CAR T-Cell and Other Immunotherapies

CAR T-Cell and Other Immunotherapies

July 15, 2020 Part of the Virtual Celebrating a Second Chance at Life Survivorship Symposium 2020

Presenter: Matthew Frigault MD, Assistant Program Director, Cellular Therapy Service, Massachusetts General Hospital

Presentation is 37 minutes with 12 minutes of Q&A.

Summary: CAR T-cell therapy is a new type of immunotherapy that’s been approved by the FDA to treat patients with certain types of leukemia and lymphoma. Some patients have lived more than 10 years after treatment.

Highlights:

CAR T-cell therapy re-engineers the patient’s own immune system cells to better fight cancer.

CAR T-cell therapy is an option for some patients whose disease has not responded to two other types of standard therapy

CAR T-cell therapy may be used before, after or instead of a stem cell transplant

Key Points:

05:08 A healthy immune system recognizes and fights elements that don’t be long in a person’s body such as organisms that cause infection and cancer cells.

11:38 Cancer cells have many different strategies to evade the immune system.

15:25 CAR T therapy is considered both immunotherapy and gene therapy because this therapy activates the immune system and reprograms DNA.

19:02 The first two types of CAR T-cell therapy approved by the FDA for use with patients who have certain types of leukemia or lymphoma are Kymriah and Yescarta.

24:08 CAR T-cell therapy may be given in the hospital or outpatient clinic.

25:26 The first step is to collect cells from the patient through a process called leukapheresis.

27:36 Prior to receiving an infusion of CAR T-cells, patients receive low-dose chemotherapy.

30:12 A major side effect of CAR T-cell therapy is cytokine release syndrome (CRS). Although serious, it can usually be successfully treated with a drug called tocilizumab.

31:29 Neurotoxicity or ICANS can occur after CAR T-cell therapy. While serious, it can usually be successfully treated with steroids.

34:14 Patients can usually go back to work one-to-three months after treatment, but fatigue can persist for three-to- six months or longer.

Transcript of Presentation

00:00 [Moderator] Welcome to the workshop, CAR T and Other Immunotherapies. My name is Marla O'Keefe and I will be your moderator today. It is my pleasure to introduce to you our speaker, Dr. Matthew Frigault. Dr. Frigault is an Attending Physician on the Bone Marrow Transplant and Leukemia Services at Massachusetts General Hospital. He is also the Assistant Program Director of the Cellular Therapy Service at the Mass General Cancer Center and an Instructor of Medicine at Harvard Medical School. Dr. Frigault's research focuses on the use of CAR T-cell therapy to help patients with blood and solid tumor cancers. He is also investigating a variety of next generation cellular therapies to treat patients with life-threatening blood disorders. Please join me in welcoming Dr. Frigault.

00:55 [Dr. Frigault] Hi, everyone. Thank you for having me here. Even unfortunately that we're doing it virtual, but we will make it work. I'm going to talk primarily about CAR T-cells and just the general concept behind how the immune system can be used for fighting off cancer.

And to start it off, I've got a great photo here of T-cells which are the little yellow things that are attacking a tumor cell on a little petri dish. And so it can kind of ... just to show you who the enemy is and who we're trying to use as our soldiers here.

01:30 So, I really want to talk about the growing role of CAR T-cell therapy and how this fits into the broader paradigm of things. Historically, bone marrow transplant, and transplanters in general, have really been pushing for therapies like this because the goal of a bone marrow transplant, especially or primarily allogeneic stem cell transplants, is to use the immune system to have something like graft-versus-leukemia or graft-versus-lymphoma where that new immune system that the patient receives is able to recognize and then reject the leukemia or the lymphoma or the tumor that's inside of the body.

02:10 And for many, many years and it still is very successful, we've always wanted to try to improve on that and help direct the immune system to exactly what we want to target, like the lymphoma or the leukemia, without directly attacking or having side effects in the patients like graft-versus-host. And so CAR T-cell therapy and other cellular therapies or gene therapies like this are a way for us to potentially try to improve on bone marrow transplants and move things like this forward in at least a subset of different types of diseases. And I'm hopeful that as we move forward, these types of treatments are going to be more applicable to a broader array of tumors.

First patient to get CAR T-cell therapy has been in remission for many years

02:51 So when we talk about it, this was some early headlines that came back. I was very fortunate to be at the University of Pennsylvania when this really first started and the first couple of patients were being treated back in the late 2009, 2010. That's where I kind of caught the bug because I really saw the commotion around this and what the potential for it was. And so as those trials started to progress forward using CAR T-cells, primarily in leukemia and lymphoma, initially the first drug that was approved was given FDA groundbreaking status, given how exciting it was.

And the very, very first pediatric patient treated with a drug called CTL019, which is now renamed Kymriah, otherwise known as tisagenlecleucel, which is the long fancy name for it, is on the left here. Her name's Emily Whitehead. She was treated at the Children's Hospital of Philadelphia. And you can see her there having a popsicle while she's getting an infusion of sorts, and the reason why she's doing that is because she's getting her CAR T-cells. And the CAR T-cells have a preservative called DSMO, and that can sometimes give a funky taste in your mouth. And if anyone's had a transplant, they may know that, and that's why you get candy or something, so she had a popsicle.

And on the right you can see that she's now many years out and she has an entire foundation named after her. She's now been in remission for many, many years. And so you have the little girl on the left and we also have adult patients who are actually benefiting from this.

