CAR T-cell Therapy: The Good, The Bad and The Long-Term

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CAR T-Cell Therapy: The Good, the Bad and the Long Term

Saturday, April 30, 2022

Presenter: Michael Tees, MD, MPH, Colorado Blood Cancer Institute, part of the Sarah Cannon Cancer Institute at Presbyterian/St. Luke’s Medical Center

Presentation is 39 minutes long with 20 minutes of Q & A.

This presentation was made possible, in part, by Kite, a Gilead Company.

Summary: CAR T-cell therapy is a new treatment option for patients with acute lymphoblastic leukemia, some lymphomas, and multiple myeloma that have not responded to prior therapies. This presentation describes how CAR T-cell therapy works, its risks and side effects, and how these may be effectively managed.

Highlights:

• CAR T-cell therapy involves removing some of a patient’s T-cells and engineering them to recognize particular cancer cells. These enhanced T-cells are then returned to the patient’s body where they can attack cancer cells.
• CAR T therapy can cause cytokine release syndrome leading to fever, lower blood pressure, and shortness of breath. The likelihood of this side effect is high, but its severity varies a lot. There are several treatments for this problem.
• CAR T-cell therapy can also cause neurotoxicity or ICANS. The likelihood, severity and symptoms of neurological problems vary with the underlying disease. Neurotoxicity  is almost always reversible.

Key Points:

(07:50): CAR-T cell therapy is currently approved for B-cell acute lymphoblastic leukemia, some lymphomas and multiple myeloma if other treatments have failed.

(09:46): Acute myeloid leukemia, myelofibrosis and some solid tumors are not yet good candidates for CAR T therapy.

(13:23): The correct T-cells must be selected for conversion to CAR T-cells in order to be effective.

(13:42): Viruses are used to insert genetic material into T-cells and convert them to CAR T-cells.

(15:38): Patients with aggressive disease may require bridging therapy to control their disease while CAR T-cells are being created.

(17:41): The major side effects between Day 0 and 28 are infection, cytokine release syndrome and neurotoxicity.

(27:46): After CAR T-cell therapy, “chemo brain” or “brain fog” can affect concentration and short term memory.

(29:45): Low blood counts and ongoing risk of infection are possible late effects of CAR T-cell therapy.

(32:33): Patients do not respond well to the COVID vaccine after CAR T-cell therapy, so precautions against COVID, like wearing a mask for a year, are important.

(33:39): Anti-viral therapy is recommended after CAR T-cell therapy to reduce the risk of shingles.

Transcript of Presentation:

(00:01): [Michelle] Introduction. Welcome to the workshop, CAR T-cell Therapy: The Good, the Bad, and the Long Term. I'd like to thank Kite, A Gilead Company whose support helped make this workshop possible.

 (00:12): It is my extreme pleasure to introduce our speaker, Dr. Michael Tees. Dr. Tees is an associate member at the Colorado Blood Cancer Institute and a leader in their Lymphoma and Autoimmune Program. He focuses on the treatment and management of aggressive lymphocytic disorders and malignancies. Dr. Tees treats patients with standard approach CAR T-cell therapy as well as CAR-based therapies on clinical trials. He favors the next phase of lymphoma care being rooted in an individualized and targeted approach and is excited about the rapid pace of development in the field. Please welcome Dr. Tees.

(00:58): [Dr. Tees] Overview of Talk. Well, thank you. Hi. My name is Mike Tees. As Michelle said, I am the lymphoma director at Colorado Blood Cancer Institute in Denver, Colorado. Thank you everybody for tuning in today and learning about CAR T-cell therapy. Today, I just wanted to talk about three major objectives: share what CAR T-cell therapy is and why it's used; explain the short term side effects and toxicities of CAR T-cell therapy; as well as

(01:39):  Bone marrow inside bones is home to hematopoietic stem cells that produce the body’s blood cells. To get a better picture of CAR T-cell therapy, I want to start from the top. I draw this picture out on paper to pretty much every single patient that I meet. If any of my patients are in the audience, perhaps you have a little more of a heads up than everybody else and this is a little bit of a biology education. Everything in the blood system starts with the bone. The bones hold up the body, but they also contain an environment where stem cells grow. Stem cells that live in the bone marrow are called hematopoietic stem cells. Heme is blood and poetic is Latin for growing; so blood-growing stem cells. Hematopoiesis means blood cell growth.

(02:23): They turn into two major types of cells: myeloid cells and lymphoid cells. For many of you in the audience, you're probably somewhat familiar with many of the myeloid cells. Platelets. Platelets help form blood clots. Red blood cells. Red blood cells carry hemoglobin and hemoglobin carries oxygen to your body. Then neutrophils. Neutrophils are very important to fight bacterial infections. Neutrophils

(02:56): The three major lymphoid cells in the immune system are T-cells, B-cells, and NK cells. There are three major types of cells. I used to just say two major types of cells, but NK cells are becoming a little bit more prevalent or prominent, I guess you could say, and we'll talk about that in a little bit. But the way I describe the lymphoid cells is like a military for better or for worse. T-cells are the front lines of the military. They fight the bad folks by recognizing what looks like you and doesn't look like you. If it looks like you, it's a friend. If it doesn't look like you, it's an enemy and it can kill it.

(03:29): The B-cells are described as like the generals of the army. They have the memory and the strategy, and the understanding of what basically needs to occur. A good example in B is if you got an infection like the flu, for example. If you got sick and then you got better again, it's because the B-cells eventually understand that. Then they tell the T-cells, "Oh, I know what this is," when you get re-exposed and then you don't get sick because the body takes care of it, because of that inherent memory that has formed. Part of how they do that is actually turning into plasma cells. For those of you who may be on the call with a history of multiple myeloma, it is plasma cells that is the derivation of your disease. That actually has a lot more relevance as we move forward because CAR T-cell therapy is being used in multiple myeloma.

