What is chimeric antigen receptor T cell therapy, or CAR T therapy? Dr. Alain Bouchard is joined by Dr. Amit Mehta, director of the lymphoma and CAR T programs at UAB, and Dr. Carrie Lenneman, a cardio-oncologist, in a discussion of this new form of immunotherapy to target cancer cells.
Learn more about CAR T cell therapy here.
About the Host
Dr. Alain Bouchard is a clinical cardiologist at Cardiology Specialists of Birmingham, AL. He is a native of Quebec, Canada and trained in Internal Medicine at McGill University in Montreal. He continued as a Research Fellow at the Montreal Heart Institute. He did a clinical cardiology fellowship at the University of California in San Francisco. He joined the faculty at the University of Alabama Birmingham from 1986 to 1990. He worked at CardiologyPC and Baptist Medical Center at Princeton from 1990-2019. He is now part of the Cardiology Specialists of Birmingham at St. Vincent’s Health System, Ascension.
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This is the MyHeart.net podcast. This show is produced by Dr. Philip Johnson in conjunction with VitalEngine.com. Please welcome your host, Dr. Alain Bouchard of Cardiology Specialists in Birmingham, Alabama at St. Vincent's Medical Center, part of Ascension.Dr. Alain Bouchard:
Welcome to our podcast and my heart that net. Today we're focusing on our cardio oncology series and we'll discuss car T cell therapy, and its cardiovascular effect. And with me today, we have Dr. Amit Mehta, who's associate professor at the University of Alabama in Birmingham, and director of the lymphoma program as well as director of the car T program. And from the cardio oncology field, we have Dr. Kerry Lindemann, who is also Associate Professor at the University of Alabama. So doctors, thank you very much for taking the time on this beautiful gorgeous Sunday afternoon. Thank you for that.Dr. Amit Mehta:
Thank you. Thank you. So,Dr. Alain Bouchard:
CAR T or this chimeric antigen receptor T therapy is basically a type of immunotherapy which provides remarkable success, and highly refractory and relapsed and relapsing in methodological cancer such as lymphoma, and, and leukemias. Today we'll try to discuss a little bit what is car T cell therapy, how it's performed from being a patient's perspective? How effective is it in fighting this cancer, we'll discuss some of the side effects and particularly the the well renowned cytokine release syndrome which kind of became famous again, during the pandemic. And finally, we'll discuss some the cardiovascular effective Carty and how we take we can mitigate it. So I'd like to start with you I met if you could explain a little bit. What is car T cell therapy?Dr. Amit Mehta:
Thank you for that question. And if we go back probably 10 or 15 years ago, that was probably the era of changing treatment for oncology. So oncology, you know, when I went in oncology, most of the people would say that hey, you know, this is a chemotherapy doctor, right? Things change when the immunotherapy has started to knock on the door, and very improved to be very, very effective. We started with monoclonal antibody therapy. And then there were multiple ways that people start to think whether we can bring in or engage the immunotherapy more to fight the cancer. Now car T therapy a step further. So Carty therapy addresses a question right at the T cell level. So what happens in car t, if you just look at the concept that the patient's T cells are harvested, what it means is the patient they get a line and they're connected to a machine we call as apheresis machine in a simple term, it is a machine like a dialysis machine. And through that, the patient's blood is blown through and the T cells are collected, the rest of the blood goes back into the patient. Now, this T cells are very, very valuable. This is the source of the immune system in anybody this T cells then they are sent to a commercial laboratory where they are stimulated, expanded. And on the surface of these T cells, there is a specific receptor which are expressed. For years people have done this in the lab for a wide variety of reason. Now, this is done commercially for a specific protein which is expressed only in cancer cancer cells. Currently, most of the T cells they express why call as an antenna on them. That antenna detects a protein called CD 19 on the B cell, there is an other set of antenna which are also being produced and they are called as BCMA protein which is present on a multiple myeloma patients. So once these T cells are ready, they're shipped back to the center for infusion in the patient's. Now these are all patient's own T cells. That's why we call us autologous. And this T cells are ready to fight so as soon as they're infused in this entiende has helped them find the receptor or protein present on specific cancer cell and immediately start attacking it. So now we have kind of prepared soldiers of your own immune system, which are infused back in you now as they're your own. They actually last for 10 years in the system technically detecting and killing the cancers.Dr. Alain Bouchard:
So for the patient, let's say for example, I'm a patient and I have multiple myeloma Do I have to be prep before I get this car T therapy? What does it involve? I mean, I go visit you and you say you offer me the car T cell therapy? What does it mean in terms of time and coming to the hospital so forth?Dr. Amit Mehta:
That's a great question. So, the car T cell therapy was approved over a period of last four years, there are multiple parties and multiple indications approved so I say the process starts when I see the patient. So first step is identify the patient that the patient is good enough and we are going to talk about further the toxicities and as you mentioned in the cardiac side effect, right, so we will make sure that the patient is fit enough. Second, as this is commercially available, there are multiple steps involved for the approval. As you know that most of the oncology treatments are very, very expensive. And car T one infusion may cost up to half a million dollar. So what happens is once I see the patient, I want to make sure that their insurance or Medicare approves it. So you have to be on label as FDA described, this is the label for this particular car t say for lymphoma yo to fail two lines of therapy for myeloma yo to spell four line of therapy. So you we make sure that you're on label and you're fit enough, at that time the car T team gets engaged, and they start getting the approvals. The insurance approval itself is not sufficient because the cost is very high. Most of the institution, they go for what we call is case based agreement with the insurance, right. So you have one contract through your insurance companies to cover XYZ, as this is a higher amount, that is a separate contract that goes into effect. That means that the money transaction will happen to the institution. Once that is done. The third step, you want to make sure that the patient has an appointment for not only line placement, but collection of the T cell. Right. So you want to make sure that our center, the apheresis unit, they have an opening so that the patient can be scheduled. Now, we held to align that date of collection with the commercial laboratories date of receipt, right, so we collect, but we only make sure that they are also ready at the other end. And the the commercial facility could be all over the US they could be in northeast, they could be in West Coast. So you want to make sure that they are ready and they have machines available to kind of process those cells. So as you can see that collection itself at our institution is not important, we have to make sure that all supply knows that these cells are going to be traveling through them. So once this all steps are made, then the collection is done, right. Once the collection is done, then we are on a wait game till the cells are ready and come back. That's when we start planning for what we call is chemotherapy. The whole intent of that chemotherapy, we call as lympho depleting chemotherapy. What do we do by that chemotherapy is we lower the T cells in patient's body. So the patient's body is hungry to get more T cells. And that's when we infuse the T cells in them. So there are multiple checkpoints that we want to make sure. And the staff, you know, right from the clinic, to all the way to commercial lab. They're all trained, highly specialized, and they exactly know what to do with the cellsDr. Alain Bouchard:
are done. And how effective is the therapy? I mean, we talked about, you know, these are cancer that are pretty advanced a lot of times you know, what is the chance of success? What kind of results are we getting at six months at a year? And are there are some patients getting resistance that treatment?Dr. Amit Mehta:
That's a great question. So this therapy, they're specifically indicated in a relapse cancer, right. So right now we have lymphomas, there are different kinds of lymphomas where this treatment is approved, diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, in multiple myeloma, those who have failed multiple lines of therapy as well as acute lymphoblastic leukemia. These are the cancers where this treatment is approved. If the cancer comes back, these are the cancers which are not only refractory, or they're smart enough that they have learned to progress over the conventional therapy that we offer. So there are multiple what we call as benchmark retrospective analysis are done that how these patients do and this therapy, the newer therapy that compared with that benchmark analysis, it is just like I would say that if you if you have say I want to test a car, which is faster and more effective than a current car, then what you do is okay, well we have a gas car Let's see how far and how much mileage it gives. And then we have a new car that we compare with them. And the new car car to color, say Tesla of the therapy, right? So that's how you compare, well, the gas prices are pretty high. So now we get a more mileage with Tesla. So similarly, those studies are done in with the conventional therapies, and the new Corki therapy were compared to them. And if you look at those studies, the effectiveness is pretty good. And one year survival, typically, I say, is 50%, that these patients are alive at one year. Previously, with the conventional therapy, the hope was very, very low compared to what what we have achieved. Still, the flipside is true that 50 person will progress on car T. And right now, there are multiple studies ongoing to explore why and how the cancer learn to bypass the attack of car T. You know, as I said that they're they're lasting in your body for more than 10 years. And if it is not effective to learn to bypass that, then we need to know how they're doing it so that we can improve upon the one that we have currently,Dr. Alain Bouchard:
there's some combination with other types of chemotherapy or immunotherapy, actually, in some of these patients, that develop a resistance or non response.Dr. Amit Mehta:
So that's, you know, I would say that once we knew about car t that how we can produce car T, right now, there is an explosion of the clinical trial related to novel approaches, right. So, at my center, we have next generation core T, also there are core NK, so I highlighted the T cells are removed, now we are removing the natural killer cells and preparing them. The other limiting step is that as I mentioned that we collect the cells and sent to the laboratory to prepare. So there is a time lag between you know, somewhere between three to four weeks, people are starting to already start to thinking whether we can have the cells ready. So we are collecting and harvesting cells from say, core blurred, and then expanding them in a different cell lines and preparing them already. So they're already available on the shelf. Then the combination therapy, as you mentioned that the different kinds of immunotherapies are combined with a car T interleukins are combined with a cell therapy to see whether we can even expand the attack on the cancer cell. So I assume that in next five years, we will have novel approaches novel therapies novel combination with I call it cell therapy, it's no more T cell therapies like various kinds of immune cell therapies that we are, we are in, you know, right now experimenting, that five years from now things will be completely different.Dr. Alain Bouchard:
Pretty amazing. Well, I'd like to get Terry involved a little bit, because I'm sure she gets some calls, sometimes from some of the patients regarding getting the car T cell therapy. And if we could start talking about maybe some of the side effects and care you're willing to I mean, please kind of chime in, you know, whenever you feel like admit as well. So you have a patient, what kind of side effects that we that we see actually, in clinical practice and patient receiving this type of therapy.Dr. Carrie Lenneman:
Sure. I mean, sort of the the biggest side effect that we usually end up dealing with is the cytokine release syndrome, like as we're using car T the immune system is getting revved up to sort of attack the cancer, which is great, it's doing its response, but it can almost become hyper immune, where you have this mass release of various different interleukins, which can then unfortunately cause cytokine release syndrome, which is almost a vaso, dilatory response similar to what we see human and amicably with sepsis. So patients can become hypotensive tachycardic, they can develop sort of acute pulmonary edema, they can also have issues with significant shortness of breath. So these are these are patients can become human and chemically unstable very quickly. So we commonly as we're monitoring patients who will be looking for signs and symptoms of early cytokine release syndrome, we try to mitigate that with just supportive measures if possible. But obviously there are therapies that can help sort of calm down and sort of dampen the hyper immune response. I think COVID has made us all a little more familiar with that, at least as many of us have heard of Tasa lism AB, which helps sort of dampens or the immune response that can happen with cytokine release syndrome. The other thing that I think is also important to talk about is that this is very complex orchestration and this is really for sort of the Select patient that is identified. And it's a huge investment both on the patient and unfortunately as far from a financial standpoint. So we want to make sure patients are optimally selected so that they do well, they don't have a poor outcome, they don't develop severe cytokine release syndrome and shock and die. So commonly, sometimes we will also get referrals for patients to make sure they're fit enough, just like we were talking about early earlier that some patients can actually look really good on paper, even really good in the clinic. But then when you start doing some sort of pre car T testing, you can realize, oh, gosh, we've got severe aortic stenosis. So you know, things patients that have significant valvular disease or have significant heart failure, like EF less than 35%. These may not be patients you want to send right on to car T and may need to find, you know, some temporizing measures until you can either, you know, fix or mitigate the cardiovascular issues, or that might unfortunately, just deeming them ineligible for car t. So we often also will get patients seen in our clinic, because I've had an abnormality, whether it's abnormal echo, where they have significant valvular disease or even significant coronary disease history to make sure that again, they've had coronary disease, maybe they've been bypassed, you know, are they stable and fit enough to sort of get through a sepsis like human dynamic response?Dr. Alain Bouchard:
So So you describe, obviously, the cytokine release syndrome, this is probably where, where you have hypoxia, and hypo severe hypotension and shock, you know, raises the mean, so we have to treat with, you know, not only fluid but pressors, and so forth. How frequently does that happen versus just a mild form of, let's say, fever, or sometimes just, you know, kind of a mild response, like it could be hypotensive with a response to fluid, they still maintain their oxygen, how frequently do you see that dramatic response, like CRS,Dr. Amit Mehta:
I would chip in in there. So Carrie actually explained it very nicely. The cytokine release syndrome is one of the limiting side effect of such an effective therapy. So you have to have a great team in place like you know, when I, Eddie will be I'm glad that care is there, when I send a patient to her she exactly knows you know, what, what is going on in my brain and how she can help me. Now cytokine release syndrome, it differs on a product by product, some products they have there is a co stimulatory domain in the receptor. And there are two of them, which are right now existing one is what we call a CD 28. And the other one we call us foreign BB. And they both have a little bit different characteristics. So CD 28 products tend to expand quicker compared to foreign BB, which expands a little bit later. So quicker, meaning that they have CRS earlier, rather than forming BB. So those are the patients. As soon as the infuser sells, you might see it within one to two days, they start having cytokine release syndrome. And historically what we have seen is that the CD 28 products, their rates are CRS a little bit higher, compared to 401 b b products. Right now, the CD 28 products, there are multiple mitigation strategies, including adding steroids earlier, there are some studies which are going on, as Gary mentioned, that Tocilizumab as a prophylactic whether we can give it to prevent that. Initially, people were very hesitant, because they didn't want to affect the efficacy of Carty. Right, so they didn't want to do any of these prophylaxis stuff. But now, with the liberal use, they are seeing their well the toxicity is lower, but at the same time, we are not seeing any compromising effect on the efficacy of this car T. But on an average, you might see like simple as grade one just to fever in most of the patients, right. But the severe grade three or four where exactly you described their blood pressure is very low, they're on pressors they are hypoxic respiratory failure. And as Carrie mentioned, like shock like picture that is getting lesser and lesser with all this early recognition, introduction of this prophylactic therapies, though, and of course, you know, like, if there are high risk patients and we send it to carry and we can prepare ourselves that this potentially can happen. So we are ready to all strategies actually helped a lot in reduction of this lethal, so to speak. side effect was car t.Dr. Alain Bouchard:
So we bring we bring about this kind of immune reaction with interleukin and so forth, but are there also some kind of direct effect or you know, for example, some of the car T has been, is being used to tweet some melanomas. And with reports of you know, severe hypotension. They're actually some mis directed effect, for example on other like the heart, for example, or what do we know about some of the different Tartine effect?Dr. Amit Mehta:
So there is a potential not only hurt but brain effect neurotoxicity is Also recall as I can see immune effector cell therapy associated neurotoxicity, which is also one of the lethal side effect. Fortunately, it's not that common. But, you know, when we started doing Carty at UAB about five or six years ago, at that time, even the grading was not established properly, right. So now the grading is there is a consensus grading out there. Even the nurses are trained and looking at their vitals and making sure that that neurological status are good. And that is an immediate recording. As a matter of fact, as this both side effects are so lethal, that FDA actually has a rems program into effect, what it means is everybody in the institution should be trained for this, the patient should be aware that this can potentially happen for CRS, any certified center like UB, they should have two doses of Tocilizumab per patient ready. So as soon as I sign a consent initial visit, our pharmacists put aside two doses per that patient. In case that happens, so that is mandatory. Now, the patients cannot drive for up to two months after the quarantine period. These are all kinds of rules and regulation that FDA has placed in for the safety of car T. And there are some late side effects that we can talk aboutDr. Alain Bouchard:
afterwards. Let's dive in into the cardiovascular effect. Carry. There's been you know, it seems like there's some increase in particularly in the patients developing severe hypotension, even some increased incidence of heart failure, and cardiomyopathy, what do we know so far, at least from the retrospective study at UPenn? Sure, IUnknown:
mean, so we definitely know that, again, hypertension, and this cytokine release syndrome can can occur, like I said, last night has been retrospective before, sort of our newer, newer, more standardized way of a pre evaluating patients, and then to also having a really consensus of the cytokine release syndrome and severity. So you know, I think data that we when we look back, probably not completely accurate of what we're seeing today, but but still very valid and something to learn from. So again, you know, I do think it's really important now that we pre evaluate our patients and making sure they have appropriate cardiovascular diagnostic testing to sort of get through a sepsis like event where it's hypotension, we're going to have to have pretty aggressive volume resuscitation, and make sure we're not dealing with anyone who's got, you know, pretty significant valvular disease or kind of, you know, concerning for three vessel or left main disease before they go into this to this process. So understanding their cardiovascular and coronary disease history is super, super important. I think that keeps us out of trouble, a little bit, for sure. And then lastly, you know, we do see stress induced cardiomyopathy in these patients it is probably goes along with this, these neurologic events are something related to the brain in the heart, where we see a lot of taka SIBO. Luckily, when we see the taka subo process, most of this has been supportive care. Or we can get patients through this just like what we see with stress induced cardiomyopathy, these, we support these patients, and then commonly put them on guideline directed medical therapy for heart failure, and a lot of times the LV function recovers. So that has been a promising thing that we have seen. And we don't really fully understand it. It's, you know, obviously similarly similar to talk a suit Well, we think it's probably a really dramatic release of stress hormones that occur at that time. But, but it's good to see that there's a pretty significant recovery.Dr. Alain Bouchard:
So really looks like the heart team approach here. The combination of the oncologist, the cardio oncologist, the interventional cardiologist is really important and plays a very important role in following these patients, prospectively now, what do you do? I mean, obviously, it looks like you're really very much involved, from the very beginning evaluating these patients, really not coronary disease, ruling out cardiomyopathy because a lot of these patients have received already. Radiation treatment, they've received Adriamycin a lot of times. So you evaluate the heart function, you really get them ready for their Carty treatment, what do you do prospectively? How do you follow these patients after the treatment? And how frequently do you evaluate them?Unknown:
A great, great question. We, you know, obviously, it sort of depends on what happens but you know, we've seen some patients where we tolerate them sort of pre Carty and find out they have severe aortic stenosis, so we end up sending them for TAVR. And then that sort of, you know, falls into typical kind of post TAVR assessment, usually getting an echo three, six, and then one year, kind of follow those patients. But I think you're exactly right. Then there are other patients who have been very heavily pretreated with various forms of chemotherapy like anthracyclines, who come in and maybe they're as kind of low normal 50 55%, then you're going to want to follow those patients more closely. You may have deemed that they're added Wait for Karthika, they've got good functional status and they probably had a good human dynamics on last right heart cath or non invasive studies by echo showing a bit great stroke volume and and, and so on those patients, you may just say, Okay, well, you know, after you get through the car T I want to see you back in three months and they echo and make sure if you can have them on good medical therapy before they go through the Carty again, kind of focusing on specifically maybe beta blockers plus or minus ACE inhibitors, if you think they can tolerate that, although we probably do pull back on some of those while we begin the initiation of Carty because of the hypotension.Dr. Alain Bouchard:
Certainly, Carty is really been exciting breakthrough in cancer treatment, expanding also to, you know, multiple indications, including even solid tumors. How do you feel how do you see the field evolving amid in the future? And what should we be looking forward to in the next four or five years?Dr. Amit Mehta:
I think you you mentioned it right, the car T application is expanding quite a bit and solid tumors is on the horizon. Right now, there are multiple studies ongoing as a matter of fact, in the in the history of oncology, it's just not car T cell therapy. In particular, there are so many studies, hundreds of studies are right now ongoing. There are so many smaller biotech companies that are experimenting different cell therapies. So next five years, things will be different, and it will be more cell therapy based approach. And in that, I usually highlight the importance of a team approach, like we just discussed upon that not only just oncologists are cardiologists and neurologists, even ICU team, BMT team, all of them, they have to come together as a team to take care of the patients, we all should be on the same page. So that's one. And second critical is the experience of the center, which is also very upper now to identify some of the special side effects of these patients and address them as early as possible to avoid the civil complications. So these are the two main things that will emerge in next five years with this novel therapies. And of course, as we already saw, in you know, recent publication that the patients with cancers, they are living longer and longer. So in other words, we will have longer follow up of this novel therapies and more issues will emerge in especially we saw in COVID pandemic, that infection was one of the side effect of these therapies, technically creating a cell to attack B cells, depleting your immune system. This patients are very high risk of infection going forward secondary cancers. And as you mentioned, with prior therapies, they might have, you know, cardiac side effect not only media, but delayed. So all of this is kind of evolving, but I do see that in next five years, the cancer treatment will completely change.Dr. Alain Bouchard:
Vegas, a good stopping point, right there being called call to the hospital. So MIT MIT and Carolina men really want to thank you for taking the time to really talk about car T cell therapy and and our patients very enlightening. And the future is bright for you know, cancer treatment. And, and we can see how we can kind of work closely together for the next several years. Thank you very much. Thank youAnnouncer:
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