CAR T-cell Therapy for Lymphoma: Benefits and Risks

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[00:03] Moderator: Welcome to the workshop, CAR T-cell therapy for lymphoma, benefits and risks.

My name is Michelle Kosick, and I will be your moderator for this workshop. Before we begin, I'd like to thank Bristol-Myers Squibb and Kite, whose support helped make this workshop possible.

It is my pleasure to introduce today's speaker, Dr. Luke Mountjoy.

Dr. Mountjoy the treatment of lymphoid disease with an emphasis on lymphoma leukemia and stem cell transplant.

He has also worked to identify novel strategies to test for drug resistance in patients undergoing treatment for multiple myeloma.

Dr. Mountjoy was part of a large research team that is actively working to identify genetic risk factors, predispositions in patients and families with newly diagnosed cancers.

Please join me in welcoming Dr. Mountjoy.

[01:02] Dr. Mountjoy: Thank you, Michelle, and thanks to all the event organizers.

I've been lucky enough to be able to give different talks to this BMT InfoNet Symposium over the years, and it's always an honor to be asked to do this sort of stuff.

It's kind of one of those premier patient-centered forums that we get to participate in, So I just really appreciate all the work that goes into it. And for the patients out there, the amount of work that the organizers like Marla and everyone go through to pull this off is substantial. So just greatly appreciate being a part of this.

[01:36] So let's dive in. I'll try and make this a little more casual conversation so it's not just reading PowerPoints and stuff and talking to you guys, so please send questions, and I'll save time at the end for that.

Just to kind of hit the highlights, we just want to talk about who's good candidates for CAR T. What does that process look like? If you wind up going through CAR T, what's the long-term risks and benefits and all of that with everything? How do you feel afterwards? What's on the horizon, you know, if you go into remission?Is that automatically a cure? What are the outcomes? All that stuff.

We're going to kind of peel this onion together here.

I'm sure you guys have all seen this slide in one shape, way, or form in the past. But reminder that, you know, all your blood cells are generated in your bone marrow from a stem cell, what we call a hematopoietic stem cell, and those stem cells can turn into different types of blood cells.

A lot of the people here are going to have B-cell lymphoma, but it's cousin disease, multiple myeloma, and it's also got a cousin. You can get T-cell lymphomas too.There may be people in the audience that have a T-cell lymphoma and might be asking like, hey, can I get a CAR T?  And we're trying to figure that out.

But for those of you that have B-cell lymphoma, you have a cancer through no fault of your own, of course. We don't know what causes B-cell lymphoma by far and away, a cancer of your B cells, but your T cells are fine. Your T cells are fine and maybe we could use these T cells to get them to attack the B cells.And that's what a CAR T is. We'll talk about that.

[03:24] Historically, people with lymphoma would get just chemotherapy up front. I'm sure there's a lot of you in the audience that have had something called R-CHOP or something called R-EPOCH or something called bendamustine Rituxan or R-CHP or whatever. You've had some form of chemotherapy.

Historically what we used to do, and am I getting old enough finally that I can say this, well, back in my day, back in my day, what we would do is if a patient got chemo and that lymphoma was resistant to chemo, what we would historically do is give more chemo and then harvest your healthy stem cells and then give you or a patient or a family member a big slug of high-dose chemotherapy with the goal to just try and wipe out every blood cell, including the cancer cells in the body.

Then we would take the stem cells that we harvested from you and infuse them back into you as a rescue from that big slug of chemo.

But the challenge with that has always been, you have a lymphoma that is resistant to chemo, you give more chemo, and then you give really high chemo. But wait, I thought we said that the lymphoma was resistant to chemo, so that doesn't make a ton of sense.

[04:51] A lot of times though, it was effective and we were able to do that because it's the analogy of a bacterial infection, right? You get a sinus infection, maybe your doctor puts you on a course of Augmentin for the sinus infection an antibiotic. It kind of gets a little better, but then comes back. Sometimes what you need to do is change the antibiotic to something different, and you could get that infection controlled. But a lot of times it's really difficult to clear that infection because the bacteria is resistant to antibiotics.

[05:20] Well, it's the same principle here where you get a lymphoma cell resistant to chemotherapy, but sometimes you can switch the chemo and get that response. But more often than not, when we find that there's a lymphoma that is resistant to chemo from Jump Street, giving more chemo is not the answer. What we need to do is use a completely different mechanism of action to attack and kill these cancer cells. So historically, that's what we did with stem cell transplant.

But like I said, if the disease isn't responding to chemo, why would I continue to give you things that can cause a lot of side effects without a benefit. But historically we just haven't had other options, and so that's where CAR T really filled this void.

[06:19] Patients with diffuse large B-cell lymphomas and really all sorts of different types of B-cell lymphomas could potentially be eligible to receive a CAR T therapy.

Reminder what a CAR T is, and I'll go through that in detail, but many of you are familiar with that. That's just, again, these T cells. The CAR stands for chimeric antigen receptor T cells, CAR T, which is where we harvest your T cells and re-engineer them to attack the lymphoma.

So all of these B-cell lymphomas have a very similar surface protein makeup to them that we can target by re-engineering these immune cells, these T cells towards it.

Right now, the people that are eligible to receive CAR T are patients with aggressive or diffuse large B-cell lymphomas that we gave chemo to. We gave chemo to that patient. That lymphoma, for reasons we don't fully understand, did not respond to chemo. 

