inside are parts of the T-cell machinery, one being the co-stimulatory domain, or the CAR ‘motor,’ which we'll talk about in a bit. And then also the CD3-zeta part of the T-cell receptor, which functions as the kill switch after the CAR has engaged with the tumor.

(07:44): This is a nice diagram of the mechanism of action of CAR T-cells. So first, viral DNA is inserted into the T-cell, which can then lead to expression of the CAR on the T-cell surface. After infusion into the body, the T-cell will then be able to find the tumor via the CAR. After that, the CAR will multiply and release cytokines, which we'll come back to later. And through this process, be able to kill the tumor.

(08:15): CAR T cell products have been approved for several types of lymphoma. Now, this is a graphic of the U.S. approvals for CAR T-cell therapy in diffuse large B-cell lymphoma, starting in late 2017, and going up to now, into 2024, where we have multiple approval approvals in DLBCL, mantle cell lymphoma, and follicular lymphoma as well, and most recently, the first approval in CLL, with Liso-cel.

(08:37): This is a list of the approved CARs in B-cell lymphoma. They're Axi-cel, also called Yescarta, Liso-cel, or Breyanzi, Tiso-sel, or Kymriah. You can see they all target the same target, CD19. And where they differ is really in their co-stimulatory molecules. So Axi-cel uses CD28, this leads to fast CAR expansion but peters out. In less politically turbulent times, we refer to this as a Tesla, but now I think you probably have to pick a different fast CAR of your choice. And on the right, we have Liso-cel and Tiso-sel, which have a 41BB, which is a slower onset with longer persistence, which we can sometimes refer to as the Prius.

(09:23): You can see that Axi-cel and Liso-cel share similar approvals in all three lymphomas that we talked about, whereas Kymriah, at the moment, is primarily used in follicular lymphoma, really not as much in DLBCL.

(09:38): So the next question is, when might I actually be eligible for a CAR? The answer is, follow the road map, which can be a little bit complicated, so we'll walk through it.

(09:48): Standard treatment for diffuse large B-cell lymphoma is chemotherapy. Starting with diffuse large B-cell lymphoma, if you look at the top, patients get first-line chemotherapy, which is either R-CHOP, R-EPOCH, or Pola-R-CHP, and then about 60% of people are cured of their DLBCL.

(10:03): But for the other 40%, the disease either never goes away, which is called refractory disease, or the patient will ultimately have a relapse of the disease, meaning the disease went away and then came back.

(10:15):  If the disease is refractory or relapses within one year, patients are eligible for CAR T. This has been shown in two phase three clinical trials, so really the best evidence that we can have to suggest use of the therapy. These trials suggest that CAR T is superior, so that is really the main way that patients will get CAR T in DLBCL.

(10:38): If you relapse after one year, it's a little bit murkier. If you're what we call transplant-eligible you may be eligible for an autologous stem cell transplant, which used to be the hallmark of therapy for second-line DLBCL for about 30 years. If you are eligible for that, you could receive chemotherapy, and then depending on your response to chemotherapy, either get the transplant, or if the disease did not respond to chemotherapy, go to CAR T-cell in the third line.

(11:04): And then patients, who are what we call transplant-ineligible. may be able to receive CAR T-cells, Liso-cel in this case, as the second line of therapy.

(11:18): For follicular and mantle cell lymphoma, CAR T cell therapy may be an option after other treatments have been tried. Looking at follicular and mantle cell lymphoma, starting on the right with mantle cell lymphoma, these paradigms are pretty fast-moving as more and more drugs are approved in earlier lines of therapy. But at the moment, patients who are not on study for mantle cell lymphoma will receive chemoimmunotherapy in the first line, plus or minus a BTK inhibitor. So you might get chemo, you might also get an oral pill, called the BTK inhibitor.

(11:51): And just to clarify, it used to be that we would give an autologous stem cell transplant to eligible patients in the first-line for consolidation of Mantle cell lymphoma. That we do not do anymore based on the Triangle study, which is a recent publication. So patients will not get an autologous transplant, but they'll get chemo plus or minus a BTK inhibitor.

(12:14):  If you do get a BTK inhibitor as the first line, and then ultimately the mantle cell lymphoma grows again, you would then be eligible for CAR T-cell therapy, If you had never received a BTK inhibitor, you could receive a BTK inhibitor in second-line and then CAR T in third-line. So, a little bit complicated, a lot of moving parts, but basically, patients who are BTK-exposed and then have progression of mantle cell lymphoma would be eligible for CAR T.

