CAR T-cell Therapy for Lymphoma - The Good, the Bad, and the Exciting

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CAR T-cell Therapy: Lymphoma - The Good, the Bad, and the Exciting

Thursday, May 4, 2023

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 40 minutes long, followed by 20 minutes of Q&A.

Many thanks to Kite, a Gilead Company, whose support helped make this presentation possible.

Summary:  CAR T-cell therapy is a new treatment option for lymphoma patients whose disease has been resistant to standard chemotherapy.  This presentation describes what’s involved in going through CAR T-cell therapy, the CAR T-cell products currently approved by the FDA, and the short- and long-term side effects of treatment.

Highlights:

• There are four CAR T- cell therapies that are approved by the Federal Drug Administration (FDA) to treat patients who have an aggressive lymphoma: Yescarta®, Kymriah®, Breyanzi® and Tecartus®.
• The success rate for various CAR T-cell therapies for lymphoma depends on the type of lymphoma, the CAR T-cell product used and the patient’s response to prior therapies.
• Three major side effects of CAR T-cell therapy are cytokine release syndrome (CRS), infection and neurotoxicity (ICANS). These usually, but not always, resolve after treatment.

Key Points:

(06:32): CAR T-cell therapy is currently FDA-approved for patients with diffuse large B-cell lymphoma, and other aggressive lymphomas that don’t respond to first line therapy, or come back within the first year.

(12:18): If you have a complete response after CAR T-cell therapy, which is measured by a PET scan at day 30, you have a higher likelihood of long-term survival.

(13:44): There are five steps involved in CAR T-cell therapy: collecting the patient’s T-cells; converting them to CAR T-cells; lymphodepletion; infusion of the CAR T-cells into the patient; and monitoring for side effects.

(16:01): While CAR T-cells are being created, patients sometimes need “bridging therapy’ to control their disease.

(17:15): CAR T-cells may be infused in the inpatient or outpatient setting.

(19:07): Infection after CAR T-cell there is caused, primarily, by the lymphodepleting chemotherapy.

(19:44): Cytokine release syndrome (CRS) is caused by the release of cytokines, natural chemicals found normally in the body, when the CAR T-cells attack the cancer cells. The likelihood and severity of cytokine release syndrome depends on the patient’s disease and the specific CAR T-cell product.

(23:29): Neurotoxicity, also called ICANS, can occur if the cytokines released cross the blood-brain barrier. Symptoms of neurotoxicity can be anything from tremors to forgetfulness and difficulty with comprehension. A severe side effect could be seizures.

(27:02): CAR T-cell can affect concentration and short-term memory or “brain fog”.

(28:03): Other possible late effects of CAR T-cell therapy include lower blood counts and a prolonged risk of infection.

Transcript of Presentation

(00:00): [Michelle Kosik]: : Welcome to the workshop, CAR T-Cell Therapy for Lymphoma, the Good, the Bad, and the Exciting. My name is Michelle Kosik and I will be your moderator for this workshop.

(00:10): Before we begin, I'd like to thank Kite, a Gilead company who helped make this workshop possible.

(00:16): Introduction of Speaker. It is now my pleasure to introduce today's 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.

(00:34): Dr. Tees treats patients with a standard approach, CAR T-cell therapy, as well as CAR-based therapies in 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 join me in welcoming Dr. Tees.

(00:59): [Dr. Michael Tees]: : Thank you for having me today. I appreciate it. So, let's get started.

(01:05): Learning objectives for this presentation on CAR T-cell therapy for lymphoma. The learning objectives today are to understand the rationale for using CAR T-cell therapy in lymphoma; know the steps involved in undergoing CAR T-cell therapy; know the short-term side effects and toxicities of CAR T-cell therapy; know the impact on your quality of life; and understand the longer-term side effects and outcomes of CAR T.

(01:26): If you're one of my patients, you've definitely seen this before. I think I draw this out for every single new patient that I have because it really starts the conversation on what we do and why.

(01:37): Everything in the blood and immune system starts with the stem cell. The stem cell is self-replicating over and over and over again. It contains blueprints for everything in the blood and immune system. And based upon signals from the body, it turns into either myeloid cells or lymphoid cells.

(01:55): There are three types of myeloid blood cells: platelets, red blood cells and neutrophils. On the myeloid side, there are three cells. Some of you may recognize all three of them: platelets which form blood clots, red blood cells that carry hemoglobin that carries oxygen to your body; and neutrophils which are very important white blood cells that primarily fight bacterial and some fungal infections.

(02:15): There are two major lymphoid blood cells: T-cells and B-cells. I describe T-cells as the front line of your military. They fight the bad folks by recognizing what looks like you, and what doesn't look like you. So, if it looks like you, it's a friend. If it doesn't look like you, it's an enemy and it gets destroyed.

(02:37): I always say that T-cells are not the brightest bulbs in the bunch. They need the B-cell to tell them what to do. The B-cells have the memory, the strategy and the understanding to know that what you've been exposed to in the past, and whether it is good or bad. It can tell the T-cells, "oh, I know what this is" and “take care of it”. That's how vaccinations work, by educating B-cells.