Or we gave the patient chemo. The lymphoma originally responded. But within 12 months of completion of that first round of chemotherapy, that first line of chemotherapy, the disease has come back. Because if you give chemo and it goes away but comes back within 12 months, it's like, yeah, you might have shrank it, but boy, we didn't clean it out of you and it's already back. That's highly associated with just being fully resistant to chemo.

[07:48] Now there are other diseases that we have FDA approval to give CAR T to, and that's follicular lymphoma, marginal zone lymphoma, and mantle cell lymphoma.

Right now the FDA wants to see that patients with those diseases have at least tried a couple different types of chemo before you say, hey, this is resistant, we need a CAR T.

I think these things are subject to change as we do more and more CAR T therapies, and my anticipation is that CAR T probably gets approved in the future, similar to aggressive lymphomas after that first line of therapy.

Then if there are any patients in the audience that have had something called chronic lymphocytic leukemia, we now use CAR T in that space too. But many of you that may have that disease might say, "Hey, I've never had like true chemo, like all this stuff you're saying. I had these targeted treatments, things like a BTK inhibitor, which is ibrutinib or acalibrutinib or zanubrutinib or BCL-2 inhibitor, which is venetoclax, those things might ring a bell to you.

[08:49] But if you have received both of those types of treatments and are still struggling with your chronic lymphocytic leukemia or CLL, then that's a window where a CAR T can be very helpful in that scenario.

[09:02] There are a handful of FDA approved CAR Ts. There's Yescarta, Kymriah, Breyanzi, Tecartus. These are all used. I would say that for the aggressive B-cell lymphomas, The two most commonly utilized CAR T is Breyanzi, which is liso-cel or Yescarta, which is axi-cel. 

We kind of abbreviate those things. It's a lot easier to say axi-cel than axicabtagene ciloleucel or tisa-cel as opposed to tisagenlecleucel. It's just a little bit easier to say these abbreviations. It's fun to play Scrabble with your family members when you know how to pronounce and say these things, but that's cheating.

So, we got a few of these things here. And then for those of you that have chronic lymphocytic leukemia, right now the only FDA approved cellular therapy in that space is Breyanzi or liso-cel, like we talked about.

[09:56] So why CAR T? That goes back to that intro that if the lymphoma is resistant to chemo, then there's no reason to keep giving you chemo. Let's switch it up, let's attack it with the immune system instead of just giving you stuff that causes a lot of side effects that has a low probability of curing the disease.

20% of people with follicular lymphoma, not all follicular lymphoma behaves the same. Some people have follicular lymphoma, and some of you might be in the audience that had follicular lymphoma that your doctor watched for years.

Or maybe you're in support forums where people have follicular lymphoma that they've been in that support forum for years without treatment.

[10:52] Whereas others, they get follicular lymphoma, it's off to the races kind of from diagnosis, and maybe you get chemotherapy and within 24 months of chemotherapy, the lymphoma is already growing back. Whereas maybe some of your friends or people in your support forums, they get treatment, it goes away, it stays in durable remission.

This is something that we don't fully understand why that happens, that some follicular lymphoma can behave a little bit more aggressive than others. And that same principle applies for mantle cell lymphoma.

[11:26] I have people with mantle cell that behave very indolently, and then other people with mantle cell lymphoma where the disease is extraordinarily aggressive. I think for all intents and purposes, We really do consider mantle cell lymphoma to be a more aggressive lymphoma, but there's always exceptions to the rules. 

That is not the case in diffuse large B-cell lymphoma. We would never sit on and not treat it diffuse large B-cell lymphoma, that would be foolish.

[11:51] The goal of CAR T is to cure. Like be very clear, I say this to all my patients, the goal of CAR T is to cure you.

But those chances of success are kind of variable and we're understanding these things better.

If we have better control of your disease burden before CAR T, that's associated with better outcomes. If an individual hasn't quite had as much chemotherapy pre-CAR T, maybe a potentially better outcome, that's a moving target. The idea here is that when you're getting chemotherapy, and the one that we have really been able to see this signal in is for people that have had bendamustine.

[12:29] Bendamustine is a great drug. Don't get me wrong. If you've had bendamustine, your doctor did it absolutely right. I use a lot of bendamustine. But one of the things we found is that if you try to go to a CAR T within six months of receiving bendamustine, we don't see as good a response.

The thought process there is that potentially that chemotherapy exposure kind of suppressed or dinged your own T cells that were swimming in your bloodstream when we gave you that chemotherapy. So they kind of take a hit from it.

Then they're not quite as fit as maybe they could be if we could stretch out the interval of bendamustine until further than six months, and then the T cells really then start to regenerate. That risk of maybe an inferior response starts to dissipate.

[13:29] Again, I told you this earlier, that CAR stands for chimeric antigen receptor, which is a mouthful, but basically we fuse a protein onto the T cell that will stick to the B cell.

That protein that we stick on there is sort of, there's becoming more and more. I actually think that maybe if me or someone else gives this talk next year, they'll be talking to you about, well, all of our CAR T historically just targeted a surface protein on the B cell called CD19. CD stands for cluster of differentiation. So I was not consulted when they came up with these sort of names for stuff.