(04:24): Now, the other one at the top or to the side right here is the NK cells; those stand for natural killer cells. It's a remnant of an archaic immune system, but it does have some natural infection-fighting and actually some natural tumor-fighting abilities.

(04:45): To understand CAR T-cell therapy, I just want to do a brief review of what the two different types of stem cell transplants are and how it fits into CAR T-cell therapy.

(04:58): In an autologous stem cell transplant, some stem cells are removed, chemotherapy is administered, and the same stem cells are returned. For autologous stem cell transplant, the treatment is high dose chemotherapy. The two major regimens that are used for most diseases are BEAM or melphalan. As you might be aware, it's not actually the stem cell transplant that's doing anything. It's really actually just bypassing the major side effect of the chemotherapy, in that it eradicates all your hematopoietic stem cells. For that reason, we have to collect your stem cells before the treatment, do the treatment, and then give you back your stem cells. The correct term is actually high dose chemotherapy followed by stem cell rescue. That's really difficult to say, too many words. So we just call it autologous stem cell transplant or stem cell transplant, which is a lot scarier of a word, but it's really the chemotherapy that's doing the job.

(05:50): If chemotherapy is not effective in treating a cancer, an autologous stem cell transplant may not be the best treatment option. What if you didn't respond to chemotherapy to begin with? For example, if you had an aggressive lymphoma like diffuse large B-cell lymphoma. If you got the standard treatment CHOP or R-CHOP, for example, or RICE, if you didn't respond to that, would you get a stem cell transplant? That's a good question. It depends on the person; it depends on the patient. But the example is that if you don't respond to chemotherapy, you might not be a good person to get a stem cell transplant because the whole reason that we do the treatment is for that higher dose chemotherapy to try to eradicate any residual disease or at least decrease the burden of disease.

(06:31): In an allogeneic transplant, it is the donor cells that fight any remaining leukemia after chemotherapy. The other type of stem cell transplant is allogeneic stem cell transplant. The idea is that we first eradicate the immune system with, what we call, conditioning therapy. It depends on intensity of conditioning, there actually might be some additional anti-cancer benefit.

(06:47): It depends on many different factors on what your regimen would be and how aggressive that would be against the disease, but what we truly want is something called the graft-versus-malignancy effect. That's also called the graft-versus-leukemia or the graft-versus-tumor effect; a lot of different names for the same thing. Maybe even graft-versus-lymphoma effect if you were a patient that got a transplant for follicular lymphoma, for example. Essentially, you want the donor's immune system to recognize the cancer as foreign. If you recall a couple of slides back, that's exactly what T-cells do; it recognizes what looks like you and doesn't look like you. If you are getting someone else's immune system, the idea is that perhaps it could recognize your cancer as foreign and take care of the disease.

(07:35): The corollary to that is graft-versus-host disease. That's what we don't want and that's when the donor's immune system recognizes other aspects of your body as foreign. But the source of all that are T-cells.

(07:50): CAR-T cell therapy is currently approved for several B-cell acute lymphoblastic leukemia, some lymphomas and multiple myeloma if other treatments have failed. Who gets CAR T-cell therapy? Right now, there are a couple of indications by the FDA. For those of you that are out of the country, I'm just speaking of what's approved in the United States. Well, for refractory acute lymphoblastic leukemia. This is B-cell acute lymphoblastic leukemia. And it's for patients who are not responding to therapy. That's refractory disease. It's currently used to achieve disease control. For most patients, it's proceeding onto an

(08:23): Other approvals are for diffuse large B-cell lymphoma, and that was one of the original approvals, and also other aggressive B-cell lymphomas. There's some [other lymphomas] that are in the same category as that disease. It's for patients who are refractory to two or more lines of therapy: in follicular lymphoma after failing two or more lines of therapy; mantle cell lymphoma after two or more lines of therapy. And then multiple myeloma after four or more lines of therapy.

(08:49): In all of these diseases, we're looking at them in other settings as well. For example, what we started investigating several years ago, diffuse large B-cell lymphoma in the second-line setting. It just got approved about four weeks ago that CAR T-cell therapy would be indicated for patients who have relapsed within one year of their initial therapy or that are refractory to their first line of therapy.

(09:23): Other lymphomas and solid tumor cancers may soon be treated with CAR T therapy. Where is the CAR driving to next? Well, we're very close to treatment for CLL and small lymphocytic lymphoma, Hodgkin lymphoma, and also, some of the "solid" tumors: that's glioblastoma; hepatocellular carcinoma, that's actually liver cancer; and prostate cancer.

(09:46): Acute myeloid leukemia, myelofibrosis and some solid tumors are not yet good candidates for CAR T therapy. Now the ones that we're a little bit far away from, unfortunately, those are the myeloid diseases: that's myelodysplastic syndrome; acute myeloid leukemia; myelofibrosis; and some of the other solid tumors. I'll explain a little bit more why we're not there just yet for those, but we're still working.

(10:06): What is it [CAR T-cell therapy]? I told you a little bit about the T-cells. They basically recognize what's good and what's bad. But right now for pretty much all diseases, I guess you could say, if you don't have a T-cell that could recognize the cancer, then you're in bad shape. But more importantly, it's because your diseases love you. Your disease looks like you.