(02:58): There's also a small population of lymphocytic cells called NK cells or natural killer cells. The reason that I am discussing this is because it now has some relevance as a form of treatment. There are CAR NK cell therapies that are under investigation, especially at CBCI (Colorado Blood Cancer Institute) and other institutions across the country and world. NK cells are a remnant of an archaic immune system that has some understanding of how to destroy tumors.

(03:33): Before we talk about CAR T-cell therapy, I want to just set the stage. Some of you may be familiar with other types of therapies, and it's good to understand what WAS the case, and where we are now.

(03:47): Autologous stem cell transplants rely on high-dose chemotherapy to kill lymphoma cells. Autologous stem cell transplant is less relevant, I would say, for lymphomas nowadays, but it is still an important treatment strategy for many patients. In an autologous transplant, you're using high-intensity chemotherapy to try to eradicate the disease.

(04:10): The major side effect of high-dose chemotherapy is that it kills off all your stem cells. I told you that stem cells can self-replicate over and over and over again, but not if you give it high-intensity chemotherapy. So, in order to give a higher intensity-chemotherapy regimen, you first have to collect the patient’s stem cells before that treatment, then you give them the treatment, and then give the stem cells right back to the patient. So, the correct term for this treatment is high dose chemotherapy followed by stem cell rescue.

(04:42): The question is: What if you don't respond to chemotherapy to begin with?' Would that be a strategy that you'd want to employ?

(04:50): What if you had recurrence after your stem cell transplant?

(04:56): Allogeneic stem cell transplants involve using someone else’s stem cells, rather than the patient’s, for the transplant. Now there's another treatment, an allogeneic stem cell transplant. That uses someone else's stem cells instead of your own. And what you're doing in that situation is you're first eradicating the patient’s immune system with what we call conditioning therapy, and depending on the intensity of the conditioning, there are some added anti-cancer benefits to that. And then we infuse donor stem cells into the patient.

(05:26): A major side effect of an allogeneic transplant is graft-versus-host disease (GVHD). The effects of an allogeneic stem cell transplant are pretty intense. You are giving a patient someone else's immune system. And because of that, there is, what's called, graft -versus- host disease (GVHD). That's a side effect that we don't want.

(05:41): What we want after an allogeneic transplant is the graft-versus-malignancy or graft-versus-tumor effect. What we do want is something called the graft-versus-malignancy effect, also known as a graft-versus-leukemia or graft-versus-tumor effect. We want the donor's immune system to recognize the cancer is bad. If you recall, I mentioned that T-cells recognize 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.

(06:05): Well, one of the biggest problems is that your own immune system, your own T-cells can't recognize your cancer is bad. So, the concept of allogeneic stem cell transplant is that you're giving someone else's immune system to the patient, and it becomes the patient's new immune system that, perhaps, can recognize the cancer is bad. And the source of that graft-versus-malignancy effect are the donor's T-cells.

(06:32): CAR T-cell therapy is currently FDA-approved for patients with diffuse large B-cell lymphoma, and other aggressive lymphomas that don’t respond first line therapy or come back within the first year. So, who gets CAR T-cell therapy? I have it highlighted there on the slide because there are other approved indications for CAR T-cell therapy, besides lymphoma, and probably next year there's going to be more, which is good.

(06:48): But I'm going to focus on the lymphomas, essentially diffuse large B-cell lymphoma and other aggressive B-cell lymphomas that aren't responding to the first line of therapy, or relapse after the first line of therapy within the first year.

(07:07): Also, approved for CAR T-cell therapy are patients with the diffuse large B-cell lymphoma that are refractory [they did not respond] to two or more lines of therapy. And patients with follicular lymphoma after several lines of therapy. And then patients with Mantle cell lymphoma after several lines of therapy.

(07:24): There are four CAR T- cell therapies that are approved by the FDA to treat patients with an aggressive lymphoma: Yescarta®, Kymriah®, Breyanzi® and Tecartus®. The first one is Axi-cel or Yescarta®.  The second one is Tisa-cel cell or Kymriah®. The third one is Liso-cel or Breyanzi®. And the fourth one is brexu-cel or Tecartus®. Some of them can be used for several different malignancies, such as Tecartus® that’s been approved for Mantle cell lymphoma and for acute lymphoblastic leukemia (ALL). However, things do change and they're under investigation for other diseases as well.

Well, what if you didn't respond to chemotherapy to begin with. And if you recall, I talked about autologous stem cell transplants. The concept is chemotherapy to try to eradicate the disease so it never comes back again. If you're not responding to chemotherapy, why would you do that approach? Doesn't really make too much sense. And inherently the disease might have acquired additional mutations where it just does not respond well to the chemotherapeutic approaches that we have.

(08:38): Or what if you had a recurrence after your auto transplant? And consider that the mortality for an allogeneic stem cell transplant is pretty high, primarily because of that graft-versus-host disease where the donor's immune system recognizes other aspects of your body as bad, not just the cancer. And then there's also the risk of infection and sometimes relapse of the disease itself. We don't really want to jump to an allogeneic stem cell transplant if we don't have to.

(09:14): We also know that in aggressive lymphomas, like diffuse large B-cell lymphoma, an autologous stem cell transplant is not as effective as CAR T-cell therapy when the cancer has returned within 12 months of the patient's first line of therapy.