It can be confusing, but just parenthetically, I'll tell you that things that define B cells, we call these surface proteins, clusters of differentiation. And B cells have surface proteins for CD19, 20, and 22. And right now, all of our CAR T just target one surface protein.

[14:37] But coming down the pipe are other CAR T products that target CD19 and CD20, and even further coming, they target CD19, CD20, CD22.

The idea here is that it's kind of analogous to the COVID vaccine in the sense that when COVID came rip-roaring through, there was that ancestral spike protein that all of our vaccines targeted just that one spike protein.

[15:09] But what happens if that protein mutates or down-regulates and doesn't express itself on the surface of the virus, now you've lost your target, and then we found that happened with the COVID virus. So what you did is the Omicron subvariant was a little bit different spike protein. And so we came up with what we call bivalent vaccines that targeted the ancestral spike protein and the Omicron spike protein to try and cover the bases.

Well, this is a concern in lymphoma, just like it's a concern in infectious issues, is that what happens if a lymphoma cell mutates that surface protein that we're targeting or down-regulates that surface protein that we're targeting?

Could we lose control of the disease? Will the immune system not be able to recognize the lymphoma? And maybe if we target multiple different surface proteins, we can improve response rates even better, and that's the hope and the prayer and what all of our research is being devoted to right now in this space.

[16:04] The current steps towards CAR T therapy. So it's a little bit of an involved process. I don't want you guys to worry about this stuff, but these therapies are expensive, so we want to be sure we have insurance approval.

I do hear time and time again from patients that are under stress. And I totally appreciate that where it's like, listen, I'll pay for it out of pocket. It's more complicated because of how much some of these things cost. And we'll kind of talk about that as we go.

So we want to get insurance approval. We have to submit to your insurance, hey, you're meeting the FDA eligibility and that you're a fit person that doesn't have, you know, a really weakened heart or some active infection or something going on.

We get the approval from the insurance. We got to get your cells collected, which I'll talk about in a moment. We got to re-engineer those cells. We got to give you some pre-chemotherapy, which we'll talk about. And then we got to infuse the immune cells, too.

[17:05] This can take time, and you might be thinking, like, wait a minute, I have a chemotherapy-resistant lymphoma, and you're telling me I've got three to four weeks or whatever somewhere in that ballpark to get the CAR T. What are we going to do about this?How are you going to keep things under control while we hustle to get you to the infusion of the immune cells?

Like I said, we get that approval, and what we need to do is collect those healthy T cells.When you guys look at your complete blood counts, your CBC, you know, you look at the red blood cells, white blood cells, the platelets.

Most patients with lymphoma know what an ANC is, right? Absolute neutrophil count.

But there's something else on your white blood cells, which is your absolute lymphocyte count, your ALC. The ALC is almost always T cells. For those of you with CLL, sometimes your ALC gets scrambled with these circulating B cells, but in general, it's T cells.

[18:06] So we need an absolute lymphocyte count of your T cells to be at least over 100. And what we do is we have you come in, we put a temporary IV in you. If you have big, juicy veins, sometimes we can get away with putting an IV in the arm. If they're a little bit weakened and those veins from the therapy you've been on, sometimes we have to put a bigger IV in your neck.

We suck the T cells out of your bloodstream. We get them in a big bag. We ship the T cells off to the manufacturer. They re-engineer the T cells by infecting them with a virus that drops a DNA payload in there. They re-engineer the T cell to recognize the surface proteins on your B cells. They come back, and then we would infuse them into you. That re-engineering process takes time.

[18:55] However, people like Kite and BMS who are sponsoring this, and we thank them so much for that, is they're getting really good and really fast at reengineering these cells. So that time that it takes to get them reengineered, this is something we call vein-to-vein time, the time to pulling the T cells out of your vein and infusing them back into your vein.

That vein-to-vein time compresses more and more and more because these pharmaceutical companies are just so good and so fast at doing that, which is great because it's making all of these concerns a lot less.

[19:26] So again, when we're doing this in clinical trial with different products, we say, "Hey man, it can take up to 42 days to re-engineer your cells." We're really down to less than three weeks really with almost all products these days which is incredible to get this stuff done, and obviously some even less than that. But again we're trying to get the insurance approval; we're trying to get you set up to get the cells engineered; we're trying to get you to the CAR T. I alluded earlier that if the volume of disease in your body is lower coming into CAR T, and that's associated potentially with a better outcome, which is very important, but the lower volume of disease in your body is also associated with better tolerance of the CAR T.

[20:22] A lot of times what we want to do is do something we call bridging therapy, which is we get the immune cells out of you, and then while they're being re-engineered, it's like, okay, what can we do to bring the volume of disease down to make this all go smoother for everyone. There's a lot of different ways to do that, and there's not a right way or a wrong way to do that.

[20:47] Sometimes we use some antibody therapies that stimulate immune activity to bring the volume down. Sometimes we use some cool antibody drug conjugate, things like polatuzumab, different drugs like that to try and get the volume of disease down.

But if we can have that volume of disease down, the side effects of the CAR T can be a little bit cleaner, and we'll dive into that as we go.

[21:13] The challenge with CAR T is that if we just take your guys' immune cells and we infuse them into you just willy-nilly, like they don't do as much as we wanna see them do.

The immune system's extraordinarily complex in the sense that there's a lot of interaction with immune cells. There's regulatory immune cells that tamp down immune response. There's all sorts of layers to that.