(12:43): In follicular lymphoma, CAR, at the moment, is pretty solidly placed in the third-line. So patients would receive two prior lines of therapy before being eligible for CAR T. But I would also mention that for follicular lymphoma, we have many effective drugs, and the decision to go for CAR T versus a different therapy, I think, comes down a lot to patient choice. Do you want, perhaps, a one-time treatment and then have a treatment-free interval, or have more consistent treatment? Do you want to be in the hospital or not? Many factors go into why someone might choose a CAR over a different therapy in the third-line for follicular lymphoma, but there are many options at that time.

(13:29): CAR T therapy involves a three step approach: removing T cells, modifying them, and returning them to the body. Switching a little bit to the logistics of CAR T, and this diagram, I think of CAR T logistics as a three-step approach. One, we have to take the T-cells out of the patient. They are circulating around in your blood, so we have to get them from your veins. What we do, is we put the patient on the machine that looks like a dialysis machine. Blood can be taken out of one arm, cycled through the machine, the T-cells are taken off, and then the rest of your blood is given back to you through the other arm.

(13:58): Sometimes the patients are not able to have this procedure through the peripheral veins, they may require a central line placed into a vein in the neck or in the groin. This is a one-day outpatient procedure. There really aren't many limitations after this procedure.

(14:14): And then the cells are sent to the company for manufacturing, which at the moment, takes about three to four weeks. During that time, you may require what we call bridging chemotherapy for disease control. It really depends on the decision with you and your doctor about whether the disease is stable, or whether you need some extra therapy.

(14:33): Then when the cells are ready, you will come back for first, three days of outpatient chemotherapy with fludarabine and cyclophosphamide. And then the patient could be admitted to the hospital for their CAR T infusion, but that really depends on which particular site you're getting your CAR T at. Some centers will let the patient start outpatient, and then admit, were there to be any toxicities, which we'll talk about in just a minute. But three days of outpatient chemo, then the cells will be administered on day zero, and then a 28-day monitoring period.

(15:12): You can see on the slide, that I've made two lines or graphs here. That is to show the differences in CAR T expansion. You can see the Axi-cel-like CARs have a much higher peak and peak earlier, whereas the Liso-cel-like have kind of a slower and steadier onset, but perhaps stays around longer than the Axi-cel-like CARs.

(15:36): Now, what are the main early toxicities of CAR T? One is cytokine release syndrome. So, if you remember from that graphic, once the CAR T interacts with the tumor, they will release these cytokines. Think of them sort of as hormones. They're not, but they function in many ways, the same way.  I liken it to when patients have the flu. If you have the flu and you feel really bad, it's actually not the virus itself that's making you feel that way, but rather, after the T-cells interact with the flu, they're ramping up to get rid of it, and those chemicals that they release, those are the things that make you feel bad.

(16:13): So CRS is really that sort of experience, just more so. You might experience what we call the worst flu of your life. There are two primary effects: one is fever, the other is low blood pressure. Sometimes patients can also experience low oxygen levels in the blood. Most patients will experience a fever. So predominantly, patients do get CRS. But what's really important is that our treatment of this has gotten much, much better. And the rate of severe CRS, where there are more complications requiring admission to ICU, for example, has become very low, and is below 5%.

(16:48): Another side effect of CAR T therapy is neurologic toxicity which can be graded in terms of its severity. The second early toxicity that I think may concern people more is neurologic toxicity. And I've tried to simplify the grading scheme here, on the left. The grade one is just confusion. So we ask patients 10 basic questions when they're in the hospital to ascertain whether they may be developing neurotoxicity. And so when patients are becoming confused, they may miss one or two of these questions, like what hospital they're in.

(17:14): Grade two, we can see that the patients experience word finding difficulties, so we ask them to say their name. They're not able to say their name. This is not a stroke, though it might look like one if you think about patients not being able to talk as a symptom of that. With CAR T, it's very much just an attention issue. The cytokines that we talked about can go to the brain and make it difficult to focus.

(17:38): Grade three, so more severe toxicity. A patient can be hard to arouse. They may experience a seizure, or what I like to call ‘lights on nobody home.’ The patient is awake and alert but not able to track or really interact with the outside world.

(17:53): And grade four can be either coma or brain swelling. Now, the brain swelling, obviously a very feared complication. I would also say it happens extremely rarely.