And this is a patient who was treated for multiple myeloma who was able to put on some weight and feel better and kind of get past some of the scary things that happen in myeloma patients as well.

04:38 So, things we're going to talk is the overview of the immune system and how it works; how the immune system fights cancer; what is a CAR T-cell - it's a term that we use, but what does it actually mean? What's the overview of a patient journey? So what happens during the CAR T-cell process? And then what happens after? What kind of side effects can you expect? What should follow-up look like? What are expectations that there may be? And then what clinical trials are out there and how are they growing, and what's coming down the pipeline?

How does the immune system work?

05:08 So, let's start by doing an overview of the immune system. So, immune system basics. Our immune system is really, really important. Without it, we can have infections, we can develop cancers. We really need our immune system to help fight off bad things. And so as I mentioned, it fights off bacteria, parasites, viruses, fungus, and it actually learns from it. So it just doesn't fight things off. It actually has memory. And that memory that it develops through vaccines or through being exposed to something is able to prevent you from getting infected in the future. And so as you get older, your immune system matures and gets better at doing what it does to the point where it can protect you for a very long period of time.

And it looks around your body, and so a big concept in the immune system is what they call self or not self. What this means is that our immune system is used to seeing what it's supposed to see, meaning our bodies, ourselves and whatnot. And if it sees things that shouldn't be there or atypical or give dangerous signals to the immune system, it rejects them or it kills them or tries to get rid of them.

It also recognizes when your own body, your own cells kind of go loopy. So, through mutations in cancer and the cancer kind of devolving into what eventually becomes whether it be leukemia, lymphoma or cancer, it starts to look odd and different, and that's why transplants work. And that's why it's supposed to be able to fight off tumors and on a daily basis when we go outside or we eat or drink something that has something what we call carcinogenic inside of it, our body's looking for small mutations and is rejecting cancer, preventing cancer from even starting in the first place in our body. So that's the the first thing to know.

Two key parts of the immune system: first responders (innate immune system) and memory (adaptive immune system)

07:02 When we look at the immune system, there's two kind of general arms of the immune system, meaning that we have the part of the immune system that's the first response. And then we have the part of the immune system that's more of the learned memory, that coordinates all of the different actions.

And, so, the innate immune system, that's the first response. It looks for danger signals. It doesn't really look for very specific things. It really just looks for things that look off, things that cause inflammation or set off a dangerous signal. And that's comprised of things like neutrophils, the eosinophils, all these different cell types. And these are cell types you're going to probably be hearing more and more about because of how immune and cellular therapy is evolving.

07:51 But we're primarily going to talk about the adaptive immune system and that's B cells and T-cells. So, the adaptive immune system is what can actually learn, and it's what targets and samples things throughout the body and generates that type of more robust immune response. And in many ways, the T-cell compartments of CAR T, which is what T-cells or CAR Ts that are made from, T-cells, they're the generals of the immune system. So, they instruct everyone on what to do and how to do it. It's extremely very, very targeted, highly targeted and it can remember things for the rest of your life. And so that's I think the very first thing or second thing to think about.

How the immune system kills cancer

08:29 So, then, how does the immune system kill cancer? How does it recognize cancer? Let's just go through this model here.

So, if you look at one, we have a tumor and that tumor is there. And we have cells in our body from the innate immune system that are gobbling up pieces of things and may gobble up a piece of tumor. And that immune cell moves over into a lymph node, and in that lymph node is basically a big billboard. It's a sampling area where all the immune system interacts. And so, everybody is showing their cards and saying, "This is what I found. This is what I found." And it educates and it tells the immune system whether something good or bad can be around.

When they recognize something bad or something that shouldn't be there, they can then activate the immune system, especially things like T-cells and B cells and other things. And that's when the soldiers and the generals get sent out and they move through the blood and they move back into the area where the tumor is. And we're going to talk about T-cells or white blood cells here. And they can recognize the tumor and they can kill it.

And so they have all the sampling going on in the lymph nodes, they get exposed to good and bad things. They get educated, they get primed, they get angry and then they go and they hunt for it. And so that's how the sampling occurs and what usually happens. And that's normal for whether you get a virus, a bacteria, or if you have a cancer cell that develops.

T-cells instruct other parts of the immune system to fight off bad things in the body

09:55 Now, getting into more detail about the T-cell. So, a T-cell is part of the adaptive immune system. They actually talk to the innate immune system. So when I was saying that they look for those danger signals, but they can actually instruct the other parts of the immune system to do certain things which can help or hinder the immune system from being able to fight off something bad.

As I mentioned, they look for things like self or not self, where there is abnormal cells like cancer, or you can look at abnormal cells being a virus that's infected a certain cell on your skin. They do so by using something called a T-cell receptor. And that T-cell receptor is what's gives it the ability to recognize and activate. This is where that HLA or the donor match for transplant becomes important because these T-cells are actually matched to the patient's HLA because they're coming from yourself. When you talk about allogeneic stem cell transplant, we talked about different kinds of matches or different degrees of matches.

Current forms of CAR-T therapy use the patient’s own cells so you don’t have to worry about graft-versus-host disease

10:55 And so the benefit of this is, since the T-cell receptor and the HLA perfectly match, you never really have to worry about things like graft-versus-host disease because they're from your own cells. There are things coming in the pipeline that use different sources of cells, but we'll just say for now that these cells can't cause graft-versus-host disease because they are part of the your own immune system. However, if they do go crazy, they can cause autoimmune disease and things, but really the graft-versus-host disease is really in the allogeneic or from somebody else's standpoint. And, so, I'm somewhat T-cell centric when it comes to thinking of the immune system.