What we have found is that if we give a patient some pre-chemotherapy that we call lymphodepleting chemotherapy, it's low-dose chemotherapy that's low enough dose, you wouldn't even lose your hair with it, to transiently deplete your current immune cells to create space in your body for these CAR T-cells, the response rate is substantially better.

[22:10] So five days before the CAR T goes in, we give you three days of a drug called fludarabine and another drug called cyclophosphamide, which very many people have probably had cyclophosphamide. That's the C in our CHOP is cyclophosphamide.

But the dosing we give is just over three days, kind of split dosing and it's well tolerated and that really substantially improves the response, but depleting the immune system temporarily, of course is associated with risk of infection, which is one of the big things we need to talk about.

Historically, when we first started doing CAR T, we admit people to the hospital and we'd watch them closely, and a lot of times you would sit there as a patient kind of twiddling your thumbs, like waiting for a shoe to drop.vSometimes it would and sometimes it wouldn't.

We've gotten better and better at trying to do these things outpatient. I'll tell you here at CBCI, we do as much as we can outpatient so you're not sitting in the hospital. We only admit you to the hospital if we need to.

Other places, put patients in the hospital. We a lot of times will put people in the hospital. Like if you're coming from Casper, Wyoming, or something like that, live a long ways away. And sometimes it might be easier for you to be in the hospital. That's something that we can work through. There's not a right or wrong way to do it.

[23:29] The side effects of the CAR T are so much different than what you have all gone through with chemo. You know, let's just use our CHOP for the example, 'cause it's so common. You know, all the nausea, the low blood counts, the neuropathy, the constipation, the hair loss, all of those things, the side effects you think of chemo.

This is different because what we're doing is we're reprogramming your immune system to recognize the lymphoma like it's an infection.

So, you infuse the immune cells back into your body and the immune cells go in and scour and kill the lymphoma like an infection.

[24:04] But wait a minute, if you have an infection that your immune system is responding to, don't you get fevers? And the answer is absolutely.

But if your immune system is fighting the lymphoma like it's an infection, can't you also get fevers just from the attack against the lymphoma? And the answer is categorical.

In fact, most people will get infectious type reactions or fevers or body aches or shortness of breath, the sort of constellation of symptoms that we call cytokine release syndrome.

Cytokine release syndrome is where those T cells that we've infused to you release inflammatory molecules to recruit more immune activity and cause the T cells infused to grow and replicate and expand. Those inflammatory molecules released are called cytokines. Those inflammatory cytokines heat your body up and create the fever.

[25:06] But wait, I just said that we gave you chemotherapy before to transiently deplete your immune system. So how do you know that my fever is not because I picked up the flu or I have pneumonia? How do you know that it's the immune cells fighting and the answer is we don't.

So anytime someone gets a CAR T, they get an infection type picture, which is fevers, all that stuff. We start them on antibiotics. We start you on antibiotics empirically.

The vast majority of time you do not have an infection, but we don't want to be flippant with a weakened immune system assuming this is just the immune system responding to the infection.

There are other medications that we can give to abort that, fever type stuff, the cytokine release syndrome. But we have to be careful about infection because this is one of the big risks of CAR T is opportunistic infections. The big things are bacterial infections, reactivations of things like shingles.But these are temporary things that we can see.

[26:09] We do worry about fungal infection and risk like that if your blood counts drop quite a bit and they stay down. And if we're needing to give you other medications to calm that immune system down, you start worrying more about fungal infections and we have to put you on prophylactic medications to protect against viral infections, bacterial infections and fungal infections. You don't always have to protect people against fungal infections. It's a case by case basis. And every center has a different protocol on how to protect you from those things.

[26:40] So again, the cytokine release syndrome, it's like you're having a bad infection.

This goes back to what I've said a few times now, which is if you have a higher burden of disease in your body at the time of the CAR T, it tends to be more rocky, but that makes sense, right?

If you think about this, if you have a sinus infection, yes, it's miserable. Yes, you can have some fevers. But the degree of those fevers and the intensity of those fevers is going to be substantially lower than if, God forbid, you know, you had your appendix burst open and you have a big belly infection.

That's where you're extraordinarily sick because the volume of the bacterial infection can dictate how sick that you get. The volume of lymphoma in your body can dictate the level of fevers, low blood pressure, all of those symptoms that you can get from these immune therapies. So trying to compress that disease burden before CAR T makes it a lot easier.

[27:44] Will I get cytokine release syndrome? Almost certainly. However, if any of you have gone through a CAR T and did not get cytokine release syndrome, that does not mean the CAR T didn't work. There's no correlation there. It's just something that we really generally see a lot.

We see it a little bit less in follicular lymphoma, but almost all of my patients that have given a CAR T have some level of fevers and stuff like that.

[28:13] We grade those things differently. I'm not going to bog you down with those things, but the level of intensity of these inflammatory responses kind of gets graded. And as it goes higher, we need to do more therapies to abort those things.

The drugs that we give to abort the cytokine release is there's a really nice drug that we use a lot of called tocilizumab. That's an antibody that soaks up one of the inflammatory cytokines being released by the immune cells.

Think of it as like a sponge. You have these high fevers from those inflammatory molecules being released. We infuse this protein in there. It soaks up those inflammatory molecules and brings the temperature down without impacting the efficacy of the treatment.