(09:26): Two studies have shown that people with diffuse large B-cell lymphoma (DLBCL), who received CAR T-cell therapy within 12 months of a recurrence of their disease, had better outcomes than patients who had an autologous stem cell transplant. To break that down, for people who have been diagnosed with diffuse large B-cell lymphoma, the standard treatment, up until fairly recently, has been the R-CHOP or EPOCH chemotherapy regimen. And if you had that response, and the disease came back within 12 months, what we used to do is take the patient to an autologous stem cell transplant.

(09:54): But two major studies in the past two to three years compared, head-to-head, CAR T-cell therapy and stem cell transplant. And it appears that the patients who received CAR T-cell therapy within 12 months of recurrence of their disease had better outcomes, meaning longer term disease-free survival. So, that's why we're now doing CAR T-cell therapy earlier on in patients' treatment plan.

(10:28): CAR T-cell therapy is a treatment option for patients who have an aggressive case of follicular lymphoma. For follicular lymphoma, that is typically considered a more indolent slow growing lymphoma. And for most patients with that diagnosis, you oftentimes do a treatment and you don't have to do a treatment for another three to four to even 10 years, because the disease is very slow growing and not causing any problems.

(10:51): However, there is a very small subset, about 20% of patients with follicular lymphoma, whose disease is more active. In those patients, their disease doesn't respond to the therapies as well. And oftentimes we were were having to do treatment after treatment after treatment, with the benefit diminishing over time. Those are the follicular lymphoma patients for which CAR T-cell therapy would be beneficial.

(11:18): CAR T-cell therapy is a treatment option for some patients with Mantle cell lymphoma. For Mantle cell lymphoma, oftentimes the treatments just become less effective, or they don't last as long. And those are the patients where there's also an indication for CAR T-cell therapy.

(11:30): The success rate for CAR T-cell therapy varies, depending on the disease and the patient’s response to prior therapies. So, what's the goal? Cure. That would be great if we could cure you of your malignancy. The success rate does vary, based upon the disease, as well as your prior therapies. If you had some response to a therapy before you received CAR T-cell therapy, it tells us that your disease is more sensitive to treatments. So, the less disease burden that you have going into CAR T-cell therapy, the less work the T-cells have to do, and, therefore, they're more effective at what they do.

(12:18): If you have a complete response after CAR T-cell therapy, which is measured by a PET scan at day 30, you have a higher likelihood of long-term survival. And then most importantly, if you have not had a recurrence of your disease by two years after CAR-T therapy, there's a very low likelihood that your disease will come back.

(12:44): So, what's the plan? Your T-cells can't recognize your cancer as bad because your disease is "of you" and the T-cells are "of you" as well. And so, your T-cells think that the cancer cells are friends and doesn't want to kill them.

(13:01): CAR T-cell re-engineers your T-cells so that they can recognize and kill cancer cells. So, why not re-engineer your T-cells so that they can do what they need to do, which is kill the cancer?

What CAR stands for is chimeric antigen receptor. Essentially, we're re-engineering those T-cells to recognize your cancer.

(13:20): For all approved CAR T-cell products for lymphomas, the target on the cancer cell is something called CD19. That's a marker on nearly all mature B-cells and nearly all lymphoma cells. And essentially what that is, is a protein on the outside of the B-cell.

(13:44): There are five steps involved in CAR T-cell therapy. So, the current steps for CAR T-cell therapy are, first, getting approval and getting the production lined up. Step two is the T-cell collection, and then waiting for that growth period that can last 14 to 42 days. Step three is receiving low-dose chemotherapy for several days. Step four is the CAR T-cell infusion, and step five is monitoring for the side effects and toxicities.

(14:24): The first step is to collect your T-cells. So, what is the process? The first step is removing your T-cells. You get connected to a machine that's like a dialysis machine. It takes out just your T-cells and returns the rest of your blood product to you. That process takes several hours and has very few side effects.

(14:43): The second step is to send the T-cells to a laboratory to be converted into CAR T-cells. Then those T-cells are sent to where they need to go, whether that's in town, whether that's in your institution or whether that's at a pharmaceutical processing site. And there, the T-cells are selected for step two. They're activated and they're enriched. Essentially, you have to pick out the right T-cells to grow and expand because not all T-cells are the same.

(15:15): And then, what we call a viral vector is used to transfer DNA to tell those T-cells to help them grow those new receptors. These viruses are inert. They're not going to cause sickness. They're just used as a vehicle to get that DNA to the right place.

(15:37): Then once those T-cells are expanded, they're shipped back to you or to the program. After lymphodepleting therapy, they're infused into you.

(16:01): While CAR T-cells are being created, patients sometimes need “bridging therapy’ to control their disease. I told you how the cells are taken out and sent away. That can take two to six weeks, depending upon the manufacturing processes and the issues that could arise with that. In the meantime, you might need disease control. Many diseases are very active and aggressive and therefore they can't just wait around for this treatment to start.

(16:22): So, many times, we have to do “bridging therapy” to maintain disease control until CAR T-cell therapy can occur.