(10:34): CAR T therapy re-engineers T cells to recognize and kill cancer cells. How do your T-cells know what's good and what's bad if the cancer itself looks like you? The idea is that, "Let's re-engineer these T-cells, so they know what they need to do, which is kill the cancer," and that the current process goes something like this.

(10:52): First step in CAR T-cell therapy is to get insurance to approve the treatment. Step 1 is get insurance approval. That's a very important aspect of it because this is a very expensive therapy. I gave some ballpark numbers right there. But every program, every, unfortunately, insurance company is a little bit different on this. Also, a lot of it depends on if you're also entering a clinical trial. Sometimes, it's actually a little bit quicker; sometimes a little bit not as quick. But it does take some time to actually get all the pieces together to allow you to proceed to this type of treatment.

(11:27):. Part of that now is also how quickly these T-cells can be created. For the majority of CAR T-cell therapy recipients, this is going to be what we call a "commercial" product. "Commercial" means that these are pharmaceutical products. These are made at an institution or program, or pharmaceutical company and that process on how to manipulate these T-cells is a process that the pharmaceutical industry has created. It allows these cells to be made under a controlled environment. For that to occur, there needs to be a slew of processes to ensure that when we send these cells away, that their production is going to occur at the right time and that it's going to be received at the right time. Are there too many cells that are going to arrive all at once and how can they actually manage that? There's a lot of moving pieces to, actually, that first step.

(12:31): The next step is actually collection of the T-cells and growth. The third step is the giving of low intensity chemotherapy followed by the CAR T-cell infusion. The fourth step is monitoring for the side effects and toxicities.

(12:51): This is outlying the exact process of the collection phase, the step 2, I guess you could say, from the slide before. This woman looks very happy, but I guess she's happy about the possibility of getting these T-cells. But the first step is that she's going to be getting the T-cells taken out and then they get shipped away. For many programs, it's actually done perhaps in-house if it's a clinical trial. Maybe we'll say it gets shipped internally, but sometimes it's also being shipped internationally. It depends.

(13:23): The correct T-cells must be selected for conversion to CAR T-cells in order to be effective. Then the next step is selecting the correct T-cells. I gave a very broad picture of what T-cells are, but there's many different types of them. We want to make sure that the correct ones are selected because if the correct ones are not and then they might not actually do the job.

(13:42): Viruses are used to insert genetic material into T-cells and convert them to CAR T-cells. The third step is transferring the genetic material to make the CAR into the T-cells. It says viral vector transfer. There's many different viruses in the world. Obviously, we're very familiar with that, but these are viruses that don't actually infect in a bad way. They're just transferring the DNA. That DNA is going to tell the T-cells to grow a certain receptor on the outside of the cell. That's what CAR stands for, chimeric antigen receptor. Chimeric just means it's a combination of molecules that physically wouldn't be made if the code wasn't there. The next step, then, is to expand these T-cells followed by returning back to the institution, to then ensure that you're treating the patient.

(14:39) It may take roughly three weeks to create and return CAR T-cells to patient. While you're waiting for that process to occur, there's a couple of things that might need to happen. The standard right now, it's about 14 to 22 days, we'll say, for those CAR T-cells to be manufactured. Depending on certain clinical trials, that can actually be up to five to six weeks. Because with newer types of, let's say, products, the CAR T products or CAR NK products, which we'll get to in a little bit, there might be longer processes that need to occur. There might need to be more checks and balances to ensure that, again, it's the right cells that are being manipulated, the right cells that are being expanded. Very, very complex stuff that's happening and I very much simplified here on the last slide. But for the most part, it is roughly about three weeks from the time of removing your T-cells to the time that it comes back to the program where you can get the treatment.

(15:38): Patients with aggressive disease may require bridging therapy to control their disease while CAR T-cells are being created. For many patients, especially those with aggressive lymphomas, for example, they might need some bridging therapy to keep that disease under control. Everyone's a little bit different on this one because you might still have an aggressive lymphoma, for example, or multiple myeloma that perhaps does not need some bridging therapy, but that's a conversation with you and your treating physician on that aspect of it.

(16:08) A few days before infusion of CAR T-cells, patients receive low-dose chemotherapy to suppress their immune system. Approximately five days prior to the CAR T-cell infusion, you're going to start some lower dose chemotherapy. The reason for that is because even though these cells are you, they're not exactly you and your immune system might recognize them as foreign. The idea is that we give two... Typically, it's two lower dose chemotherapeutic agents and they're designed just to somewhat knock down the immune system in order for you to accept these cells back. We call it lymphodepleting chemotherapy.

(16:43): CAR T-cells may be re-infused in the hospital or outpatient setting. On Day 0, you get the CARs infused into you. Some programs are doing this all in the inpatient setting; some are also doing this in the outpatient setting. We're doing a mix of the two and it depends on a couple of different factors. Well, actually, it's the next topic, which are the side effects and toxicities. But you get the cells infused and then it's watching and waiting. It's not exactly like a stem cell transplant, where you are waiting for those stem cells to find its home, which is back into the bone marrow, start to grow, and reproduce. The reproduction of these T-cells actually happens relatively quickly. It starts to expand and ideally starts to do its job, which is to start to kill the cancer. With that process comes some side effects. To be honest with you, some of these side effects can still occur even if these CAR T-cells don't do what you want it to do, which is to kill the cancer.

(17:41): The major side effects between Day 0 and 28 are infection, cytokine release syndrome and neurotoxicity. For these reasons, if you are not in a hospital setting, if you're not admitted to the hospital, you would definitely need to be close to that treatment center.