(18:04): Other things to know about neurotoxicity, the onset is after cytokine release syndrome. I'll show you a graphic of that shortly.

(18:10): Most neurotoxicity after CAR T therapy is short-lived. The way that we think about it is that it is typically short-lived. When it comes on, it may last about three or four days and then subside. Classically, we talk about it as a very, very quick recovery. We do not think of this as a permanent situation in the overwhelming majority of patients, but I would say that in patients who are older, or those who have mild cognitive impairment in the pre-CAR setting, they may have a more prolonged recovery. But I would say on the whole, almost every patient does have a complete recovery.

(18:42): Different CAR T products have different rates and timing of side effects. Now, the rates of cytokine release syndrome and neurotoxicity are where we really see differences between the two types of CARs. So those CARs with that CD28 CAR motor have a little bit higher CRS, so 90% versus 75%. Again, the rates of severe CRS are very low for both types of products.

(19:02): Where they really differ is with the neurotoxicity. So with CD28 CARs, it's about 50 to 60% versus 10 to 30% with the 41BB CARs. The rate of severe neurotoxicity is higher, about 25% versus five to 10%. There are numerous trials ongoing that examine various strategies to mitigate neurotoxicity in CD28 CARs, with varying degrees of success.

(19:32): The onset of CRS tends to occur between day two and day five, and the neurologic toxicity tends to occur after that, somewhere between day six and day 10.

(19:48): At my institution, patients are admitted to the hospital on day zero, and if they develop CRS and then neurotoxicity, they might stay admitted for about two weeks. If you're at an outpatient facility getting CAR, you might be admitted with your onset of CRS, you may be able to stay out of the hospital for two to three days after infusion, then be admitted, then released after resolution of the neurologic toxicity.

(20:22): Patients may have a partial or a complete response to CAR T therapy. Turning to how we think about how a CAR works, we want to talk about, how effective is it? There are different ways to think about that. One is response, which really looks at the tumor.  So there are two different types of response, one is partial response (PR), where the tumor shrinks by greater than 50%, versus complete response (CR) where there's no detectable tumor on the scan.

(20:44): On the left is an example of a patient of mine that had a partial response (PR) to therapy. Ultimately, the disease progressed. This is, I would say, more common than not. Patients who achieve a partial response will end up having progressive disease. There's a proportion of patients, perhaps between a quarter and one-third, that may have ultimate resolution of the disease on the PET scan after achieving a partial response, but most patients with a PR will ultimately have the disease grow again.

(21:19): And on the right, is a patient in complete remission (CR). This patient is in an ongoing complete response, but not everybody that achieves a complete response will stay in a complete response.

(21:28): Outcomes can also be measured in terms of overall survival and progression-free survival. So while a PR and CR are important metrics, I think there are more important metrics to think about. From the patient perspective, patients want to know how long will I be alive, how long will I be in remission? The way that we think about that as oncologists, we rely on what we call Kaplan-Meier curves, which you can see in the graphic on the right, which we'll walk through, and they can look at the effectiveness of a treatment over time. So time is obviously a very important part of this.

(21:56): Two of the major metrics, one, perhaps the best metric is overall survival. So this just measures whether the patient is alive or dead. The second, which we call a composite endpoint, is progression-free survival, (PFS) so is the patient alive and in remission?

(22:13): Now, coming over to the curve, if we start at the top over here, 100% of patients are alive and they have not experienced an event, whichever event you're trying to measure. If it's overall survival, then the event is death. If it's PFS, it's death or relapse. And every time there's a step down, that signifies that a patient has experienced an event. So obviously, in a perfect world, the curve would be flat at the very top, meaning that 100% of people are alive and in remission. But if there's a step down, it signifies a patient has experienced the event of interest.

(22:49): And then over here, at the end, we're looking for a flat line, so that is the percentage of patients that remain free of events. So, the higher that flat line is, the better it is. It means your therapy is effective.

(23:04): Studies of patients who had CAR T-cell therapy found that five years after treatment, 30% of those with diffuse large B-cell lymphoma (DLBCL) and 50% of patients with follicular lymphoma (FL) remained in remission. The number was lower for patients with mantle cell lymphoma. Now, we do have an example of a curve in lymphoma with CAR T. This is a PFS curve from one of the earliest trials in diffuse large B-cell lymphoma, and you can see that at about five years, 30% of patients remain in remission. So that's what that flat curve shows, a proportion of patients who, after five years following a single infusion of CAR T, remain in remission.