How cancer hides from the immune system

11:38 So, let's talk about how is cancer going to evade the immune system? Going back to the same diagram, we can see that maybe the tumor prevents the innate immune system or those messenger from even being able to sample things. Or maybe it turns them off, or maybe it prevents or tries to hide or mask the danger signals that are supposed to be there. So, they never actually get gobbled up and move into the lymph node.

Sometimes in the lymph nodes, the tumor can secrete things that make it to the lymph node that actually prevent the immune system from activating in the lymph node. Sometimes the immune system can prevent the migration of the immune system, meaning that the cells can't move from the bloodstream into the tumor, and that's something that prevents them from getting in and doing the killing. Sometimes the tumor can down-regulate or can hide the targets that the T-cells would normally go after. And then sometimes the tumors are resistant to the killing mechanisms that T-cell usually use. As we're all aware, cancer is very, very sneaky unfortunately. And, so, we've had to come up with some creative ways to try to outsmart it, and CAR T-cells is one of them.

13:07 And just to reiterate this ,is that with the current iterations of CAR T-cells, there is no graft-versus-host disease at all. It's a risk for allogeneic stem cell transplants but right now with the current approved products, there really isn't a risk of graft-versus-host disease.

Immunotherapies available to kill cancer include checkpoint blockades, stem cell transplants and re-programming the immune system with gene therapy.

13:20 So, let's talk about what happens when it doesn't recognize cancer. We have options. We have treatments that we can sometimes use and these things include cancer immunotherapies. These types of immunotherapies include checkpoint blockade. So, when a cancer puts up a signal that shuts off the immune system or tries to hide from the immune system, we can block that. That's called immune checkpoint blockade. If the bites and the things aren't moving into the lymph nodes and causing an appropriate immune response, we can use vaccines just like we use a vaccine for a virus or other bacterial type thing. So, we can we can create those.

We can use someone else's immune system, like a bone marrow transplant, and bone marrow transplant was the original cell therapy. So this was the original type of cellular therapy. It just wasn't gene engineered and as expensive as what we're talking about for cell therapies.

And the other thing we can do now that we have more understanding of molecular biology and immunology is we can actually reprogram the immune system and re-target it. And so this is a gene therapy. So we're talking about using a gene therapy. And so we can do gene therapy with viruses and adenovirus, lentivirus, retroviruses. Those are all types of viruses that we can use to reprogram the immune system.

Gene editing such as CRISPR is a new type of gene therapy to fight cancer

14:40 Some people may have heard about other types of gene therapy like gene editing. CRISPR is a very big new technology that's out in the news a lot, and there's other forms of it called TALENs or ZFNs, which are zinc finger nucleases. And these are just ways to edit the genome or edit the cells differently. And you can actually delete genes using gene editing technologies like this. You can use ancient viruses that are called transposons that hop around in our bodies normally that never cause any problems. You can re-engineer them to deliver new information to the immune system. And we can even temporarily reprogram the immune system to have a self-destruct switch where it can target things for a period of time and then it goes away.

CAR T-cell therapy is both an immunotherapy and a gene therapy that fights cancer

15:25 And so when we're thinking about CAR T-cells, CAR T-cells are immunotherapy, right? So, it's a type of cancer treatment that helps the immune system fight cancer. So, it's an immunotherapy. It's also a gene therapy because it's a type of treatment that reprograms and changes the DNA of the immune system that you're using.

And what we're talking about here is a CAR, and what CAR stands for is a chimeric antigen receptor. That's what CAR stands for. So we're putting a chimeric antigen receptor into the immune system and by doing so, we're then creating a new type of cellular therapy. So, it's a cancer therapy that uses a specific cell type here, and in this place, it's T-cells. So that's where you get CAR T from. The chimeric antigen receptor T-cell. That's a immunotherapy. That's a gene engineered cellular therapy. So, it gets complicated, but it is what it is, and it's what we're using, what we're really trying to grow right now in cellular therapy.

What does a CAR T-cell look like?

16:26 So, what does the CAR look like other than these mythical things that can fight off a whole lot of things? The simplest form of a CAR T-cell is that this gray thing you have here is like the cell membrane. It's the barrier between the inside and the outside of the cell. And on the outside of the cell where it sees cancer, it is something called a single chain variable fragment, or SCFV, and that's derived from antibodies.

So we have antibodies that are in our bodies and we can select them, things like Rituxan, if anyone's ever had Rituxan or rituximab or Campath, these are ... or daratumumab, these are all types of antibodies that we have and we can cut them up and take pieces of them, and then we can super glue them to something on the inside of the cell.

Here, we have a signaling domain which if you remember the T-cell receptor that I talked about earlier which is what usually recognizes things, you cut off the top part of an antibody and the bottom part of a T-cell receptor, and you super glue them together, you get a CAR T-cell and that's essentially what we have. And, so, the outside is what recognizes the cancer while the inside is what tells the cancer to activate. And, so, we're really just reprogramming the T-cell to activate whenever it sees what we tell to see. And in this case, we're talking about CD19 for a lot of lymphomas or leukemias. And, so, it's for anything that has an antibody, we could theoretically redirect a T-cell to target.