(18:03):. On Days 0 to 28, infection; I just brought that up. It's primarily for a couple of different reasons. The first one is lymphodepleting chemotherapy. They're two lower dose chemotherapies that does knock down immune system to a level where you would be, what we call, neutropenic, which is probably familiar terminology to many of you. You will be on some prevention antimicrobials. This typically occurs between Day 0 through Day 14. After the neutrophils recover, you will also be continued on an anti-viral medication to help control the risk, primarily, of shingles.

(18:43): But this is the big one. This is the biggest concern and the biggest possibility for why you need it to be treated at a program that really knows what they're doing. If you are being talked about CAR T-cell therapy by a provider, you're probably at a program that knows what they're doing because it's actually well-controlled, the programs that are able to do this type of treatment.

(19:10): Cytokine release syndrome can cause fever, low blood pressure, and shortness of breath. But as the T-cells expand in your body, they do release natural chemicals. These are called cytokines and these are the natural chemicals that the immune system uses to communicate with each other. If you have a fever, when you get sick, that's actually being driven by cytokines. It's telling the body to basically cook out these bacteria that's maybe causing you to get sick. It's a natural immune phenomenon that occurs that comes from T-cells.

(19:43): If you are given T-cells to help fight the cancer and it starts to do its job, starts to grow and reproduce, it's going to start to throw out these natural chemicals. It's going to mimic like you're very sick. There's a very wide spectrum of how ill you could potentially get. We call it cytokine release syndrome. You could get absolutely nothing, which would be great, to it being very severe. The big three is fever, lower blood pressure, and shortness of breath. Shortness of breath comes from having fluid, basically, in the lungs in this reaction that occurs. Your oxygen level could go down; you might need oxygen support.

(20:25: The risk of developing cytokine release syndrome varies depending on  amount of disease one has before CAR T-cell therapy and the type of CAR T product you get. Those with a higher disease burden before CAR T-cell therapy do have an increased risk of CRS. The risk is also dependent upon the exact product that you get. There's a couple reasons for that, but primarily it's because of how the CAR T-cells are "built". Sometimes, there's different genetic makeup that, basically, turns on the cells in a different way. It might turn on very quickly or it might turn on a little bit later on but expand out in a different way. Long short is basically that everyone's risk cannot be clearly defined. For that reason, we have to watch you very closely no matter what.

(21:12): Most patients develop cytokine release syndrome. Oh, I guess that's the next slide. I'm sorry. But will you get it? It depends, but the short answer would be probably yes. For ALL patients, it's about 80 to 90%. For diffuse large B-cell lymphoma, follicular lymphoma, it can range between 40 to 80%. Mantle cell lymphoma is actually up to 80%. In multiple myeloma, fairly high. But the severity might be different amongst all of that. If I said, "Oh, yeah. You have an 80% of getting it, but you might get a fever that's different than 80% of patients getting it and then needed blood pressure medicines and advanced cardiac support, for example." But it is something to be aware of going into it, that it tends to start between Days 3 to 5 and lasts about five to 10 days. It's a wide variability if and when it does present, how severe it is, and how long it lasts.

(22:07): There are several treatments for cytokine release syndrome but they have their own side effects. The treatment is a medicine called tocilizumab or comparable medicines such as one called siltuximab and steroids. It is completely reversible, but there can be secondary effects. That's where there can be some longer term injuries that can occur. For example, if your blood pressure drops too low and you can't get the blood and the oxygen to support your kidneys, for example, that could cause kidney injury. Steroids can increase the risk of infection. If you're very sick and you're not able to move out of that hospital bed, you could get deconditioned and lose lots of muscle mass.

 (22:49): Neurotoxicity, also called ICANS (immune effector cell-associated neurotoxicity syndrome) can occur after CAR T-cell therapy. The third major side effect is neurotoxicity. You can probably guess what that means, but really the correct term is actually immune effector cell-associated neurotoxicity syndrome; that's where ICANS comes from. But it's actually a similar process. It's driven by cytokines. Those natural chemicals that are released by those T-cells can cross over the blood-brain barrier and basically jumble up the wire. That's why I describe it to patients, is that all the neurons in your brain that allow you to remember what day it is, what your children's names are, allow you to connect your brain, your main computer system to your body to tell you to breathe, those can get jumbled, all those wires by the cytokines. That can make you very, very sick. It can be something from a simple... Sounds simple, but just forgetfulness to actually not being able to comprehend. Severe is something like seizures; that can actually occur.

(23:54): To monitor for this, you're going to get very frequent, standardized assessments. It's repetitive. Patients don't get offended. You're going to be asked the same questions. What day it is? Can you write a sentence out? Because if we start to notice some change in your writing, for example, that could be a signal of things to come. The idea is that we're identifying it sooner rather than later.

(24:25): The likelihood, severity, and symptoms of neurotoxicity depend on the underlying disease. Will you get it? It depends. It's not easy to predict, but there are certain diseases and certain treatments for those diseases that do have a higher risk. ALL is another one. Again, mantle cell lymphoma is also high on the list. Now for multiple myeloma, it's actually... I apologize. This is not probably the correct way to put this in this slide, but there is a lower incidence of the standard neurotoxicity that we tend to see for other types of CAR T-cell therapies. But we do see a unique type of neurotoxicity that's related to multiple myeloma CAR T. There can be these Parkinsonian-like symptoms. There's other unusual tremors and motor neuron-type issues. It tends actually to be perhaps a little bit later than Day 0 through 28. We're going to understand a little bit more about that one over time, but it is something that your CAR T physician will probably be talking with you about.