(16:31): A few days before infusion of the CAR T-cells, patients receive low-dose chemotherapy, called lymphodepletion, to create a good environment for the CAR T-cells. Approximately four-to seven-days prior to the CAR T-cell infusion, low dose chemotherapy is needed. We call that lymphodepleting chemotherapy. Essentially, we need to give low-dose chemotherapy to knock down that immune system so it will accept your CAR T-cells back into you. The reason for that is that these CAR T-cells are "of you" but they don't entirely look like you.

(17:15): CAR T-cells may be infused in the inpatient or outpatient setting. So, the T-cells are then infused into you after that lymphodepleting therapy, and you're closely monitored for side effects from day 0 through 30. The cells can be administered either in the inpatient or the outpatient setting. It depends on the program, it depends on many different things.

The current standard across the country, maybe world, is to do this in the inpatient setting. Many programs are moving toward treating in the outpatient setting, such as our institution. But the most important thing is that we're closely monitoring you for the side effects and toxicities that occur right after that infusion, roughly through day 30. And those three major side effects are infection, cytokine, release syndrome and neurotoxicity.

(18:22): If you are not in the hospital, you will need to stay close to the treatment center.  If you have an issue and you go to a local hospital that has no idea what CAR T-cell therapy is, that could be dangerous and risky. So, if it's in the outpatient setting, you need to ensure that there's a safe plan of action for you.

(18:53): The three major side effects of CAR T-cell therapy are cytokine release syndrome (CRS), infection and neurotoxicity (ICANS). I'm going to talk about the three major side effects I just mentioned: infection, cytokine release syndrome (CRS) and neurotoxicity (ICANS). These can occur within the first 30 days.

(19:07): Infection is caused primarily by the lymphodepleting chemotherapy. There's a risk of bacterial and fungal infections that are typically seen during a period of neutropenia, when those neutrophil counts are low, due to the chemotherapy. That's roughly day zero through 10, maybe even up to day 14.

(19:28): To reduce the risk of infection, you will be on an antiviral, an antibiotic and antifungal. If you get a fever, it might not be from infection. It might actually be from cytokine release syndrome or CRS.

(19:44): Cytokine release syndrome is caused by the release of cytokines, natural chemicals found normally in the body, when the CAR T-cells attack the cancer cells. The way I explain cytokine release syndrome is to imagine what happens to your body when you get sick. When you get sick, it's very common to get a fever. Sometimes if you get very sick, sepsis occurs that's associated with low blood pressure, and another aspect of infection can be a shortness of breath, what we call a capillary leak of the lungs, hypoxia. All those things - fever, low blood pressure and shortness of breath - are caused by T-cells.

(20:26) And T-cells, when they are trying to fight an infection, they release natural chemicals called cytokines to corral the troops and say, “we need to fight a fight, we need to fight an infection, let's grow and reproduce to do that together.” So, these natural cytokines, these natural chemicals are the communication tools for your immune system.

(20:46): So, what happens when you get CAR T-cells infused? They start to grow and replicate to do what they were designed to do, which is to fight cancer. In the process, they can release those natural chemicals, those cytokines, in minutes of critical illness. The first signal is fever. Ideally you don't get low blood pressure, shortness of breath, but those are things that are watched for very closely, inpatient or outpatient, wherever you are. Classically, it's within, roughly, the first five days of your treatment.

(21:20): Those patients who have a higher tumor burden prior to CAR T-cell therapy do have an increased risk of cytokine release syndrome. And the risk also depends upon what cell product is being used.

(21:34): So, will you get cytokine release syndrome? It depends, but you likely will. And that's the reason I say that is expect the expected. Be pleasantly surprised if it doesn't happen.

(21:46): The likelihood and severity of cytokine release syndrome depends on the patient’s disease and the specific CAR T-cell product. Depending upon your disease, and depending on the CAR T-cell product, there's a very wide variability on what you will get and the severity of that cytokine release syndrome. Grade one is just a fever. Grade two is fever with lower blood pressure or low oxygen saturation. Grade three or four is when the patient needs supportive medications to get that blood pressure up and keep it up, or even advanced breathing support, perhaps ventilator support to ensure that you're getting the oxygen that your body needs. It tends to begin on days three to five and it tends to last for about five to 10 days, but there's wide variability on when it presents, how severe it is and how long it lasts.

(22:36): There is a treatment, it's a blocking agent for those cytokines. It has not been effective using it to prevent cytokine release syndrome. You have to use it at the time that you get the symptoms. Steroids can blunt the immune system response, too.

(22:53): Cytokine release syndrome is entirely reversible. However, there can be some secondary effects. Let's suppose that your blood pressure drops. Well, that could cause some kidney injury. If you need steroids, that can increase the risk of infections. And if you need steroids or you're in the hospital because of lower blood pressure or illness, you can become deconditioned. But for the vast majority of patients, it's treatable and reversible with no long-term side effects.

(23:29): Neurotoxicity, also called ICANS, can occur if the cytokines released cross the blood-brain barrier. The third major side effect is neurotoxicity. We call that ICANS which is short for immune effector cell associated neurotoxicity syndrome, or just neurotoxicity. Neurotoxicity is driven by the same process as cytokine release syndrome. Those cytokines can cross the blood-brain barrier and lead to many, many different side effects of the central nervous system.

Neurotoxicity does not cause your wires to be cut, it causes your wires to be jumbled. The brain is full of neurons, they communicate with each other through their tentacles. It's like the most complex electrical system on the planet, and it can get injured, but the injury is completely reversible.