17:51 And so this is kind of the end product. You have a T-cell and you have a tumor cell that happens to be CD19 positive. And when you see these CD proteins, different types of cells have different billboards on their surface. And I use the analogy, a lot of car analogy is no pun intended, where you're driving down the highway late at night and it's really dark out and you can't see exit signs. If you don't have the exit signs, you can miss an exit and you can drive for 30 miles and don't even know you missed an exit. So, you really need the exit signs to know where you are.

Same thing for the immune system. You need those billboards and those exit signs and say, "Hey, I'm a B cell," or, "I'm a T-cell." And one of those billboards is called CD19. So, if we have a T-cell and we have a B cell that has a billboard that's CD19 that's not supposed to be there, and then we zap the T-cell, we put the virus inside of it. This is what happens here. And then they start to express the CAR T-cell on their surface, so they get expressed on the cell surface. They then bind to that billboard because we told them to. They move on in, and they kill the tumor. And so that's the whole premise behind what we're doing.

The first two CAR T-cell therapies approved by the FDA are Kymriah and Yescarta

19:02 When we talk about what's approved so far, we actually have two approved CAR T-cells that are FDA approved that have gone through clinical trials and we're currently using them and prescribing them. There's other clinical trials that are ongoing, but the first one is called Kymriah, and its long name is tisagenlecleucell. They can't make it easy. They have to call it tisagenlecleucel. You may also hear it called tisa-cel. And this was first approved in pediatric and young adults, B cell leukemias, and up until the age of 25. And so that's the first. That's why it's pediatric and young adult.

It was later approved for relapsed refractory large cell lymphoma or high-grade B cell lymphoma or diffuse large B cell lymphoma, spinal B cell lymphoma, these all fall under the high grade label, and relapse refractory means they have to have been treated with two types of chemotherapy. So,if you get two types of chemo and it doesn't work, we have CAR T-cells for you.

19:58 The next drug is called Yescarta, or axicabtagene ciloleucel, which is also referred to as axi-cel, and this is only approved in relapsed refractory large cell lymphoma just like Kymriah. So, they're kind of redundant in that sense, but there are other things coming.

How well does CAR T-cell therapy work?

20:14 And how well do these things work? Well, if you look at a patient here you, can see that this is a PET scan of a patient with lymphoma. And you can see that the things that are lighting up, that should light up, are actually the brain which is really dark because our brain uses a lot of sugar. You can see that in the abdomen area, there are these smaller dark parts. That's actually the kidneys because the dye and things go into the kidneys and it goes into the bladder, which is down in the groin area. And you can see this stuff in the chest wall. So, in the anterior chest wall, there's all this black stuff. That's actually the lymphoma, and that was there.

When we look 30 days later after CAR T-cells, you can see that those things that I mentioned are still there because they're supposed to be, but that lymphoma, that chest wall mass has completely dissolved away and is no longer there. And I can tell you that this patient is actually now about three years out from CAR T-cells and is still doing well.

So it's pretty powerful, and these things can work pretty fast, but I will say that you don't need to have ... First of all, you don't need to have ... There are side effects we'll talk about in a couple of minutes, but you also don't need a response within 30 days. Usually we talk about two or three months as being when we see our best response, and then over time we continue to follow patients.

CAR T-cells can also work inside the brain

21:30 CAR T-cells are actually ... They also work inside the brain too. So, CAR T-cells as part of the immune system are able to move around the body, and part of what the immune system does, it can get into the brain and get into other areas.

And so this is a patient who had secondary CNS lymphoma meaning that they had lymphoma that was in their central nervous system, in the CNS, that was refractory or not responding to chemo. She had already relapsed after a bone marrow transplant. And she had lymphoma in her body initially in her abdomen, but it had moved into her brain and couldn't make it go away.

You can see here in the upper left-hand corner, you can see all that white stuff that's there right below it, and you can see edema or swelling. And then 30 days later, you can see that's now gone. And so very similar. This is for secondary CNS. Primary CNS lymphoma is actually ... The FDA won't let us treat that because that was never studied in any clinical trials. But there are clinical trials that are underway and especially here ... that are available here that we're starting to treat patients who are looking for kinds of responses.

22:39 So as we move forward, this is something I saw back in 2010 or 2011 and I thought was pretty appropriate. So, what we say is that in the first cartoon, the guy is talking to his friend and this kind of encompasses CAR T-cells, right? It says, "Hey I'm going to this new leukemia trial that's helping my immune system fight off the tumors. It's got a lot of promise behind it." And his friend goes, "Oh, what do these guys do and how do they do it?" And so he says, "Well, they took some patients' T-cells and they patched some new genes in to attack the cancer. Hasn't really been done enough in the past, and then they added some new codes and then all of a sudden the T-cells grow in the body all over the place and grow rapidly." And so then that caused some problems and some crazy things started growing out, and going and saying this must've been a crazy conversation. You're talking about having one type of tumor that's growing, then you re-engineer their immune system to grow out of control and attack things.

And it looks at the doctor's office and the guy goes, "So I have blood cells growing out of control. You're going to give me different blood cells that also grow out of control." And the doctor goes, "Yes, but it's okay because we treated this blood with HIV." What he means by that is the virus that we use to reprogram the T-cells is based off the HIV virus. We kind of took it apart and we put pieces of it back together, and we're now using it to our advantage, which is pretty incredible. And then the patient's like, "Are you sure you're even a doctor?" And the guy goes, "Almost definitely." So when this first started, this was really sci-fi-ish. And it's really exciting to see it continue to grow.