(25:34): Neurotoxicity can be treated with steroids and is almost always reversible. Now neurotoxicity tends to begin around Days 6 to 9 and it tends to last about 11 to 20 days. It's a little bit shorter for those with multiple myeloma. There's a wide variability of if and when it presents, how severe it is, and how long it lasts. The treatment is steroids. Neurotoxicity is almost always reversible, but there can be those secondary side effects. If you're on steroids to treat anything, you can oftentimes become deconditioned. It's always important to stay as active as possible if it's safe.

(26:09): CAR T-cell therapy is very expensive and it takes time to get insurance approval. Now is a good time to talk about the financial toxicities. That's a very real issue. I do need to bring this up because this can come up at the wrong time. Well, there's never a good time to talk about this. I brought it up earlier, but the cost of this cell therapy itself is absurd. It's absurd; I'll just say that. The cost of the supportive care also somewhat absurd. But if you think about it, you could do great, not have any complications whatsoever, or you could get very, very sick, and be in a critical care unit needing to be on medicines that are helping support your heart or you need to be on a ventilator for a brief period of time. You need to be on antibiotics if you're having a fever. All of that adds up in the cost of overall care. That makes it very difficult for insurance companies and those who are covering the cost of care to determine what is the best price to pay.

(27:14): For that reason, it does take some time before the treatment even begins for your coverage entity, we'll say, to agree with that program on how to cover the cost of your treatment. More than you ever want to know, but it does sometimes cause some unnecessary delay. I'm hopeful that over a time as the treatment is becoming more and more prevalent and necessary, that this is less of a problem.

(27:46): After CAR T-cell therapy, “chemo brain” or “brain fog” can affect concentration and short term memory. Now, the longer term. I guess we'll say the intermediate term. There is a concept of something called brain fog. This is something that I'm going to probably put in the anecdotal-type realm, but it's something very real that my colleagues across the country also notice. It's getting out there a little bit. It's a little bit of a delay in that maybe neurotoxicity. All right? Essentially, some people could put it in the realm of the chemo brain. There's two major things of chemo brain. I would say there's two major things that I've noticed with brain fog; it's concentration and short term memory. One of also the reasons why it's not advised to drive about two months after the cell infusion because your reaction time might be a little bit decreased. It's one of the main reasons that even though people say, "I feel fine." I say, "You know what? Maybe just take the bus. Actually, don't take the bus. Wear a mask if you're going to take the bus." But maybe find a different way to get to work. Take an Uber type of thing.

(28:52): But in those patients with this brain fog, it is actually a little bit difficult to get back to work. It does resolve. I've seen it in every single one of my patients, but it's something just to be thinking of because it's not something that's very well reported. If you have the ability to maybe take some time off of work for a little bit longer to allow your body to heal and recover from a very serious type of treatment like this, please consider that if it's available to you. Now there is a real thing. It's likely because of the cytokines that are lingering and some disruption in the communication of the neurons across the body perhaps, but something that's not to minimize.

(29:45): Low blood counts and ongoing risk of infection are possible late effects of CAR T-cell therapy. The other late effects and something that's underreported from the initial studies that led to many of the CAR T-cells being approved is blood counts. You actually can have a prolonged cytopenia; basically, low hemoglobin, low platelet count, and of course, low neutrophils, neutropenia. This can actually last up to, I would say, about six months for some patients. It resolves over time. You could say that some of the bad comes with the good on this one because it is associated with patients who have persistence of their CAR T-cells. That's important for some diseases because if they're sticking around, it's probably because they have some work that they still need to do. As long as you're being supported appropriately and know that that's going to resolve over time, then you should be okay.

 (30:43): On that note, somewhat related to these late effects is risk of infection. I told you about the shorter term risk of infection that's typically related to the neutropenia; so low neutrophils that fight bacterial infections. But CAR T-cell therapies target for the most part... Actually, I do a quick lesson on this I guess, but for the B-cell lymphomas, for follicular lymphoma, for mantle cell lymphoma, for diffuse large B-cell lymphoma, for acute lymphoblastic leukemia, it's CD19. It's called Clusters of Differentiation 19. It's something on the outside of the cancer cell that's unique to that ,for the most part, and that's how the T-cell recognizes the cancer. For myeloma, it's called BCMA.

(31:34): Now both of those targets are actually on healthy immune system cells, healthy B-cells. It's not too much of a concern if the CAR T-cells attack healthy B-cells for a brief period of time. But if it's persistently attacking the healthy B-cells, you'll have an effect on that memory aspect of your immune system. If you recall on one of the first couple of slides, I said that the B-cells were like the generals of the army. If you knock out the generals of the army or they all quit, then the troops don't know what to do. The rest of the crew won't know how to fight something and that's exactly what we see. This could be actually up to a year or so where patients who have received CAR T-cell therapy have a weakened immune system to the extent that it's more than likely very much similar to those who get an autologous stem cell transplant.

(32:33): Patients do not respond well to the COVID vaccine after CAR T-cell therapy, so precautions against COVID, like wearing a mask for a year, are important. For those who have received an autologous stem cell transplant or even an allo transplant, more than likely you receive post-transplant vaccinations. In some programs, it starts at six months and others, it starts at one year. We start ours at one year. That's just to re-educate the immune system. Also, within the era of COVID, we have been seeing that patients don't respond as well to the COVID vaccine after CAR T-cell therapy. That's because we're knocking down, unfortunately, the good immune aspect of immune system. It will eventually come back, but it's important to know this that you do have a prolonged risk of infection. If we wanted to say that there was anything good about COVID, which is nothing, no one looks at you funny if you're wearing a mask anymore. I would be advising that patients wear masks for at least a year after CAR T-cell therapy in public.