(23:28): So, does that signify a cure in DLBCL? Some people would like to suggest that it does. So this is an example of the potential of CAR T, and the real question, I think, is does this also apply to those indolent diseases that we talked about, follicular lymphoma and mantle cell lymphoma?

(23:46): And on the left, is a table. Again, it's a composite of many, many trials, so that's why it's a bit of a range. But if you focus on the progression-free survival for DLBCL, you can see about 30 to 40% of patients remain alive and in remission at five years. That number is higher in follicular lymphoma, at about 50% at five years, and is a little bit lower in Mantle cell lymphoma, so about 20 to 40% depending on the trial you look at, with a little less follow-up, so four years’ worth of follow-up.

(24:18): And then looking at overall survival, whether the patient is alive, in DLBCL it's about 50% at five years, higher in follicular again, it's 70% at five years. And in mantle cell lymphoma, about 35 to 50% at four years. So, some of the things that we're going to be looking for going forward, is how does that curve flatten out, which we hope it does.

(24:44): Patients might ask "What really mediates whether the CAR is going to work for me?" And there are really lots of different factors that go into it, which we don't really have time to focus on, like T-cell health and things of that nature.

(24:57): CAR T effectiveness may be limited if patients have a high tumor burden and inflammation. But I think some of the most important things to think about are high tumor burden and inflammation within the patient. Both can impact CAR effectiveness. They're both interrelated, so perhaps high tumor burden can also drive high inflammation.  But I think conceptually, it makes sense. We put in a fixed dose of these CAR T-cells, and you can think of them just running out of steam if they really have too much tumor to deal with.

(25:23): Similarly, in an inflammatory environment, there are lots of things that can actually turn the CAR T-cells off. So they go in raring to go, and the inflammation slows them down, weakens them, and ultimately mediates the disease progression.

(25:36): This  takes us back to what I mentioned previously, about the potential need for bridging therapy, or therapy to reduce disease burden. If patients have large disease burden on the way to CAR T, they may benefit from additional therapy that we think could reduce disease burden before they get their CAR T.

(25:58): Later toxicities from CAR T therapy can be secondary cancers. We talked a little bit about the early toxicities of CAR. I wanted to talk a little about the late toxicity. One which we've begun to note is second cancers. So patients getting lymphodepletion chemotherapy as well as CAR T-cells, can then have CAR T-cell expansion, which mediates its own inflammation, resulting in a weakened immune system for a period of time. This can lead to the  growth of second cancers, blood cancers, such as acute myeloid leukemia, as well as solid cancers.

(26:28): On the whole, I think blood cancers are more common and occur in about 5% of patients. I think that might be a little bit on the high end, but I wanted to bring that as the number when we have this conversation.

(26:39): I think that a lot of questions still revolve around this, whether that's mediated by a patient just being in later lines of therapy, so they've gotten lots of treatment already, which in and of itself, we know chemotherapy has an association with development of blood cancer. So if we move CAR T earlier on in the therapy paradigm, will that reduce this, or is it really mediated, in some part, by that CAR T-cell expansion and inflammation? And that really is an ongoing research question.

(27:10): Infection can be another type of late toxicity after CAR T therapy. Then we also have infection, which perhaps is one of the most important late toxicities after CAR T. You can see on the left, a diagram talking about when patients are at high risk for infection within the first 28 days. Patients have also received chemotherapy, so their white blood cell count could be low, so they're at risk for infection from that perspective as well.

(27:32): But we also know that even going beyond day 28, patients can experience infection in an ongoing fashion. About half to three-quarters of patients will experience an infection in the first year after CAR, and that could be something as simple as an upper respiratory infection, but could be more severe as well, like a bacterial infection requiring antibiotics. And in some longer-term studies, we have noted that up to a quarter of patients that we were able to get information from did have severe infections requiring something like hospitalization or IV antibiotics, and that can result in something called non-relapse mortality.

(28:12): Non-relapse mortality (NRM) is when a patient dies of something different than their lymphoma. So, to put that in perspective, we actually want all patients to not die of their lymphoma. So in theory, we're looking for 100% non-relapse mortality, patients growing old and dying of something else. But this is not what we're talking about here. We're talking about non-relapse mortality early after CAR, while the patient is in remission.