(24:32): Symptoms of neurotoxicity can be anything from tremors to forgetfulness and difficulty with comprehension. A severe side effect could be seizures. You will get frequent assessments to monitor for any neurological changes. You will probably get the same questions and evaluations before changes occur, to monitor, objectively, for any changes that might be identified after CAR T-cell therapy.

(25:05): Will you get neurotoxicity? It depends. There's wide variability on whether you will get it and wide variability on the severity. Depending on your disease state, there may be a risk of neurotoxicity. So, for example, patients with Mantle cell lymphoma have a higher incidence of neurotoxicity compared to patients with follicular lymphoma.

(25:26): Financial toxicity is an issue for some patients seeking CAR T-cell therapy. What are the other toxicities? Well, one of the biggest issues, and one of the reasons why there could be a delay in getting this treatment for patients, is financial toxicity. There is not really a standardized cost for these CAR T-cell products. So, it's very expensive and it can take some time for insurance companies to ensure that the right patient is getting this therapy.

(26:27): The cost of the supportive care adds to the cost. Things like managing blood pressure issues. You could be in the hospital for quite some time, you might need ICU level care, and that could add to expenses. It's less of an issue for patients with certain types of insurance, more of an issue for some government-funded insurance plans, primarily because they haven't caught up with this treatment, but they're getting there. It's less of an issue now than it was five years ago.

(27:02): CAR T-cell can affect concentration and short-term memory or “brain fog”. So, intermediate term side effects. There's this “brain fog” for roughly the first two-to-three months that is definitely under-reported. There was recent article that found that CAR T-cell therapy does affect your concentration and short-term memory. So, getting back to work after day 30 could be difficult for a period of time. It does resolve over time and is a shorter-term issue. However, most programs advise patients not to drive for the first two months after the therapy because you might have some issues with your reflexes and have difficulty responding to risks on the road.

(28:03): A possible late effect of CAR T-cell therapy is lower blood counts. There is real world data that says that about 30% of patients have prolonged lower blood counts. In initial studies, it was more like 10% of patients. It's actually closer to about a third of patients that have lower blood counts for an intermediate period of time. It could be because the CAR T-cells are sticking around, throwing off those natural chemicals and maybe suppressing the natural hematopoiesis, the natural blood production system. It does resolve over time, though. It is not long term.

(28:36):  There may be a prolonged risk of infection after CAR T-cell therapy. And somewhat related to that, there could be a prolonged infection risk because those neutrophils are delayed in returning. But a lot of it has to do with the CAR T-cell and its target.

(28:53): I told you that CD19 is a target for lymphoma. CD19 is actually on healthy B-cells, too, and those B-cells are the ones that have that memory, the strategy and understanding of what you've seen in the past and what you're protected against. So, the T-cells might have an "off-target “killing effect on your memory B-cells. How that shows up is an increased risk of viral infections.

(29:24):  There are certain recommendations to reduce the risk of infection. We definitely want to reduce the risk of shingles. Many of us have been exposed to chickenpox, as a child. That basically integrates into your DNA and can pop out and cause a problem when your immune system is weak. So, we do want to reduce the risk of that. You will be on antiviral through at least 12 months post CAR T-cell therapy.

(29:59): There is a rare, but real risk of a certain type of lung infection called pneumocystis jirovecii. Because of that, you're going to be on an antibiotic for at least 12 months post CAR T-cell therapy. Some programs might have different recommendations on length of time for these agents, but in general, it's pretty well standardized.

(30:23): Somewhat related to those B-cells being targeted, the ones that have that memory and understanding of your immune system, is something called hypogammaglobulinemia. The B-cells grow into other cells called plasma cells that make natural antibodies to things. If you don't have as many B-cells to turn into those plasma cells that make the natural antibodies, you might not have enough natural antibodies to fight infection. So, around day 90 after CAR T-cell therapy, I advise that we check an IgG level. If it's low, we advise giving you those natural antibodies monthly.

(31:09): In patients who have a prolonged low neutrophil count, typically a shot called GCSF or natural growth factor does help. COVID re-vaccination is advised around day 90, it says day 30 here, but I think I messed that up. And I also advise an influenza vaccine at day 90 as well.

(31:41): It’s unclear whether CAR T-cell recipients need revaccination for all their childhood immunizations. What we're less clear on is if you need to be re-vaccinated for anything else. It kind of goes hand in hand with what I already discussed. Those B-cells, those healthy B-cells, the ones that have that natural memory and strategy and understanding, they might be affected. And we don't know if that causes long-term weakening of the immune system. So, some programs advise re-vaccination of all your childhood immunizations. It's a little bit too early to say that's a national standard. Even our program has not advised that just yet.

(32:27): However, if you do get re-vaccinated, you don't want to do that at day 30. You want to give it at least three months after CAR T-cell therapy because the immune system is compromised. That memory formation might not occur if you do it too soon after your treatment.

(32:45): New, second cancers have been reported after CAR T-cell therapy. There are some other late effects. Second malignancies are a real issue. There is an increased risk of skin cancer and an increased risk of another type of hematologic malignancy called myelodysplastic syndrome or MDS. A lot of times, this can be associated with multiple therapies in the past, so, it might not be directly related to CAR T-cell therapy.