And if you're getting really high fevers and feeling really sick, sometimes what we have to just do is start steroids to just calm everything down.

[29:11] The other thing that you can see in anyone that's had a family member go through treatment with this, usually the patient doesn't recall a lot of these symptoms, but the family members vividly recall these things, and that can be stressful for family members.

So, for those of you who are family members listening to this, you know, we need to recognize that, you know, this is hard for you guys, too, to watch some of this stuff.

Any of you who are parents in the audience, if you've ever had a kid, and this happens a lot, and kids get a really high fever, high fever, they can get really sick really quickly. And sometimes kids can get really high fevers to the point that they have a seizure, a febrile seizure. Those things are more common in kids than they are in adults.

[30:02] But these inflammatory responses that we can see from the CAR T can really cause confusion. They can cause tremors. They can, God forbid, cause seizures. So most patients, we put on prophylactic anti-seizure medicines temporarily. 

You can have these neurologic side effects without fevers. You can have them with fevers. But this is something we call neurotoxicity or immune effector cell-associated neurotoxicity syndrome. That's a mouthful. That's why we call it ICANS.

When someone's getting that, the treatment is steroids, steroids, steroids. And sometimes your doctor might have to do a lumbar puncture and squirt a little bit of low-dose chemotherapy into the spinal column to break down those inflammatory cells.

We see it more commonly in the aggressive lymphomas because the immune response to that is robust, and that's the risk for those things.

[31:06] For those of you that have maybe mentioned that to your doctor, and like I said, I hear it a lot when I say, listen, I just want to get to this as fast as possible. I don't care about the insurance. I'll pay for it out of pocket.

This is the challenge, you know, is that the drugs are very effective, but they're expensive.Then when you compound that with all the supportive measures, it is a lot. 

But thankfully, Medicare and Medicaid, at least Colorado Medicaid, they do cover these things.

Dr. Tissot, one of our lymphoma doctors here, has gone to Capitol Hill, has gone to Washington to really advocate for those of you on governmental payers for coverage for this thing. We are all indebted to him doing that out of his own free time. So big tip of the cap to Dr. Tissot, he's one of our lymphoma doctors here.

[31:59] Post-CAR T, one of the things that's really under reported, but I want you all to be aware of this, you just kind of have this like brain fog that tends to resolve over time.

You know, people say chemo brain, it's not really chemo brain, she didn't really get chemo, it's just the inflammatory milieu smoldering very common and it is because of some of this interruption between connections, neurologic connections from these inflammatory molecules.

Another thing that's really common post-CAR T because of all the inflammation, not directly from the chemo, but from the massive inflammation that we get from these immune responses is some low blood counts. That's a notorious problem that generally resolves over time.

[32:47] Those of you that have had a lot of bone marrow-based disease burden in the past can tend to have this prolonged even further because there's so much inflammation taking place in the bone marrow and that inflammation suppresses stem cells.

Then infection, we've been talking about infection. So we're giving you chemotherapy to deplete your T cells initially to make room for the new T cells we infuse. And then the new T cells we infuse are going around killing all these cancerous B cells, but they don't discriminate cancerous B cells from healthy B cells.

[33:24] As a reminder, your healthy B cells make your antibodies, you get influenza, your immune system responds, it releases antibodies directed to influenza, and then I just gave you an immune therapy that kills all of those cells, and now you're not making antibodies anymore. So now you're at risk for infection.

So, we wipe those out. A lot of times we call something we call B-cell aplasia, meaning we've wiped out all the B-cells in your body. And that weakens your immune system ability to fight infection.

Almost all patients post-CAR T for lymphoma require supplemental immunoglobulin infusions every one to three months for the better part of a year, sometimes longer, sometimes shorter.

In general, the B cells will recover. However, there is a chance you might require supplemental immunoglobulin infusion indefinitely. I have not personally seen that happen, but that is well reported.

[34:28] So we want to prevent infection from happening, you guys. We put you on, everyone here who's got lymphoma has been on either valacyclovir, Valtrex, or acyclovir.

We generally recommend shingles prophylaxis at least 12 months post-CAR T. We recommend Pneumocystis coverage with things like Bactrim, or if you have a sulfa allergy, Dapsone or atovaquone or Pentamidine for at least 12 months until those immune cells recover.

Immunoglobulin supplementation, and sometimes you need some G-CSF, right? Neupogen, Nulasta, OnPro, Granix, whichever your hospital uses to kind of keep stimulating those white cells to stay up. Very common. It's nothing ominous. It's just part of it. Doesn't mean something went wrong if you're needing those things.

[35:16] We do recommend a lot of repeat vaccinations. There are recommendations through the transplant societies. There's a little bit of variance in that, but in general, we're recommending repeat vaccinations for things like COVID, flu, shingles, some of your pneumococcal infection things, Tdap boosters, hepatitis B boosters, things like that. Each center has a different sort of cocktail on how they do that.

People that get CAR T can get secondary cancers. Your immune system plays an incredibly important role at protecting you from skin cancer. You get burned by the sun, you take radiation damage because DNA mutations, the immune system is a critical component of mopping up those damaged cells.

So, anytime your immune system is suppressed, you're at risk for non-melanoma skin cancers. Then anytime you've had chemotherapy, there's a risk of something called MDS, which could evolve into AML. Just parenthetically, Robin Roberts on Good Morning America, I say this all the time, she had breast cancer, got similar chemotherapy that we use in these spaces. One of those things is cyclophosphamide.