(28:39): And what you can see from the graphic on the right, is from perhaps the largest study looking at these events, about half of non-relapse mortality in total is driven by infection. So this is a very important facet of CAR therapy that we're trying to work on to reduce the risk of NRM the further out people get from CAR T therapy.

(29:01): If patients relapse after CAR T therapy, options include bispecific drugs or a clinical trial. Lastly, what if a patient were to relapse after CAR T? And this is a little bit dependent on the fast-moving paradigm, where different therapies are moving earlier on in therapy. So this may change quickly, but right now, if you have not been exposed to a bispecific and ultimately relapse after CAR T, that would really be the next best therapy. You can see in DLBCL, I listed a number of bispecifics, Glofitamab, Epcoritamab. For mantle cell lymphoma, Glofitamab. For follicular lymphoma, Glofitamab and Mosunetuzumab.

(29:35): And then there are other options which I've listed here, but I think it's also important to put in a plug for clinical trials. I think if patients get into the third and fourth lines of their therapy, that is certainly a time to consider clinical trials with novel agents.

(29:51): So, in summary, what we've talked about today is that CAR T has gained approval in both aggressive and indolent lymphomas. The five-year follow-up shows that a proportion of patients do have durable remissions, which I do think is suggestive of a potential cure.

(30:05): CAR T remains an involved logistical process, both before and after treatment, so a good support system is really important to make this process smooth, both for patients and their caregivers.

(30:15): The longer-term toxicities are increasingly recognized as an active area of research, to allow patients to enjoy remissions induced by CAR T.

(30:17): Lastly, the treatment paradigm in lymphoma is changing rapidly, and when CAR T is used, it may differ in the coming years. But as a very powerful modality, CAR T will likely remain a mainstay of treatment for the foreseeable future.  

(30:36): And with that, I'd like to thank you for your attention. I'll be happy to take any questions.

Question and Answer Session

(30:41): Susan Stewart: Thank you, Dr. Spiegel, for this excellent presentation. We'll now begin with some questions. So let's start with the first one, a listener would like to know, how long do CAR T-calls keep doing their thing?

(31:07): Dr. Jay Spiegel: That's a great question. There is some data for the 41BB CARs, that is the slower onset CARs, the Prius, if you will. In some people, they can stay in the body for years. So, there's data from the earliest patients treated at the National Institutes of Health and at the University of Pennsylvania, where they found that, actually, 10 years later, patients with circulating CAR T-cells. I don't think that's true in most people. I think for those Prius-based CARs, it will be a number of months.

In a different treatment paradigm, acute lymphoblastic leukemia, they actually monitor whether a patient will have their B-cells suppressed. So not only do CAR Ts kill the cancerous B-cells, but they also kill normal B-cells. So, in acute lymphoblastic leukemia, doctors actually monitor B-cells, for what we call B-cell aplasia. If there are no B-cells, we assume the CAR Ts are still doing their thing. If the B-cells come back, we assume that they're not. And in ALL, that is a concern for relapse.

In lymphoma, that's not quite the same story. We see B-cell aplasia last maybe six to 12 months, and then the B-cells can come back, but that does not actually cause relapse in a lot of patients. So, I would say on the whole, for most people, several months, some patients, a little longer. But even if those B-cells come back, which suggests that the CAR Ts aren't actively doing their thing, it does not mean that relapse is guaranteed.

(32:49): Susan Stewart: All right, thank you. And this gentleman wants to know specifically about Axi-cel, are there any studies on this, how long it works?

(32:59): Dr. Jay Spiegel: Yes. For Axi-cel, it's detectable in the blood by flow cytometry or by PCR, which is a little bit more at the genetic level, probably one to two months.

There are some interesting data looking at different methods of measuring these CARs. So cell-free DNA, where we know that cells can actually secrete their DNA into the blood as they die, and that might give you a measure of whether CAR T cells are actually hiding in the tissues and not detectable in the blood. And there are some studies that suggest that CAR T may actually be hiding around in the tissue, even if we can't detect it in the blood. But I would say that that's still really experimental. So I'd say from what we know in the blood, one to two months, but perhaps they're hiding out in the tissues and we just can't find them.

(33:55): Susan Stewart: All right. Next question, are people immunocompromised after CAR T, and for how long?

(34:04): Dr. Jay Spiegel: Yes, that's a great question, very important question. So people are immunocompromised after CAR T. How long, I would say depends.