Steps involved for the patient undergoing CAR T-cell therapy

24:08 So, let's talk about what the patient journey is. The overall premise is that there's the patient here. We need to collect the immune system and that's called the leukapheresis. That's where we take the T-cells out of the body, and we'll talk about what that looks like in a second.

We then need to activate the T-cells inside of a big bioreactor, this big petri dish where the T-cells can be happy and grow. And that's where we introduce the virus and reprogram them. And then those T-cells inside of the big petri dish start growing, growing, growing, growing, growing and then we isolate the T-cells and then we freeze them down and we send them back to the hospital.

And the patient who's sitting there waiting, get's a little bit of chemotherapy. Not chemotherapy that's meant to really target the leukemia or the lymphoma strongly. But it's really just meant to ... We'll talk about what it does in a second. You get a little bit of chemotherapy a couple days before and then the T-cells get infused.

So, very similar for bone marrow transplant, like an autologous stem cell transplant where the cells are collected, they're stored and frozen, and then you get some chemotherapy and then you get the cells infused. Except in this circumstance, we're actually re-engineering and re-educating the T-cells. And the type of chemotherapy we give right before we get the cells back is very, very low dose. Lymphodepleting but low dose chemotherapy.

How immune system cells are collected from the patient: leukapheresis

25:26 So in the leukapheresis step, this is where we collect the cells. You can see here on the left, this is what a leukapheresis machine looks like. When I was a poor medical student at the University of Pennsylvania, I used to donate my T-cells once a month for the research studies because they would pay reasonably well and it would help pay my food bills. So I've done this probably 30 something times.

But essentially you get two big IVs or you get one big central line and the blood gets pulled out and then you spin it inside of a centrifuge, so it spins really really fast. And then we give you back the red blood cells and platelets.

The middle picture shows you what that centrifuge looks like. You can see where all the blood goes after it comes out of your body, and inside of that middle cylinder part, you can see that by spinning it really fast, it separates things into plasma, white blood cells and red blood cells, erythrocyte. So, the blood comes in on the left, gets put in, gets spun, and then you're able to suction off the white blood cells that get collected. And then everything else goes back into the body. That's what leukapheresis does.

Manufacturing process for CAR T-cells

26:32 We talked about manufacturing of the cells. This is the activation and expansion component. So, essentially what happens here is that the cells that were collected get mixed with a bunch of things. They get purified first. So, we take out all the other types of white blood cells because I said there were a bunch of different types, and you just get the T-cells. We activate them to excite them so that they grow and grow and grow.

We transduce them. That's the word for putting the virus in or putting the new genetic material into the cells. These transduced cells start to divide rapidly. So, if you start with say a million cells and all million of them get the virus inside of them, a million becomes two million, two million becomes four million, four million becomes eight million, and they keep growing and growing and growing. And since you've changed the DNA of the cells, they are able to replicate and grow and grow and grow, and they actually pass that new information and those new instruction off to their children daughter cells. So, they replicate and they grow and they do the same thing inside of your body. Then those cells are purified and they undergo extensive, extensive testing.

Patients get low-dose chemotherapy (lymphodepletion) before receiving CAR T-cells

27:36 Once those cells come back, the patient's now either inpatient or outpatient, and they get something called lymphodepleting chemotherapy or low dose chemotherapy or LDC. And again, going back to a car analogy, we've just made you brand new Ferraris. You have Ferrari T-cells and you can have a Ferrari. You can be ... For us in Boston, it's I-93. You always get stuck in I-93 rush hour traffic. It's horrific. But if you're in rush hour traffic and you're in a brand new Ferrari or you're in a 1982 Ford Pinto or Chevy Nova, little tiny thing with like two cylinder engine, it doesn't matter. You're not going to go anywhere whether you're in a Ferrari or a Pinto because you're stuck in traffic.

So, by giving lymphodepleting chemotherapy, it primes your immune system. The typical chemotherapy is something called cyclophosphamide and fludarabine. Other drugs could include bendamustine, but it depletes. So, lymphodepleting. Depletes other immune cells inside of your body. So, it's basically you before your Ferrari gets on the highway, you basically just move all the cars off the highway by depleting them with the chemotherapy in it's low doses.

Then the cells and the Ferraris go back into your bloodstream and they grow a thousand times inside of your body, and that happens for a period of time. And that's how they start attacking and doing their job. And the symptoms of this kind of chemotherapy are actually very very mild. They're such low doses, and we give this as an outpatient all the time, that maybe you'll have some nausea. People don't typically lose their hair. It's pretty benign.

How CAR T-cells are infused into a patient

29:06 And so then you get your CAR T-cell infusion, and your CAR T-cells are frozen. They're monitored the entire way. I can actually look at my patient's CAR T-cells when they're coming back to Mass General. I can see where they are, what altitude they're at, whether they're tilted to the left, to the right, what temperature they're at. You can track everything because they're they're delivering this lifesaving treatment.

They're typically infused by a central line like ... Once they're thawed. So, they're thawed here at Mass General in front of in front of the patient and then we infuse them. It usually takes about 30 minutes and it's really this tiny, tiny volume. So, after all that work, what we end up with is about five tablespoons of fluid. That's it. And within that five tablespoons, you can have upwards of 600 million CAR T-cells. And that's all you need. And in fact, all you need is one single CAR T-cell. There are some patients who had one T-cell that actually worked. It took much, much longer, but it worked. These are what the bags look like. These tiny bags are sufficient to potentially cure cancer.