(33:39): Anti-viral therapy is recommended after CAR T-cell therapy to reduce the risk of shingles. This is essentially saying the same things. I'm just going to be a little bit briefer on this one. But essentially you do have a risk of shingles, which is why the recommendations that you would continue an anti-viral therapy. There's a risk of a certain type of lung infection called Pneumocystis pneumonia. You would want to be on an antibiotic for likely about 12 months after a CAR T-cell therapy; three times a week is not too bad.

(34:04): Natural antibodies are called immunoglobulins. IgG is the most common one and that helps fight mainly sinus and pulmonary infections, respiratory infections. In many patients, it is low for a period of time. For this reason, IV immunoglobulin, IVIg is oftentimes administered on a monthly to every six-week basis for some patients after that CAR T-cell therapy just to simply support the immune system and reduce the risk of viral and sinus, and pulmonary infections.

(34:35): Now if you had a decrease in neutrophil count, then you could also get a medicine called G-CSF. Brand names are called Neupogen or Zarxio or Granix, but they do help support the neutrophils. Many CAR T-cell patients respond beautifully to that medicine. Again, vaccinations would be advised.

(34:57): Late neurological effects after CAR T-cell therapy have been reported. Other late effects, there have been some rare, long term neurologic effects. I am not entirely sure that this is as much as perhaps been reported. It's definitely less than 1%. It's not clear if they're actually associated with the therapy or perhaps it was associated with other therapies in the past. Or it was something that maybe was undiagnosed and then it's presented afterwards, and saying, "Okay. Well, maybe it was associated with CAR T-cell therapy."

(35:38): Some patients have developed skin cancer or myelodysplastic syndrome (MDS) after CAR T-cell therapy, but it is unclear whether that’s related to CAR T or prior treatments. Now there is some second malignancy risks. I can probably tell you that a lot of it is not necessarily directly related to the CAR T-cell therapy. It's probably because many patients had required several lines of other therapies prior. That addition of all those treatments do make patients prone to have an increased risk of skin cancers and an increased risk of something called myelodysplastic syndrome, which is another type of blood cancer. There are some things in the pipeline that is allowing us to decrease the toxicity and allowing us actually to do more treatments in the outpatient setting. One example is using steroids at Day 0 through 2 after CAR T-cell therapy. It's shown to reduce the severity of cytokine release syndrome in lymphoma patients. Many clinical trials are investigating ways of reducing a toxicity.

(36:39): Many studies are underway to improve CAR T-cell therapy and expand its use to other cancers.. The future, well, when CARs fly, there's different ways of looking at where we're going to be going into the future. There's so many different paths and the field is changing so quickly, but it's very exciting. One way is actually instead of having to wait three weeks perhaps for the CAR T-cells to be produced, what about just educating your body to make the T-cells themselves? That's under investigation right now at several programs across the country.

(37:10): What about using those natural killer cells, the remnants of an archaic immune system that can recognize you versus not you? What about just re-engineering them to recognize another aspect of what the cancer is on the outside and use that one-two punch effect? We're investigating that at CBCI [Colorado Blood Cancer Institute] using different immune system cells. Monocytes are one cell that turns into something called a macrophage; that's one example.

(37:42): What about using T-cells or NK cells that are available and ready to go from donors? That's another aspect of the future. Then re-engineering the drivers of the toxicity, re-engineering and taking out those genes that's called knockout. Knocking out those specific genes that could actually drive the toxicity.

(38:11): One last thing is that we are actually investigating this type of treatment for the "solid" tumors and those are the ones that are non-blood cancers. If you have a target that's unique to a cancer, you might be able to create a CAR T-cell to fight that. Now there's a lot of aspects on why that has some work to do and why we're a little bit farther behind on that. But we're getting there and it's quite exciting. With that, I want to thank you all for your time.

Question and Answer Session

(38:49): [Michelle ] Wow. Thank you, Dr. Tees, for an excellent presentation. Very, very informative. We will now take questions. We've got a lot of questions, Dr. Tees. I hope you're ready. What is my role as a caregiver for my husband who will go through CAR T-cell therapy? What can I expect and how does my role as a caregiver differ from caring for someone during or after transplant

 (39:28): [Dr. Michael Tees ] Oh, that's a great question. Well, I would say big picture, your role would be the same as it would be if you had an allo or an auto transplant as you would for a CAR T caregiver. You are the second set of eyes and ears for that patient. You're their lifeline. Not in that term, I guess you could say, but you are the one that will be calling or bringing in your loved one if and when he or she gets sick. You are going to be educated. You should be educated on what are the signs to be looking out for. If your loved one gets a fever, you're going to be calling the on-call service, where you're going to be bringing in. You're going to follow to the T what you're educated [to do] because each program's a little bit different. But you're going to be looking out for a fever, most importantly.

(40:25): Then I would also be saying that it's typically family members that notice the first nuances, the first signs of those neurologic changes. Years ago, when the first patients were being treated for CAR T-cell therapy, it was quickly realized that it's almost like those wires just aren't connecting correctly. Your loved one might say just the wrong thing or just not act who they are for brief periods of times. It's oftentimes the loved ones that are picking up on that even before we objectively identify that. That is something to share when you're at the appointments or share with the care team if your loved one's in the hospital, but your role is to be the eyes and ears when you're not in that healthcare environment. Know what you need to do and ask questions on, if you don't know, how to actually reach out to your care team when you're not in that office or when you're not in the hospital.