The way that we monitor that is by looking at patients' B-cells and also their T-cells. So, after you get chemotherapy in CAR T, your T-cells will not return to normal, probably for more than a year. So your adaptive immune system is not functioning at its best. B-cells, as we mentioned earlier, typically take six months to a year, sometimes even longer.

So we do keep people on two medicines, one is acyclovir, to prevent shingles, and the other is Bactrim, to prevent pneumonia that can occur in patients who are immunocompromised. And what I do at our center, is keep patients on that until their CD4 count is greater than 200. So if the CD4 count recovers and they hit a year, I'll take them off. If they're at one year and their CD4 count's still less than 200, I will keep the patients on Bactrim and acyclovir.

(35:13): Susan Stewart: All right. The next question is, I have diffuse large B-cell lymphoma. I had a stem cell transplant and CAR T last April. Recent PET scans showed suspicious lymph nodes in my neck and armpit. Excision biopsies revealed no abnormal cells. Why are we getting false positives? Can we prevent that in some way?

(35:39): Dr. Jay Spiegel: That's a great question. So, I think that is a phenomenon after CAR . So certainly, we know that patients can have abnormal PET scan findings after CAR T that are benign. I think that it's also important to note that PET scans do have a false positive rate in all lymphomas.

The thing about a PET scan is that it is sensitive but not specific. So when something lights up on a PET scan, it could be a problem, but it might not be. For example, if a patient has had a recent infection, they might have swollen lymph nodes. If you get a sore throat, you might feel that your lymph nodes in your upper neck are a little bit swollen. If I took you and gave you a PET scan while you were actively sick from that, your neck nodes might light up, so PET scans have a false positive rate anyway.

Now, there are different modalities that people are working on. For example, there is a test called ClonoSEQ, which looks for the genetic blueprint of the lymphoma. So every B-cell has its own B-cell receptor, which is unique to it, and we know that every B-cell cancer began initially from one B-cell. We can find the genetic blueprint for that B-cell receptor, which we would associate with the cancer. We could find that in a patient's blood, and that has been approved for monitoring in DLBCL and in Mantle cell lymphoma.

Now, for patients such as yourself, you could, in theory, do that test as a second way to look for the cancer, but that also has problems. I think the tests are only as good as they can be, and there will always be some false positives and false negatives associated with them.

(37:50): Susan Stewart: All right. Well, that's good to know. Very clear. The next person wants to know is CAR T-cell therapy still an option in mantle cell lymphoma if you already had CAR NK therapy in a clinical trial?

(38:06): Dr. Jay Spiegel: That's a good question. There's the insurance answer for that, and then there's the scientific answer for that. I would say the insurance question is they may try to deny it on the basis of you having received the therapy before.

That said, from the scientific perspective, it depends on what the CAR NK targeted. If the CAR NK targeted CD19, I would suggest retesting for the presence of CD19. We know that one reason that CAR Ts don't work is that the lymphomas are smart and they manage to down-regulate CD19, so it's not on the surface anymore. So if there's no target, the CAR T won't be able to find it.

Now, that happens much more in ALL than in lymphoma. Lymphoma, maybe it's a quarter of the time, 30% of the time. So I think what I would say is that if the CAR NK targeted CD19 but you still have CD19 present on your cells, I think you should still be able to get CAR T and get a remission. But then unfortunately, we have to deal with the other part of that, which may require a little bit of work on behalf of your treatment team.

(39:23): Susan Stewart: All right. All right. The next question, if a person is taking medication to keep depression and anxiety under control, will it affect the risk for CAR T side effects?

(39:35): Dr. Jay Spiegel: No. No, it does not. We don't have evidence that SSRIs, or medications like that, affect the rate of neurotoxicity. I would say that patients with seizure disorders, were excluded from the initial studies. But patients that are stable on anti-epileptic medications, we still have taken to CAR T, and we do not see really an increase in toxicity.

(40:01): Susan Stewart: Great, that's good to know. This person wants to know what exactly is a caregiver expected to do while caring for a CAR T patient? Why is one needed 24/7, and for how long are they needed?

(40:17): Dr. Jay Spiegel: Yes, that's a great question. The way these things were developed is they were developed eight years ago, and perhaps the FDA requirements around them haven't necessarily evolved.

So, when a patient is in the hospital, a caregiver certainly is great, to help the patient, advocate for the patient in dealing with the medical staff. But in terms of absolute necessity, if you have to be at work and you only can visit your loved one every so often, certainly, the medical team is going to be able to take care of them.