And she got MDS slash AML from her breast cancer treatment. She had treated for that and a stem cell transplant for that. And of course, she's great. She wrote a book about it. She sits on the board at Mayo Clinic. She's been a great proponent of these secondary cancer things and has talked about that, and she's been a great help in that raising awareness about those things.

[36:48] There are rare neurologic events from this. I will tell you that most of the permanent neurological complications we've seen post-CAR T are actually in people with multiple myeloma because the target protein that we're targeting is different. And that target protein we're targeting myeloma is on the brain stem, but we don't see that much in lymphoma.

The goal though is that 30 to 90 days after CAR T, yes, you're gonna have kind of a poor quality of life, but that it gets better and better and better. And that brain fog goes away. Your immune system reconstitutes, counts get better, but there's some variability on that.

[37:35] As we do this more, we're getting better at controlling those side effects 'cause we know what to look at on the front line of things, and the CAR T is getting safer and safer. We used to say that you couldn't drive or do anything, anything for 30 days, and many of you know that that change, the FDA says, hey, you really just gotta keep that 14 days. If you make it through the first 14 days, most of those bad side effects go away.

[38:00] Many centers use this routinely. Some prophylactic steroids upfront has been shown to reduce the severity of these complications. That's a standard of care at our institution. I don't know that that's mandatory, but most people are doing that now 'cause it reduces the side effects of these things.

Like I talked about, clinical trials are coming, we're targeting more surface proteins. And for those of you with T-cell lymphomas, we're trying to figure out how to do that.

[38:29] Because if you have a cancer of your T cells, how do we harvest healthy T cells and then infuse those T cells back into you to attack the cancerous T cells, but not have the CAR T-cells attack each other, something we call fratricide.

And so they're looking at using donor T cells and all sorts of stuff that's been really challenging. We have those things in clinical trials right now, and they're kind of open across the country, but they're just not prime time yet like the B-cell CAR T is.

So we're looking at expanding these different subtypes of CAR T therapies. Like I told you, there's this idea of off-the-shelf CAR T where a healthy donor donates their immune cells and they really re-engineer them.

You can just pluck them off the shelf and infuse them so we don't have that time lag in between harvesting your own immune cells, re-engineering your own immune cells, and re-infusing them into you.

[39:29] We're looking at trying to unlock this immune therapy and all sorts of other types of cancers, colon cancer, breast cancer, everything under the sun. We're trying to figure this out because I don't want to sound cliche, but this has been a game-changing therapy for patients with lymphoma, and so trying to unlock the power of the immune system in all diseases has been a high, high priority.

And that's the whirlwind CAR T, at which point I'm happy to take questions.

Q&A

[40:09] Moderator: Thank you, Dr. Mountjoy, for this excellent presentation. Now let's take some questions.

If you have additional questions for Dr. Mountjoy, please use the question box on the lower left side of the screen. We will answer as many questions as possible.

Our first question is around the dosing and schedule for tocilizumab to address CRS.

[40:36] Dr. Mountjoy: Yeah, so there are some studies looking at giving what we say prophylactic tocilizumab. You just give it up front and you have that drug swimming in the bloodstream to really make this process smoother.

That's not standard of care right now. What we generally do is we wait to see if and when you get those cytokine release syndrome things.

When that happens, you start getting the fevers and the shortness of breath. We administer tocilizumab, and then we could administer it up to four times. And if we give it to you four times, you know, give it every eight hours four times, and you're still fevering through it, that's when we tend to kind of use more aggressive intervention steroids or combinations of steroids, tocilizumab, to tamp down the immune system.

I would say that by far and away, usually one or two doses of tocilizumab is all a patient generally. This is just general, need to abort those symptoms.

[41:46] Moderator: The next question is, can you get CAR T-cell therapy if you have T-cell lymphoma? So perhaps you could go into all the specifics.

[41:58] Dr. Mountjoy: Yeah, we have that in clinical trial here at CBCI.

They're looking at targeting a surface protein and T-cell lymphoma. There's two of them they're looking to target. We have the one in clinical trial right now targeting.

If you remember going back, talking about those CD markers, cluster of differentiation markers, the B cells are CD19, CD20, CD22.

The T cell surface proteins are CD2, CD3, CD4, CD5, CD6, CD7.

So, there are two research targets right now, targeting CD5 and targeting CD7. And so, what you do is you harvest the immune cells. You manipulate them. You downregulate their surface proteins. You make them target CD5. You re-infuse those immune cells targeting CD5.

What's really challenging about that is that the infection risk of T-cell CAR T, T-cell-directed CAR T, is high. Because your T-cells play a very important role at your protection from things like Epstein-Barr. So that's one of the things that we can see.

We can see Epstein-Barr viruses reactivate due to that immune suppression.

We're figuring it out. We're way closer to figuring that out than we were even when I, a couple of years ago, gave this talk.

It's coming.It's in study right now. But I don't want you to, if you wind up getting a study, that's great. And I don't want you to feel like you're a guinea pig.

But there are still some kinks that we're trying to work out there to make it just prime time.

Here we go like we do for B-cell lymphoma. It's coming. We just need a little more time because it's nuanced and complicated.