Cytokine release syndrome (CRS) is a common side effect of CAR T-cell therapy

30:12 So, what happens after CAR T-cells and what are some of the side effects? The first one is something called cytokine release syndrome, and I'm just really ... Just like when you get chemotherapy, your counts go low, you can get infections, you can get other things. But I'm going to talk about two of the main side effects, and the first one's called cytokine release syndrome or CRS, and it usually occurs in the first couple days and it can last for up to a week. It can range and just be like having aches and pains, kind of like having the flu, or it could end up where you have to go to an ICU and it can be life-threatening and you can have organ failure and it can be scary. It can be fatal in some patients.

And I just want to emphasize, you do not need to have side effects for CAR T-cells to work. Okay? More people respond and are cured by it than actually have side effects. So, it's not required. I don't want people to think that it's necessarily required. And it's driven by these cytokines or messenger molecules that the T-cells are sending out all these orders to the immune system, and they're so excited, and all these cytokines or messenger things causing it to get really inflamed. And we think about the most important one in CRS being something called IL-6. And we can treat that and block IL-6 with a drug called tocilizumab. And, so, we do that if we need to, if things are getting too excited.

Neurotoxicity (ICANS) after CAR T-cell therapy

31:29 The next one is something called neurotoxicity and it was recently renamed ICANS, or immune cell associated neurotoxicity syndrome but I'm just going to call it neurotoxicity. And it usually happens after CRS and as people become encephalopathic, which means confused. They're delirious. They may have seizures and they may even have swelling in the brain which is that white stuff that you can see on the MRI. Sometimes it can just be headaches. Other times patients can be in a coma for a week or two, but these are usually always reversible. And sometimes, patients need to be put on a ventilator if they aren't breathing on their own.

We mainly use steroids to treat this. And we really don't think by giving steroids which are anti-inflammatory or trying to calm down the immune system, we don't think that this impairs the likelihood of you getting CAR T-cells. Some people are worried that by getting steroids, may hinder their response. It doesn't.

CAR T-cell therapy can reduce the number of normal B-cells in patients, known as B-cell aplasia, and cause other low blood cell counts

32:24 And so the long-term side effects of this are that B-cell aplasia. By targeting CD19, that billboard that's on the bad leukemia cells, you also target the good, normal B-cells. And so the B-cells go away entirely until you have something called B cell aplasia. As a result of that, you have something called hypogammaglobulinemia, which is meaning low antibody levels. And because B cells make antibodies, by not having B-cells, you don't make antibodies and so you need to get infusions, things called IVG or intravenous immunoglobulin.

You can also have low blood counts. From all the inflammation in your body, you may have low neutrophil counts or low other white blood cell counts or low platelets. And because this is a gene therapy, we have to follow you for 15 years on a registry called the CIBMTR. And so people will explain that if you go through it a little bit longer, but we're following from afar to make sure that you're okay.

Patients need to stay within two hours of the hospital for the first 30 days after CAR T-cell therapy

33:22 Expectations after CAR T-cell. If you get admitted to the hospital and you get discharged, you can be treated as an outpatient. You can get followed as an patient. You usually have ... The FDA requires that for the first 30 days after the CAR T-cells, you have to stay within two hours of where you got infused. And that's just for safety, because even when you go home, you could have these side effects, because side effects can occur any time in the first 30 days.

You'll have blood work and exams that are performed to make sure that the T-cells are working and things are responding and you're healthy and you're not at risk for infection. You may get PET scans or MRIs or biopsies done to restage your disease. You may require medications to prevent infections like acyclovir for herpes virus or Bactrim for PCP if you've had those before for about six to 12 months. You may need transfusions or things that help boost your immune system during that period of time.

Patients can usually go back to work one-to-three months after treatment, but fatigue can persist for three-to-six months or longer.

34:14 You can usually expect to go back to work probably one to three months after your CAR T-cell therapy depending on the course. So it's actually pretty quick and life can return back to normal and things go well.

Although some people can really complain about what I've seen is fatigue for three to six months, and fatigue is just like when you get the flu and your immune system gets overly active. You can have a lot of fatigue and that can persist for months on end.

There are new CAR T-cells being studied in the event that the first ones don't work, that we have other options. And we're also looking at combining CAR T-cells with other medications to make them work better. And we have some patients who have CAR T-cells that are now alive and cancer-free more than 10 years like Emily Whitehead, 10 years after their treatment. So, these do appear to be durable responses.

How does CAR T-cell therapy compare to a stem cell transplant?

34:59 How do they compare to transplant? It's very similar to an autologous stem cell transplant where you collect your cells, you get chemo and you get your cells back. However, the side effects, primarily cytokine release syndrome and neurotoxicity are the unique things here that you really don't see in autologous transplants. And unlike allogeneic transplants or transplants from using donors like siblings or unrelated donors through Be the Match, they don't require a long-term immunosuppression. You're not taking tacrolimus. You're not taking sirolimus. And there's no risk of graft-versus-host disease.

CAR T-cell therapy can be done before or after a stem cell transplant

35:29 And you can give T-cells before or after bone marrow transplant. So, you can get either way, if you get an auto[ologus] or an allo[geneic] [stem cell transplant], it doesn't really matter. You can get CAR T-cells before or after. And some patients may then go on to have a bone marrow transplant like an allogeneic transplant after CAR T-cells if they have really scary disease.