(33:13): There have been some rare reports of neurologic toxicities that don't resolve. That's a little bit less concerning, I would say, because the data's a little bit murky on this. CAR T-cell therapy is now being used for other patients with diseases such as multiple myeloma. There are some additional neurotoxicities that are a bit longer-term that can develop in these patients, but we haven't seen that with lymphoma CAR T-cell therapy.

(33:48): CAR T-cell therapy has a short-term impact on a patient’s quality of life. There will be a short-term impact on your quality of life. You’re going to be hospitalized or you're going to come into clinic on a daily basis. You're going to need a caregiver with you 24/7 who knows your therapy and will be your support for everything. You're going to need blood and platelet transfusions. You might have infections, or need to reduce your risk of infection with IVIG infusions on a monthly basis, and then there are those toxicities.

(34:24): So, for the short-term, yes, it does affect your quality of life. But the way I describe it is that there is a short-term sacrifice for a long-term gain. It's a one-time treatment and ideally it does what we want it to do, which is cure you of your malignancy.

(34:39): Potential intermediate and longer-term effects of CAR T-cell therapy include risk of infection and ongoing worries about whether the disease will come back. However, it does have side effects. The intermediate, longer-term effects on your quality of life are mainly the infection and infection risks. There's also the psychosocial aspect of things. Is my disease going to come back or not? And then maybe, in some patients, there could be some longer-term neurological side effects, not necessarily for lymphoma patients, though, so, I don't want to talk about that much more.

(35:15): How can we decrease the side effects, all the things that affect your quality of life? The cytokine release syndrome, neurotoxicity? Well, we are doing certain things. We're giving prevention steroids on day zero through two for certain cell products, and that's reduced the severity of the cytokine release syndrome and neurotoxicity.

(35:38): There are many clinical trials looking at how to reduce toxicity. Our program is pretty robust with outpatient CAR T-cell therapy. And the reason for that is if you're going to develop the side effects of CRS and neurotoxicity, we can't entirely predict when that's going to occur. But does that mean that you have to be in the hospital indefinitely, waiting for it to occur?

(36:09): In our program we have remote patient monitoring to identify signals we can look at to see when that risk occurs.

(36:27): What does the future look like for CAR T-cell therapy?  So, where are we going to in the future? Where are we driving next? I'm trying to play on that CAR in CAR T-cell therapy. So, we're investigating other lymphocytic disorders to see if CAR T-cell therapy works with them.

(36:42): I think the most exciting aspect of CAR T-cell research, other than the field of hematology/oncology, are the solid tumors, the non-blood cancers. Glioblastoma, for example, a deadly brain cancer. It has exciting data and exciting outcomes after using CAR T-cell therapy.

(37:02): Hepatocellular carcinoma, liver cancer, prostate cancer, we're investigating all of these. Where we have some ways to go are in the myeloid leukemias and myelodysplastic syndromes, other solid tumors that don't have a good marker that we can educate a T-cell to target. That's where we're kind of falling behind.

(37:31): Clinical trials are looking at better ways to re-educate T-cells to fight cancer. So, in the future, we're looking at many different ways to re-educate the immune system. How can you manipulate that immune system, your own immune system, to fight the fight?

(37:56): Instead of having to wait around several weeks for those CAR T-cells to grow and expand outside of your body, could we do that within your body? That's something that's actively under investigation right now.

(38:10): Research is also looking at whether natural killer cells or monocytes can help fight cancer. Another approach being investigated is using those natural killer cells that I discussed very early on. They have some inherent anti-cancer benefit and they do seem to have a significantly less incidence of cytokine release syndrome and neurotoxicity. Because of its mechanism of action, how it works, it doesn't need those cytokines to grow and expand and fight its fight.

(38:33): Another type of cell that we're looking at is monocytes. Another aspect of your immune system. We're looking at different targets instead of just CD19. We're looking at CD20, we're looking at CD22, CD29, many different targets.

(38:49): We're also looking at using someone else’s T-cells for CAR T-cell therapy and making your own re-engineered T-cells less toxic. And we're looking at genetically re-engineering T-cells, but removing the drivers of those toxicities. Do those cytokines really need to expand so abruptly, so aggressively? Perhaps you can still get the job done without as much of the cytokine toxicity.

(39:20): CAR T-cell therapy is very exciting for solid tumors, but there are a few things that need to be addressed before we get too excited. There are some off-target effects, for example, that that can occur in those diseases that are being investigated. And one of the biggest issues, whether it's solid tumors or blood cancers, is how do you penetrate what we call the tumor microenvironment. The tumor has found ways to evade the immune system to begin with, so how do those T-cells punch in there to knock down the disease?

(40:11): And when I say solid tumors, it's basically non-blood cancers. They are different than lymphomas. So, we have many ways to go, but the future is extremely bright. And now I guess we have some questions.

Question and answer Session

(40:39): [Michelle Kosik]: : Thank you Dr. Tees for this excellent presentation. We will now begin the question and answer session. Our first question is actually for someone who is day plus 10 post-outpatient CAR T and he wants to know, Is there any way to determine CAR T-cell count post therapy to know how long they will reside in the body?