[43:44] Moderator: So complicated.

Next question is, with donor T cells, would you experience similar problems as you see in an allogeneic stem cell transplant?

[43:56] Dr. Mountjoy: So that's a great question because that was always the concern.

You take donor immune cells, you infuse them. Like, aren't I going to get, like, horrible graft-versus-host disease?

No, you don't, because these companies are very bright young people, or old people, not to cast tones at old people, but that are figuring this out.

And what they do is when they do the gene editing, they can deplete the T-cell's ability to recognize something called HLA, human leukocyte antigen. So those off-the-shelf T cells, allogeneic T cells, will not cause graft-versus-host disease.

Furthermore, they're looking at off-the-shelf cells, something called gamma-delta T cells, or natural killer cell CAR T products, that at baseline don't recognize those differences in surface proteins between you and the donor. That was always a concern, but we've figured that out.

The next question is efficacy.

That's the next question about off-the-shelf CAR T that we're trying to figure out.

[45:02] Moderator: Excellent.

Can progressive peripheral neuropathy be a CAR T long-term complication?

[45:10] Dr. Mountjoy: Yeah, we generally don't see that.

But I think there's always room for humility with us physicians.

I would always caution anyone to say, there's sort of an adage, never say never and never say always, you know, where it's like, for someone to say, no, that can never happen is a leap.

Is there a strong signal that that could not, we're not seeing that. Anything is possible. Anything's possible to get off target effect of the immune cells to irritate the nerves.

If you're having progressive peripheral neuropathy, two brief things on that. The most common drug associated with causing neuropathy in the lymphoma space is vincristine.

Sometimes you get something with vincristine called the coasting effect. Imagine driving down the highway at 80 miles an hour and then putting the car into neutral. You're not hitting the brakes and the car's stopping. The car is going to coast for a while.

So, a lot of times what happens is after your last dose of chemotherapy, you're like, hey, I stopped the vincristine. But a month and a half later, my neuropathy is still getting kind of worse. That's the coasting effect.

It's still kind of progressing before it gets better. It can take up to 12 months to kind of see how the nerves heal. 

I personally have not seen progressive peripheral neuropathy from a CAR T, but if that's happening, I would strongly suggest getting it with neurology for all of the antibody testing, the nerve conduction studies, maybe a nerve biopsy to see if we're seeing activity in that space.

[46:45] Moderator: So, Dr. Mountjoy, let's talk outcomes.

How does CAR T-cell treatment compare to an allogeneic stem cell transplant?

[46:54] Dr. Mountjoy: Yeah, great question.

So, there was a nice study done in sort of a counterpart of one of the premier medical journals. There's something called BLOOD, which is the American Society of Hematology Journal. And then there's a counterpart to that journal called BLOOD Advances.

Blood Advances did a very nice study where they looked at outcomes of patients getting CAR T for diffuse large B-cell lymphoma or getting allogeneic stem cell transplant for diffuse large B-cell lymphoma.

And what they found is that the disease control, the ability to cure the disease, CAR T versus allogeneic stem cell transplant, we saw almost identical cure rates there. It's about a coin flip, 50-50 cure rates.

The big differentiator here is that the chances of dying from other complications of an allogeneic stem cell transplant is 25 to 30%, whether that's infection, graft-versus-host disease or whatever.

The chances of dying from complications of a CAR T was three to 5%. The risks and benefits, a stem cell transplant is very effective, but it is much more dangerous than a CAR T. So that's starting to fall by the wayside more and more. Sometimes we still do that.

If you've had a lymphoma that has been relapsed, refractory to all of our treatments, including CAR T, sometimes the best path forward is an allogeneic stem cell transplant.

[48:24] Moderator: We have got such an incredibly smart group of folks on this symposium. They've got a great question here.

Any thoughts on microbiome modulation to increase CAR T efficiency and side effects reduction?

[48:42] Dr. Mountjoy: That is one of the more exciting things happening right now.

To answer that question directly, we don't know yet. But let's think about a couple of things.

So this has been a really interesting thing for me for several years because when I was at Mayo Clinic, my co-fellow, Dr. Ertz, was doing a study with blood cancers. And she showed that people with leukemia, she checked all their gut microbiome and saw that the higher the risk of leukemia, the more dysregulated the gut microbiome was. And the lower risk of leukemia, the healthier the gut microbiome looked.

That was really interesting to me because it's like, is it a chicken or the egg thing is the gut microbiome affecting that.

And then you go back further and then you say in diseases, in solid tumors, things like melanoma, kidney cancer, stuff like that, we use immune therapies, things called checkpoint inhibitors, things called Keytruda or pembrolizumab or Opdivo or nivolumab, these different immune-based therapies for solid tumors.

And that gut microbiome plays such an important role there that they're actually doing studies where they're doing fecal transplants in people to try and get them healthy gut flora to capitalize on immune response and prove that.

And of course, that's stretching over into the CAR T space. We're seeing some of that data in mouse models about a healthier gut microbiome may be associated with a better response to CAR T.

But ultimately, the jury's out right now, but that is a fascinating question and something that is of a lot of interest to those of us in the field.

Great question.

[50:28] Moderator: Indeed.

What do you think the long-term survival rate from CAR T is for DLBCL?