COVID -19 Impact on CAR T Therapy

35:49 So, how has COVID changed all of this? You may have to get a COVID test or you likely will have to get a COVID test prior to starting chemotherapy and getting your T-cell infusion. And again, we just don't want to weaken your immune system while you may have COVID. If you have a new fever and I spelled COVID wrong there, you may get retested for COVID just to make sure. You may be limited by how many visitors you can have in the hospital. You may not be able to bring visitors to your appointments, and we try to do everything virtually. But we really still recommend that people avoid crowded and public places just like we do with transplant, because of their risk of getting infections.

CAR T-cell therapies being studied to treat additional cancers

36:24 So, let's talk about ongoing trials. With clinical trials, there's a lot going on. When I started back in 2010 or so, there were less than five clinical trials going on, and now within the United States, we have about 400 and even probably more as of today. And so there's a lot of things you can look at. The Jason Carter Clinical Trials Program or clinicaltrials.gov if you're looking for clinical trials with CAR T-cells. I always hope to point people in the right direction.

And I've talked a lot about leukemia and lymphoma, but there are other types of CAR T-cells and other types of cellular therapies that are coming soon. There are things coming from mantle cell lymphoma. There are things coming for adult B leukemia, and there are things coming from multiple myeloma. And there's also therapies that are coming for solid tumors like melanoma and sarcoma.

And so, here's a pet scan of a patient who had sarcoma who got a cellular therapy and you can see all these black dots lining the patient. That's all sarcomas disease. And after therapy, you can see the black disappears. So these things can work well, even in some cases of solid tumors. And so with that, I will open it up for questions.

Question and Answer Session

37:33 [Moderator] Thank you, Dr. Frigault. That was an excellent presentation. We will now take questions. If you have a question, please type it into the chat box on the left side of your screen. Our first question is, are the considerations for patient selection for CAR T-cell therapy the same as for stem cell transplant?

37:58 [Dr. Frigault] Each center is going to have their own criteria to treat because of the types of patients they treat and the types of CAR T-cells they use. But in many cases, CAR T-cells can be used in patients who would not otherwise be able to receive bone marrow transplants. And so I've given CAR T-cells with people well into their 80s and that's not something we typically think about for transplant. There are certain things that would prevent us from moving forward with CAR T-cells safely, and that's something you should talk to your doctor about, but I would say that CAR T-cell criteria and eligibility are probably less strict than bone marrow transplant.

38:40 [Moderator] Thank you. Please explain the little bit of chemotherapy before injecting the modified CAR T-cells. What makes it necessary? What is it intended to do and what is its success? So there's many multiple questions there.

38:56 [Dr. Frigault] Yeah. No, no. So the purpose of that chemotherapy is actually not to do anything to treat your disease. So, we do not give that chemotherapy to try to make your disease go away or to decrease your tumor burden. That's not their primary intent. We give that chemotherapy to really open up the highways of your immune system so that when the CAR T-cells are infused, there's nothing in their way. They have all the nutrients in the body that are available to go hunt down and kill the tumor. So we're really just opening up the highway of your immune system by weakening it with low doses of chemotherapy, not targeting your leukemia or lymphoma or your disease, but just making sure that when these new CAR T-cells get in there, that they're not going to be blocked by anything in their way. That's the primary purpose of that. In most cases, it works very, very well.

39:46 [Moderator] Okay. Thank you. How long do low IgG levels last? Is there anything that the patient can do to raise IgG levels? Are there any foods or natural products that help?

40:04 [Dr. Frigault] The duration of low IgG levels can vary depending on what CAR you get, how long the T-cells last in your body. They can last for many, many, many, many years. And as long as they're there and working, you really aren't making B cells. And so the patients who do need IV IG could actually be a lifelong thing, but people survive like that for their entire lives. And so it's not necessarily life threatening.

As for whether there's anything you can do, there really isn't because the issue is not so much that you don't have a certain type of a drug or you don't have a certain nutrient. It's that you just don't have B cells. The CAR T-cells are doing their job and they're getting rid of any new B-cell that comes into the body. And so really it just takes time and being cautious and making your appointments. And in some patients, it may come back and again, it doesn't matter if it does or does not come back in terms of therapy working. It just means that you may be at an increased risk for infections.

41:04 [Moderator] I have been feeling extreme fatigue almost two years after CAR T. How long does this last and how can I make it better?

41:14 [Dr. Frigault] First off, I'm sorry to hear that. Like I said, fatigue is probably one of the bigger complaints people have. It depends on what it's related to. It's hard to say as I don't know your case in particular, but usually we just recommend time, and two years is a lot of time, but making sure that your blood levels are okay, making sure that there aren't other causes like a thyroid problem or low hormone levels. Those are things that can also mimic that. But I would speak with your doctor, but I'll just emphasize that fatigue is something that can last for a while after CAR T-cells. I'm sorry I don't have a direct answer for that.

41:56 [Moderator] Thank you. Why don't we just skip bone marrow transplants and go to CAR T-cell? I had an autologous transplant and it seems that CAR T might have been a better option.