(41:12): [Dr. Michael Tees]: : That's a really, really good question. It is extremely difficult to count the T-cells and the reason for it is because they're still "of you". They still actually look like you. The only way that we can do this is by DNA analysis, looking at snippets of the DNA fragments that were actually used to educate the CAR T-cells.

So, it's not very easily done. And it's part of the reason why we have difficulty understanding if the CAR T-cells persist or if they don't expand. That test is part of clinical trials, but for those that are getting what we call standard of care, we don't really have good tests to look and say, “okay, are the T-cells expanding the way we want them to or is it going to do what we want to do?”

(42:15): The best test is that day 30 PET scan. Now there are a lot of patients who have what we call bulky disease, disease that, on examination, we feel on their arms or in their neck. If you get the treatment and it shrinks down, you already know that it's doing what it needs to do. But the question always is, “ if it's doing what we want it to do, will it last?” And really time, and that original day 30 PET scan, is very predictive of that long-term benefit.

(42:51): [Michelle Kosik]: : Thank you. The next question though that we will be covering is What are the chances for recurrence or new cancers following CAR T-cell therapy and how survivable are they?

(43:21): [Dr. Michael Tees]: : So, another good question. I'll be honest with you, I have not seen meaningful second cancers. What I reported on that slide is what was seen in initial clinical trials. The issue with that is that patients who have received multiple lines of treatment will have an increased risk of other cancers because of the injury that chemotherapy and other medicines does to healthy cells. This why there could be a more value to doing a therapy like CAR T-cell therapy earlier on in patient's journey. Hopefully they don't ever need it, because they've responded initially, but, if it comes back, using CAR T-cell earlier on, instead of having to do multiple lines of treatment, perhaps that actually does decrease the risk of other second malignancies in the future.

(44:32): However, the more common ones that we do see for those who have received multiple lines of therapy tend to be skin cancers. Those are very relevant here in Colorado because we're a mile high and closer to the sun. But I strongly advocate all patients see their dermatologist on a regular basis to monitor for any skin changes and remove the malignant lesions before they become more serious. But primarily, the big one is skin cancer.

(45:08): I did show on that slide, myelodysplastic syndrome, MDS. That is across the board. If you look at almost all of our treatments, that comes up a lot as a slightly increased risk compared to the standard patient population. That's not something that we can do anything about. It's not advised to do frequent lab checks to look for any changes. It's simply having an ongoing relationship with your hematologist/oncologist and having that dialogue when those concerns come up.

(45:52): [Michelle Kosik]: : Do you have any recommendations on how to treat hyper skin sensitivity? Any fabric that brushes against my skin, especially my legs feel very prickly. My CAR T was done May, 2019. The side effect presented itself in August of 2019.

(46:12): [Dr. Michael Tees]: : Well, that's unique I would say. I have not seen that before. One of the first questions I have is are there other sensitivity issues? Are you having what we call proprioceptive issues, where you might not know where your feet are? I'm wondering if this is a form of neuropathy or full neuropathy.

I'm also curious if this is from a nutritional deficiency, like B12 deficiency. So, I can't answer that, to be honest with you, because I'm not familiar with exactly how this is playing out for you. There could be some medications, maybe they've already been tried, such as gabapentin that could perhaps help with the nerves, but that's unique even in of itself.

(47:30): [Michelle Kosik]: : And hopefully they would reach out to their provider that gave them the CAR T-cell therapy for some support.

(47:37): [Dr. Michael Tees]: :. Yes. If your current hematologist is not the one that did your treatment, I would also say reach out to the hematologist that did your CAR T-cell therapy and see if this has been something that they've identified.

(48:01): [Michelle Kosik]: : The next question is asking for some guidance around some prophylaxis vaccine boosters, pediatric immunizations and titers. They're permanently immunocompromised from CAR T-cell therapy, including leukocyte subsets in IgG since 2021. This person's been taking oral prophylaxis both acyclovir and Bactrim and boosters for influenza and COVID-19. This approach assumes a minimal vaccine response is better than none. However, pediatric re-vaccination and titers aren't available to me. Can you clarify the guidance for post cellular vaccinations?

(48:42): [Dr. Michael Tees]: : Yes, well, there isn't any guidance. There is not a national standard on advising whether or not patients should be re-vaccinated. It sounds like what I'm hearing, though, is that this person has had their titers looked at and checked to see if they were responding to vaccinations. That would be the ideal state for all patients. If we could check titers to know if someone needed re-vaccination, that would be great.

However, we stopped doing that for our stem cell transplant patients to identify whether or not they needed re-vaccinations. And one of the reasons for that was that we are unclear whether those titers are truly detecting the strength of the patient’s immune system. And if you have those titers, does that mean that there could be value in re-educating the immune system with vaccinations, whether or not you have titers, or don't have titers? Definitely if you don't have titers.

(49:47): So, what I would say is that it sounds like that person is doing the right thing by getting vaccinated. But it is a possibility, yes, that your immune system has been permanently injured by the CAR T-cell therapy and perhaps, that does increase your risk of infection.