When you go home, it depends. If the patient has experienced some toxicity, they may be weak, they may have some difficulty eating, so they might need help with that. They might need help with mobility, depending on how mobile they are when they leave. If they've had steroids in the hospital, they may be a little bit weak when they get home.

The requirement for 24/7, I think, is really directed around the concern for neurologic toxicity, which does require urgent treatment. I think that in truth, the late onset of neurotoxicity is very rare. So I would say if you get beyond day 14, but certainly, beyond day 18 or 20, the rate of new onset, or even recurrent neurologic toxicity, is very rare. From the absolute perspective, I think the risk is very low, but it is there for if a patient develops neurologic toxicity.

(42:01): Susan Stewart: All right. The next person wants to know if you have DLBCL in the CNS, is CAR T effective?

(42:11): Dr. Jay Spiegel: That's a great question. Now it depends a little bit, if you have primary CNS lymphoma, that is if the lymphoma was only ever in the brain and never anywhere systemically, CAR T is not approved. There have been some studies ongoing for CAR in that situation, but it is not part of the commercial approval for CAR T.

Secondary CNS involvement, meaning that patients have lymphoma elsewhere and then it goes to the brain, patients can receive CAR T on the commercial label. It doesn't exclude them. They were excluded from the initial trials though. I would say on the whole, it is less effective. And perhaps if we're talking about durable remission, that's somewhere in the 20 to 25% versus the 40%-ish that we were talking about before for DLBCL.

(43:09): Susan Stewart: Okay, great answer. Next question: Is there an age limit for CAR T-cell therapy?

(43:16): Dr. Jay Spiegel: I would say no. For example, Liso-cel was specifically studied for older patients who were not transplant eligible. The trial is called the PILOT trial. One of the criteria that they used for transplant-ineligible was age. I have treated patients in their late 80s, and I know there have been centers that treat patients in their 90s.

I think the question really is a matter of discussing with the patient potential quality of life concerns. So certainly, CAR T is an involved process, may involve a hospitalization, lots of doctor's visits, so I think it's important to go over that with the patient, but I don't think that there is necessarily an age limit, a priori, for CAR T.

(44:17): Susan Stewart: All right. This woman has had CAR T-cell therapy, and she said "I had to learn how to walk without help and how to swallow again, among other challenges. Is this common?"

(44:32): Dr. Jay Spiegel: I would say no, but it depends, so everything is qualified. What I would say is that patients can experience significant neurotoxicity, we talked about that. Even in the more "gentle" CAR Ts, a 41BB, up to 10% of patients can experience severe toxicity.

So if a patient experienced grade four toxicity, I may need her to be on a breathing machine, for example. A lot of the things you're describing are part and parcel of being on a ventilator. If you get intubated and then you come off the breathing machine, you may need to learn to walk again. You may need to learn how to swallow again.

Patients who require lots of steroids to control their neurologic toxicity, particularly if they're older, can experience weakness. Steroids can cause weakness. And then also, just a patient remaining in bed for a long period of time can have weakness.

I would say physical weakness can be more common after CAR T if you experience toxicity, because of, A, the steroids, and B, getting your "sea legs" back, if you're in bed for a week. When you get up, you may have significant weakness because you haven't been out of bed.

I would say there is definitely a proportion of patients who experience physical weakness. We have had to send patients to rehab after CAR T if they experience toxicity. I do think anecdotally that that is getting a little bit less. We are getting a bit better at preventing those, but the truth is that that still does happen.

(46:16): Susan Stewart: All right. The next question is, how long does it take for blood counts to recover after CAR T?

(46:23): Dr. Jay Spiegel: That is a great question. Again, it depends. I would say on the whole, patients will recover their blood counts within two to three months. So the main thing that is affected blood count-wise after CAR T is the white blood cell counts. About one-quarter of patients will require transfusion in the course of CAR T, but the hemoglobin and platelets do recover pretty quickly.

White blood cells on the whole, probably recover about two to three months out. But when we've looked later, we've had about 10% of patients with ongoing low white blood counts, even a year post-CAR therapy. A lot of that depends on what your blood counts were when you started CAR T-cell therapy.

There's a very interesting set of papers from a group from Germany, led by Kai Rejeski, and they have a calculator called the CAR-HEMATOTOX, which you can access online, and that will help calculate your risk for low blood counts after CAR T. If you're interested before the CAR T process, I would certainly ask your team to calculate that for you, because it can give you a sense of what your particular risk might be.