42:10 [Dr. Frigault] Good question. We're actually doing clinical trials that are asking that question right now. There are randomized trials, meaning that we're we're randomizing people to either get a bone marrow transplant or CAR T-cells for certain types of lymphoma. We're going to see what happens and see who does better, and if people do better with CAR T-cells with less side effects and get better remissions, I think that would then make things actually the new standard of care. For these types of treatments which initially were very experimental, it's really hard to put things like this that were very high risk in the otherwise healthy people when you have something that works. And so I think as time goes on, we'll hopefully see these types of CAR T-cell therapies moving up earlier in the line of treatment. And we're already seeing that happen in things like lymphoma and myeloma.

43:02 [Moderator] What is the cost of CAR T-cell therapy, and does insurance cover this therapy?

43:09 [Dr. Frigault] CAR T cells are very expensive. As you can imagine, it's something engineered specifically out of your immune system as a gene therapy. So it's on the order of a couple hundred thousand dollars. The good news is that most insurance companies do, if not all insurance companies, do cover this. If they don't cover it, there are usually access programs to get access to these types of treatments. And if you're a Medicare patient, CMS which is the body that governs all the Medicare approvals and things, recently said that all CAR T-cells are approved. Whether centers and people get completely paid for that, it's a different question. But that's something we keep advocating for, but in my view and in our center, everyone who's eligible for a CAR T-cell should be able to get a CAR T-cell regardless of insurance and other things. You know, we'll find a way.

44:05 [Moderator] Is CAR T-cell therapy being used in the treatment of AML?

44:10 [Dr. Frigault] It is. There are very early clinical trials that are going on right now. AML is a little bit trickier because that CD19 billboard on B cells, there's not something as unique for AML. Although we're looking at it and there have been some successes, so I think in the coming five years or so, we're hopeful that we're going to have something that could potentially used in AML.

44:34 [Moderator] Would this possibly be a therapy for Ph+ B cell ALL?

44:40 [Dr. Frigault] It is, actually. The clinical trials for the pediatric and young adults up until the age of 25 for the approved indication for Kymriah, that included patients with Ph+ B ALL. And I've treated patients who have relapsed after allogeneic stem cell transplant with CAR T-cells for Ph+ ALL. And Ph meaning Philadelphia chromosome positive. Those are types of diseases require things like the afatinib or imatinib or ponatinib. But it is something that's approved in young adults and children, and there are ongoing clinical trials right now trying to move this into the adult setting so that everybody with Ph+ B ALL or just B ALL in general would have access to it.

45:23 [Moderator] Thank you. Is CAR T-cell therapy more or less likely to help patients with the p 17 deletion or other high risk cytogenetics?

45:35 [Dr. Frigault] Another good question. The high risk cytogenetics usually referring to high risk in the context of no response to chemotherapy, meaning that those types of mutations you have are associated with ways of being resistant. Since CAR T-cells use the immune system and tend to kill in a different way than chemotherapy, we have yet to find, and I'm not aware of and I could be wrong, but I'm not aware of any specific high risk feature or mutation that CAR T-cells have shown decreased efficacy in. What I mean by that is the typical things like p53 mutations, any type of high of risk feature has not in any of the clinical trials shown to be predictive of a better or worse response. So, they seem to be somewhat ignorant to high risk cytogenetics.

46:34 [Moderator] Is there any understanding of the molecular mechanisms that lead to a less durable response for multiple myeloma compared to leukemia?

46:45 [Dr. Frigault] Another really good question, and those are things that are being investigated. I'll just say it's complicated and there are a lot of speculation as to why that may be the case. Nothing definitive yet, but trials are now investigating that. We're trying to make things work better. We have new versions of CAR T-cells that may work better. And I'm hopeful that in the coming years we'll have things that raise the numbers that make it look more like the responses that we see in leukemia.

47:19 [Moderator] Okay. Why do some patients have the side effects and others do not?

47:27 [Dr. Frigault] Some patients have side effects because of features of their disease. There are characteristics of the disease that may hint at ... I can look at them and see a whole lot of tumor burden where you have a lot of inflammation in your body. That may actually increase the risk of having side effects. But we as of yet today can only tell people who are higher or less risk of these side effects, but I've been surprised. There's no way of completely predicting why some people have it and some don't. But again, reiterating, you don't need to have side effects for these to be working.

48:00 [Moderator] Okay. What percentage of CAR T patients get GVHD?

48:06 [Dr. Frigault] With the current approved products, there is no risk of GVHD with CAR T-cells.

48:12 [Moderator] Okay. Is the cell surface marker for myeloma CD19, or another marker?

48:21 [Dr. Frigault] The marker for myeloma that's been most extensively studied is something called BCMA or B cell maturation antigen. If you do some googling, I don't want to say CD19 is not on myeloma. If you do some googling, there's some very rare cases where they report about it, and there's some case reports of CD19 CARs working in myeloma. But I will just say that the majority of what we're looking at right now is something called BCMA.

48:52 [Moderator] Okay. And where are the CAR T-cells manufactured?

48:59 [Dr. Frigault] If you get a commercially approved CAR T-cell from Novartis or a company called Kite, which is Yescarta, you either get them manufactured in Morris Plains, New Jersey for Novartis, or Santa Monica, California if you're going with the Yescarta or the Kite product. But if you're getting CAR T-cells on clinical trials and other things, they could come from any other place in the United States. Here at Mass General, we're even manufacturing our own CAR T-cells here within our own hospital on clinical trials. So, manufacturing is becoming more widely available.

49:33 [Moderator] Okay. That was our last question. So, thank you very much, Dr. Frigault on behalf of BMT InfoNet and our partners. We want to thank you for your very helpful remarks, and thank you, the audience, for your excellent questions

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