[50:36] Dr. Mountjoy: Well, I would tell you that the long-term, so there's two, the chances that a CAR T cure you around 40 to 50%. We still do see about half of patients, 50 to 60% of patients can recur. Thankfully, therapies have advanced substantially.

So we have multi-antigen directed CAR T. I mentioned one that we're targeting three surface proteins right now.

We actually have a study here targeting six different surface proteins all at once. We have these things called bispecific antibodies. We're getting things called trispecific antibodies. We're getting enzyme degraders. There's stem cell transplant. This is something that's kind of coming back.

Let's just run that scenario. If God forbid the lymphoma comes back six months after CAR T and we have to urgently give you chemotherapy and the tumor responds again and shrinks down, meaning that it has regained chemosensitivity, you can do a stem cell transplant in that setting.

And on the original CAR T clinical trials buried kind of in the supplementary appendix, a lot of those patients that had recurrence did go to a stem cell transplant using their own stem cells.

And some of the data through the big research consortium is that if you can get someone back in remission with chemotherapy and then do an autologous stem cell transplant on them, that you can cure up to 60% of those people. But that's a big if.

I will tell you that independent of research right now, a relapse post-CAR T, that's when we're worried. That's when we get really worried about the long-term outcome.

But in general without a recurrence of the disease, that's where we start flirting with calling you cured.

Now we've seen some exceptions of that where people can recur after, but

[52:30] Moderator: I would say right now it would be 50-50.

Now we want to get your views on CD19-based CAR Ts versus NK cells-based CAR Ts versus in vivo CAR Ts.

One of our watchers is considering a clinical trial.

[53:10] Dr. Mountjoy: On a research study, the in vivo CAR T and the NK-cell CAR, I can't comment on.

We have, in terms of what specific study, I can tell you that we have done a lot of studies with NK-cell CARs, and we don't see the responses near to the level that we're seeing with your standard cytotoxic CAR T, FDA-approved CAR T, standard CAR T.Just don't see the responses as good.

That's not to say that whatever research study you're eligible for, that maybe they figured out how to really get those NK cells to engage with the tumor and kill it. I would just ask your physician what kind of responses they think they're seeing on that study.

The in vivo CAR T is a very interesting thing, too, because the idea there, and we are opening that clinical trial here in the near future as well, which is where instead of harvesting the T cells and re-engineering them in the lab, we give you an injection of sort of a modified viral particle.

And some of them are using gene editing CRISPR to do that, CRISPR gene editing, to re-engineer the cells within your body, but they're re-engineering your T cells, your cytotoxic T cells.

And so I think that if I personally were picking between clinical trial of in vivo CAR T or NK-cell CAR T, and I might be wrong, obviously this is in research, but if I were a patient and you were my family member, I would definitely lean towards the in vivo CAR T because it appears that that T cell right now seems to be the answer there. That is clearly subject to change based on data.

[54:38] Moderator: Dr. Mountjoy, after CAR T, you talked a lot about the infection risks.

How long can a patient expect to be on drugs like IVIG, or does it really depend?

[54:49] Dr. Mountjoy: It really does depend.

You know, I will tell you, you know, the wonderful young lady who was the first person ever to receive a CAR T for B-cell acute lymphoblastic leukemia, I want to say she's 15 or 16 years out from that, she's still getting intravenous immunoglobulins. So she'll probably be on that for the rest of her life.

I will tell you that's an extreme example.

I've had most patients, their IVIG demands start diminishing after 12 months. Some go longer. But I'd say in general, I would anticipate at least a year ballpark to need that. And in some instances, it could be permanent.

That's been more of an exception, the permanent to that. What was the other layer to that question, the immunoglobulin and the infection thing, Michelle?

[55:34] Moderator: Yeah, just how long we can expect it.

[55:37] Dr. Mountjoy: Yeah, and then here our protocol is shingles prophylaxis for two years with acyclovir or Valtrex, and then Pneumocystis prophylaxis with either Bactrim, Dapsone, and atovaquone for 12 months, and then we'll actually check the concentration of your T cells to be sure they've recovered before fully stopping that after 12 months.

[55:57] Moderator: All right, so this will have to be our last question as we are running out of time.

I have two types of lymphoma, LPL with a Bing-Neel syndrome and DLBCL. I just finished six cycles of chemotherapy. The BTK inhibitors were stopped in December of 2025.

If my DLBCL had complete response to the chemo, am I still a candidate for CAR T for my LPL?

[56:27] Dr. Mountjoy: You would not be a candidate for CAR T for LPL as a standard of care, meaning that if the LPL came back and you wanted to get the insurance to cover Yescarta or something, that's not approved yet. It's not yet approved for LPL.

However, I do think that is coming, and there are research studies looking at CAR T for LPL. I have multiple times given CAR T to people with LPL with the secondary DLBCL.

So, if there's any signal that the DLBCL is trying to recur with the LPL, I would categorically, and it would be a layup to get you approved for CAR T, even if it's in your central nervous system, like the Bing-Neel.

[57:16] Moderator: On behalf of BMT InfoNet and our partners, I'd like to thank Dr. Mountjoy for a very helpful presentation. And thank you, the audience, for your excellent questions.

Before you leave, stay on the line to complete a brief survey. Your feedback is very important to us.

[57:34] Dr. Mountjoy: Thank you, guys. Thank you for having me. Thanks to the organizers. Thank you, Dr. Tissot