(41:37): [Michelle] Dr. Tees, well, if a patient was exhibiting new signs of weakness, would that be something you'd want a caregiver to report as well?

(41:47): [Dr. Michael Tees] Absolutely. 100%. Absolutely. Yeah. Because it could be something normal if your immune system is weaker, but it might not be. It might be a signal of something else. It could be that their blood pressure is a little bit lower or maybe it's a reaction to one of the medicines, but absolutely.

(42:13): [Michelle] Great response. I have multiple myeloma. What do you consider a line of therapy? Your slide said I must have a minimum of four lines of therapy before I can qualify for a CAR T.

(42:27): [Dr. Michael Tees] Yeah. That's a very good question as well. As of right now, the standard of care treatment for multiple myeloma in the United States is induction therapy. Well, say just Rvd [Revlimid], it's a very common one, followed by stem cell transplant, followed by maintenance therapy. Many studies look at that as one line of therapy. Then if your disease comes back, you get another line of, let's say, daratumumab-based treatment. That's a second line and so on, and so forth.

(43:05): But each study actually has their own unique criteria on what they determine as a line of therapy. For example, if you received radiation to a lesion, for example, some studies might actually consider that a line of therapy. It ends up being the institution that determines if you meet the internal criteria and then they decide if you meet the candidacy of either trial or standard of care for multiple myeloma. When I say standard of care, I mean that "commercial" products, the ones that are already proved by the FDA.

(43:47): [Michelle] The next question is: What is meant by bridging therapy?

(43:53): [Dr. Michael Tees] Yeah. Good question. When you get the T-cells removed from you and when they move on to the production of those cells, it typically takes about three weeks for that to occur. For many diseases, three weeks is a long time. It's not the case for all cancers, but sometimes, for example, an aggressive diffuse large B-cell lymphoma, if you're not responding to all the treatment, three weeks is a long period of time for that cancer to keep growing. Let's suppose it's in a bad area of your body where, let's say, it's pushing upon your kidneys. Well, I don't think we can wait three weeks to see if this medicine will work or the CAR T-cell therapy will work.

(44:43): Bridging therapy is done between the time of your leukapheresis, or removal of your T-cells, and from the time it takes for it to come back in order for you to get the treatment for CAR T-cell therapy. It's about three weeks roughly. You would get treated soon after the cells are removed in order to try to control the disease for a period of time. Now some programs actually do that even if your disease maybe isn't "taking off" or being that aggressive because some evidence suggests that going into CAR T-cell therapy with as little disease as possible have better outcomes. Your provider might be recommending it even if your disease isn't very aggressive, I guess you could say.

(45:33): [Michelle] Terrific. Our next question is: How long do people stay in remission after CAR T? Is it a cure or a temporary remission?

(45:44) [Dr. Michael Tees] Yeah. Tough question. Well, it depends. It depends. I always tell patients I don't like to use numbers. Everybody likes numbers, of course. But you're one person, right? Your response is either it works or it doesn't work. Your doc and your care team would ideally have a plan of action if it doesn't work. If it does work, then great. In general, roughly speaking for diffuse large B-cell lymphoma and the related aggressive lymphomas, it is at roughly 40 to 50% long-term response rate. Response rate, we would call, perhaps a cure. For acute lymphoblastic leukemia, that could be closer to 40%. For mantle cell lymphoma, that could be about 60%. For follicular lymphoma, it's looking like it's about 50 to 60%. It's tough to say.

(46:56): If you think about where we were, I don't know, let's say just 10 years ago, where we are now is that we're using this for many patients that don't have an option, who didn't have an option in the past. Where we're also going more quickly though, is, well, if this is a treatment that actually works for the longer term for many patients, what if we did it earlier on in their treatment? That's one thing that I showed a slide, for example, for aggressive lymphomas, diffuse large B-cell lymphoma. It was approved on April 1st for patients in the second line setting if they've had a relapse within one year of their first line therapy or didn't respond to their first line therapy.

(47:43): In many patients, you would be actually replacing a stem cell transplant. It's actually taking away one of the therapies that we have currently been using for a long time that has shown benefit because perhaps CAR T-cell therapy actually has an additional benefit on top of that. We have a lot of understanding still to know what a complete response truly means, if it's actually a cure. We're starting to see that more with, what we call, real world data following patients for the long term.

(48:26): [Michelle] This next question really aligns with what you were just talking about it. It's asking more questions about number of lines of therapy and I'm going to assume this one is about lymphoma. It says, "When you say that the treatment has been approved after two lines of therapy, can you give examples of the lines of therapy that are considered?"

(48:48): [Dr. Michael Tees] Yeah. For lymphoma, if a patient has received their first line of therapy, we'll say it's R-CHOP and they got a complete response, that's one line of therapy. If their disease comes back, then they would be getting another line of treatment; that would be a second line of therapy. If that doesn't work, they would be a candidate for CAR T-cell therapy. If it did work, then they moved on to a stem cell transplant, that's considered a line of therapy right there. Then if their disease comes back again, then they're a candidate for CAR T-cell therapy. That's the example, I guess, for aggressive lymphoma.

(49:38): For other types of lymphoma such as follicular lymphoma, for example, maintenance therapy would not be considered a line of treatment. A standard induction treatment for follicular lymphoma will be bendamustine/obinutuzumab or bendamustine/rituximab followed by maintenance therapy thereafter. Maintenance therapy would not be considered another line of treatment because it's basically piggybacking off the success of the first line of treatment. It depends on every single patient and their actual treatment history. I encourage you to talk to your hematologist on this because they would be able to more clearly tell you what lines of treatment means and how that applies to your treatment history.