Now that being said, even though the past couple of years have been really different in clinicalization of lots of things that we wouldn't have thought in the past, despite that, herd immunity becomes your best friend. Herd immunity is what actually protects most of us. And it's important to know that even among those who get the annual influenza vaccine, only 60 to 70% of them actually respond to that. Yet, if no one got it, we'd have many, many, many more cases of deadly influenza.

(51:00): It's kind of the same concept for all vaccinations. Yes, it is accepted that not everyone will respond to them, but the more people that get them, it will actually help those who don't have that protection. So, at the end of the day, I think all things considered, you're doing the right thing by getting re-vaccinated. It could be giving you some sense of protection, but those around you are also giving you that protection.

(51:48): [Michelle Kosik]: : Terrific. How many months should a CAR T survivor wait before getting back on a bicycle or a mountain bike or rollerblade?

(51:56): [Dr. Michael Tees]: : So, I think it's person-specific. I had one slide in there that said that some patients have prolonged cytopenias or prolonged lower blood counts for a couple of months after CAR T-cell therapy. That's not the case for all. But for some, you could still have a low platelet count and that could be risky if you're doing activities that could have a higher risk for bleeding, for example, or injuring your skull. So, my assumption is that you probably are aware of what your most recent counts are.

I would say that there are a good two months of that brain fog , and that you might not be able to react as quickly to things if you're mountain biking, for example. So, I would give it at least two months after CAR T-cell therapy before jumping on the bike. And especially if your counts aren't robust, then you need to wait until the counts are better.

(53:13): [Michelle Kosik]: : Good advice. Is there anything I can do in remission after I receive CAR T-cell therapy?

(53:22): [Dr. Michael Tees]: : That's a good question. There's no evidence right now that anyone benefits from maintenance therapy or taking a medicine to reduce the risk of recurrence. I do tell patients that keeping your body active, keeping your muscles strong, eating well and healthy, that does have overall benefits for your health and that strengthens your immune system in different ways.

(54:00):  Another thing I tell patients, and this is based upon a ton of data, is vitamin D supplementation. Pretty much every single patient with lymphoma should be on vitamin D. I'm not going to make specific recommendations because those whose kidneys, for example, don't function as well as they used to might need a lower dose of vitamin D. But vitamin D is available over the counter, and roughly 2000 international units daily should be fine even for patients with kidney dysfunction. So, physical activity and vitamin D, those are the big things.

(54:47): [Michelle Kosik]: : Dr Tees, Can you comment on the response rate with CAR T-cell therapy for diffuse large B-cell lymphoma during clinical trials versus after approval? And what is the current data on effectiveness? How does Kymriah® compare to Yescarta®and Breyanzi®?

(55:07): [Dr. Michael Tees]: : Let me just finish off on vitamin D. So, vitamin D actually promotes a stronger immune system and the theory is that a stronger immune system reduces the risk of recurrence. So, that's why vitamin D supplementation has been associated with better outcomes.

(55:30): So, Kymriah® is approved for diffuse large B-cell lymphoma. There are three products for diffuse large B-cell lymphoma: Kymriah®, Yescarta®, and Breyanzi®. You cannot compare them because there has never been a clinical trial comparing them where patients are randomized to one versus the other versus the other. And because of that, it's extremely hard to say one is better or worse than another.

(56:06): Generally speaking, the inclusion criteria for all the studies were somewhat similar. For Breyanzi® and Kymriah®, the mechanism of the CAR T-cells is a little bit different than Yescarta®, but that's not the whole story on slight differences in outcomes and responses.

(56:36): I'm really trying to be vague here because if you look at the initial studies, there's an extremely wide variability in responses, anywhere between a 40 to 60% response rates. And I think, at the end of the day, it's more about the patients that have a sustained response. And in general, across the board for all the cell products, that sustained response is roughly the same. For diffuse large B-cell lymphoma, roughly 40% of patients have a long-term disease-free survival, 40 to 50%. And that does not vary too much between all those cell products.

But again, a huge caveat is that you cannot compare them, because they were never really compared head-to-head. That being said, depending upon whom your cell therapy specialist is, they're probably going to have a preference on which one to use and why, because they are a little bit different regarding  toxicity profile, whether or not they're safer to be administered in one place versus another, or perhaps some other data that can be used to determine what's best for you.

(58:07): [Michelle Kosik]: : Is there a marker for residual and replicated CAR T-cells?

(58:15): [Dr. Michael Tees]: : Is there a mark? No, there's not, not one that's readily available for a clinician to get. It goes back to having to know the snippets of those T-cells that are different from your T-cells, that aren't CAR T-cells, and trying to compare them to see if they're present. There is not a good marker to know if the T-cells are persistent or not.

(58:55): [Michelle Kosik]: : What CAR T-cell therapies are available for Mantle cell lymphoma?

(59:01): The only one that's approved right now is Brexu-cel ,or Tecartus®, and that is for patients who have had two or more lines of therapy with one of them being Ibrutinib (Imbruvica®) or a BTK inhibitor. For Mantle cell lymphoma, it's really patient specific on whether or not a CAR T-cell therapy is indicated for you.

(59:43): [Michelle Kosik]: : Super. Such great questions. On behalf of the BMT InfoNet and our partners, I'd like to thank Dr. Tees for his very helpful presentation and thank you, the audience for your excellent questions. Please contact BMT InfoNet if we can help you in any way.