(47:37): Susan Stewart: Interesting. Next question, do you need to be re-vaccinated after CAR T like you do after a transplant?

(47:46): Dr. Jay Spiegel: Another great question. It depends. What we have started doing, is after a year, we will check the titers of the antibodies for various conditions that are vaccinatable. So if a patient has adequate protection, we will not re-vaccinate them. If they don't have protection, then we will give them that vaccine.

You could have patients that have protection against nothing, and we'll have to re-vaccinate them for lots of stuff, or they could actually be protected against everything and we won't vaccinate them.

You might get shingles again, because that's more of a booster to prevent shingles, but if you have protection against measles, you don't need another MMR shot. If you have protection against pneumonia, you don't need a pneumonia shot. So we do it based on titers.

There is a paper from the group at Fred Hutch in Washington, where they looked at this, and they found that lots of patients with lymphoma actually do maintain their protection against these diseases, so they retain their vaccination status even after CAR T.

(49:01): Susan Stewart: Oh, that's great to know. This is a question about long-term follow-up care. If a patient has to travel to go to their CAR T center, do they need to go back to visit periodically for follow-up care, or is that all handled locally by their local doctor?

(49:20): Dr. Jay Spiegel: I think that also depends on the relationship with the center. There are certainly centers that are internationally renowned, and patients will come internationally, and then they're not going to come back again. So certainly, it can be done.

I like to see patients, because I think that CAR is still relatively niche. As much as I love it, and it's what I do for a living, it is niche, and I think that there are things that come with that that do require some extended care.

But I would say that can be intermittent, and you could also, if your home physician has a good relationship with the treating center, they can communicate, and they can manage you at a distance. I do think it's not a bad idea to go periodically, but do I think is it necessary? I think it can be done if there's close collaboration between the treating center and the home physician.

(50:19): Susan Stewart: All right. The next question is, we have stem cells left after an autologous transplant, would these be helpful to boost the immune either before or after the CAR Ts procedure?

(50:32): Dr. Jay Spiegel: Another fantastic question. The answer is it could be useful. If a patient has persistent low blood counts, stem cells could be helpful to boost that later. So that is currently more commonly used in multiple myeloma post-CAR. where there are more significant low blood counts, patients are using banked stem cells as a stem cell boost. In lymphoma, I would say we tend not to have to use it, but it could be useful if necessary.

(51:10): Susan Stewart: All right. The next question is, can you share the paper about post-CAR T vaccination? For example, can you send it to BMT InfoNet?  

(51:20): Dr. Jay Spiegel: Sure.

(51:20): Susan Stewart: And then we can send that out to people on the call.

(51:22): Dr. Jay Spiegel: Absolutely.

(51:25): Susan Stewart: So we'll take care of that later today or tomorrow. And then the final question is, can you comment on any clinical trials or research that's ongoing to expand the use of CAR T-cells to other types of lymphoma?

(51:42): Dr. Jay Spiegel: Yes. There have been a variety of clinical trials in other types of lymphoma. Those tend to be rare lymphomas, so they're harder to get numbers for patients.

I would say for something like Burkitt lymphoma, which is very aggressive, there hasn't been the same degree of success. And with some of the other indolent lymphomas, I think it's been very hard to get data.

There are some clinical trials with Waldenstrom's that have been a bit promising; for example, lymphoplasmacytic lymphoma. Burkitt, I would say on the whole, hasn't been terribly successful.

Hodgkin lymphoma, there were some earlier promising studies, but I would say it's not particularly close to being approved.

And T-cell lymphomas, which is really a huge area of need, for a variety of reasons, this approach is quite difficult because the cancer is in the T-cell, so you run the risk of actually putting a CAR into the cancer. You also run the risk of the CARs killing themselves, which we call fratricide.

There are lots of novel approaches to trying to make CAR T viable in T-cell lymphoma, but I would say we're not quite there yet.

(53:07): Susan Stewart: Closing. All right. And with that, I think we'll have to wrap up the session. I want to thank Dr. Spiegel for this excellent presentation, and I also want to thank the audience who offered some very good questions. If you have any needs, please contact BMT InfoNet at the number on the screen, or the email on the screen, and we'll be happy to reach out to you. Enjoy the rest of the symposium, and enjoy the rest of your day. Thank you.