(50:27): [Michelle] Excellent response. Our next question is: Has CAR T-cell therapy been approved for mantle cell lymphoma? If so, what is the efficacy of the therapy on MCL?

(50:41): [Dr. Michael Tees] Yeah. It is approved for mantle cell lymphoma. It was approved, I want to say, in 2020, maybe 2021 for patients who have failed two lines of therapy. What that means is that the standard treatment for mantle cell lymphoma would be first line treatment followed by stem cell transplant, followed by maintenance. That's all one treatment. Then if you received another line of treatment such as ibrutinib, for example, or acalabrutinib and then fail that, then you meet the candidacy for a CAR T-cell therapy. It has been investigated actually in the second line setting, too. You would maybe not even get that second line of treatment and just maybe get CAR T-cell therapy, but the response rate is fairly good. It's a roughly 60-somewhat percent response rate and it drops a little bit down for that long term response, though. Somewhere between 50 to 60% of patients get a long term response.

(51:44): [Michelle] If okay, I'm going to answer this next question. One of the viewers asked if we could list some facilities that offer CAR T-cell therapy. If you go to the bmtinfonet.org site, you will be able to click on find a treatment tab and it will list multiple centers that have CAR T-cell therapy available in your area.

(52:16): The next question is: How far down the road is CAR T treatment for myelofibrosis? One to two years? Five to 10 years? Is it worth waiting for to avoid massive chemo or transplant?

(52:31): [Dr. Michael Tees] Yeah. Myelofibrosis, I can tell you, is far down the road. As of right now, we don't have a very good target that's specific to myelofibrosis. Part of the reason is for everything that's a myeloid disease, myelofibrosis, MDS, myelodysplastic syndrome, acute myeloid leukemia, the issue tends to actually be far higher up towards that stem cell. When you get higher up, when the issues start higher up, if you target those cells, you could actually be injuring the healthy stem cells. We have a lot of work to do to what can we target that's unique to some of these cancers. Whereas for the lymphomas and multiple myelomas, we already have an understanding because it's a little bit of a different mechanism on how that disease evolved to that point.

(53:39): For myelofibrosis, unfortunately, we are a little bit behind the times and hopeful that we're moving in that direction. But I will tell you that the time for identifying that to the time when this treatment would be available to patients, we're talking years. Many times, diseases can't wait that long. That's why if you're considering not pursuing the treatment that is advised, for example, do your homework first before making that determination. Get that information that you need. Go to clinicaltrials.gov. Use other resources like Leukemia and Lymphoma Society. They have a clinical trial support center where you could ask to see what other clinical trials could be available and see if there's something out there that you would want to consider. But I will say, unfortunately, myelofibrosis, we don't have a good target just yet.

(54:37): [Michelle] The next question is: Is there an age group that has the highest success rate with CAR T-cell therapy?

(54:51): [Dr. Michael Tees] Yeah. Good question. That's a tough question to answer because often with age, as patients get older, they often come with other conditions that have developed over time such as heart disease or chronic kidney disease, that type of thing. That still adds some additional risks to the overall treatment itself. But for the most part, I will say that there isn't an age group that does better or worse than others. In fact, going back to that real world data, we have not seen that. Now some places might not want to treat patients maybe a little bit older because of the risk of that cytokine release syndrome, for example. If the body isn't robust enough to be able to get through that, our goal is to not have the treatment cause any compromise to you. It's person-specific. It's patient-specific on the recommendation sometimes if CAR T-cell therapy is the best treatment strategy.

(56:06): [Michelle] Terrific. We're down to our last couple of questions. Our session timing is almost up. Which do you suggest, an allogeneic transplant or CAR T? Which one is better for relapsed mantle cell lymphoma patients?

(56:23): [Dr. Michael Tees] Yeah. Oh. Ooh. Another tough question to answer. Mantle cell lymphoma, just like all other cancers... I always tell patients this, is that there's no one in the world that has your cancer, even though it's the same name. Because your cancer came from you, of you, and it still continues to evolve over time. For example, patients with mantle cell lymphoma, sometimes there are certain mutations that confer a poor risk, a higher risk. I will say, though, generally speaking, I would be advising that most patients try CAR T-cell therapy first. If that doesn't work, try to get the disease under control and then proceed to an allogeneic stem cell transplant. Now here's a problem though, is that CAR T-cell therapy was studied and is used for patients who are refractory to treatments. Meaning that the treatments aren't working; that's why you're getting that treatment.

(57:28): Now allogeneic transplant, you have to proceed when you have as little disease as possible. You have to be in almost a complete response to get that. When you say, "Okay. We'll do CAR T. We'll try that first and then we'll do allo in the future," there could be a problem with that because you might not respond to treatments after CAR T-cell therapy to get you to a point where an allo transplant provides the benefit. In an allo transplant historic data, it does show it's just as good as perhaps CAR T-cell therapy, but it's different patient populations that you're comparing it to. That's a very tough question to answer, but I would say it's a different scenario for different patients.

(58:17): But in general, we're all thinking that we would try CAR first and then maybe an allo transplant in the future if it doesn't work. With that understanding, that could be a risk. Because if we can't get that disease under control, then we can't do that allo transplant because that donor's immune system is not going to be able to recognize what's good and what's bad if the disease isn't under control first. That's called that graft-versus-malignancy effect.

(58:47): [Michelle] Closing. Wow. This has been an incredible Q&A session and such a great presentation, Dr. Tees. Thank you for sharing your expertise and thank you to our audience for your excellent questions. Please contact BMT InfoNet if we can help you in any way. Enjoy the rest of the symposium.