What's New in CAR-T?

- This is Lab Medicine Rounds, a curated podcast for physicians, laboratory professionals, and students. I'm your host, Justin Kreuter, transfusion medicine pathologist, assistant Professor of Laboratory Medicine Pathology at Mayo Clinic. And today we're rounding with Dr. Timothy Wiltshire, assistant professor of Laboratory Medicine and pathology in the division of Transfusion Medicine at Mayo Clinic in Rochester, Minnesota, to talk about what's new with CAR T-Cells.

Thanks for joining us today, Dr. Wiltshire. - My pleasure, Dr. Kreuter. Thanks for the invite. - Absolutely. I always like kind of kicking off with the, you know, why is this an important topic for, for our audience of clinicians, laboratory professionals and students. So, you know, why, why is CAR T important for healthcare

folks to appreciate in 2023? - So CAR T really is a, a relatively new modality, and I think it's fundamentally changed the, the way we're treating some cancers. We call these living drugs because we're using cells as a living drug and, and CAR T has shown promising results and impressive response rates in patients that have already had two or three lines of treatment already. So it's really offering new hope to patients who have failed multiple lines of prior treatment.

I think it's a significant breakthrough for the handful of heme malignancies that have, that are being treated using CAR T, which we don't come across a lot of these in our lifetime. That significantly changed the landscape of CAR T therapy.

If you think about it, in, in therapy a typical drug is, is considered a success if there's a, you know, maybe a 10% difference in overall survival or, you know, a a a few months increase in, in survival with CAR T, we're talking greater than 80% initial response rates in people that have already had prior lines of therapy. And many of these people, the five-year survival rate is 40 to 50%. So it's a pretty significant number of people you know, who respond to this type of therapy.

And like I said, these types of breakthroughs don't happen very often in, in cancer therapy. I think the most powerful illustration of this is the, the first pediatric patient named Emily Whitehead, and if you haven't read her story, this, this little girl's alive over 10 years after being treated as the first pediatric CAR T patient. We're talking about somebody that only had a couple months to live and kind of did this as a, you know, a Hail Mary.

So this is hope not provided through any other conventional treatment modalities. And I think we're still in the early stages of CAR T development in use. So it's a pretty exciting field. - Wow. Well you certainly got my attention when you're talking about what kind of success we're, we're seeing with this. And you know, I'm kind of reflecting on, as you were talking about, you know, this is a living drug. I definitely am gonna be using that with my immunology students next week, but these,

these are the patient's own cells, right? And like, it it's kind of maybe a little confusing of like, okay, this patient was on their deathbed, how are we taking their own cells and then turning them into this, this living drug. Can you give us a little bit of background on like, you know, what, what should healthcare professionals understand about CAR T? I mean, people might hear the acronym, but what, what should we appreciate about these? Right.

- And I think that's the exciting thing is CAR T uses the body's own T cells, which, you know, the, the, the human immune system is a pretty delicate and intricate response. And our best, you know, our best fight, you know, against developing cancer, I often tell lay people that ask me what, you know, what I do?

I said, you know, I make CAR T cells and it's really harnessing the power of the human immune system to treat cancer because your, your body has, you know, hundreds, even thousands of cancer cells in it each day. It's only when they can, you know, avoid the immune system that they can actually develop a tumor or it only takes one of those cells.

So I think this's an exciting class of treatments and I think, you know, to try to get people to understand it, we're really taking the T cells out and genetically modifying them with a receptor that's specific towards their tumor type. So we can, we can make a CAR, which is a chimeric antigen receptor that's specific for a, a target that's expressed on the tumor. And then we, we use some genetic modification to basically prime these.

So as soon as that receptor is engaged, it activates and kills the tumor. And so it's very intriguing part for me because one of the hallmarks of tumor development is the evasion of the immune response, like I said.

So we're harnessing the immense power of the human body to reintroduce the tumor to the immune system. So all we have to do is reintroduce 'em to each other and they can, you know, it can have its effect on the tumor and more specifically as opposed to, you know, traditional chemotherapy where you're just trying to find a therapeutic window to kill, kill the cancer cells and not the healthy cells.

- Now I, heard you earlier in your first answer kind of talking about, and I picked up on you, you dropping kind of the hematologic malignancy specifically and is that like, is it true to say that we've seen success specifically in the hematologic cancers like leukemias, but not necessarily like the solid tumors like maybe breast cancer or prostate cancer?

- Correct. So obviously this is the low hanging fruit when you're talking about a heme malignancy, it's something that's circulating in, in the bloodstream and is much easier access. It's also most of the ones we treat at this point are, are B cells. So we have lymphomas or multiple myelomas where there's a target such as CD 19 or BCMA that that makes it the low-hanging fruit.

So you know, there still remains a huge untapped potential for CAR T in in several areas that is moving it closer up to the first line therapy because you know, data now is showing that earlier we can get the treatment with CAR T, it's leading to higher complete remission rates versus standard standard chemotherapy as a first line.

We're also moving into solid tumors as you kind of hinted towards there, a lot of, a lot of difficulties with that because obviously a solid tumor is much different than something circulating in the body. But there's a pretty significant amount of research going into that. I did actually look it up just to see, and there's over 300 INDs with the FDA now for CAR T trials. - Oh, and - I'm - Sorry, can you explain IND what do you mean by that?

- Oh, sorry. So for IND, sorry, I'm in my world where that's what we do is clinical trials. So it's an investigational new drug application. So this is how you run a clinical trial. Basically you submit to the FDA and IND basically says what drug you're gonna use, what population you're gonna use it in and how are you gonna manufacture it. And so there's only over 300 of these applications with the FDA right now running CAR T trials.

So the major push are to make these more broadly used in solid tumors as well as make them more effective in the tumors that we're already treating effectively. - Hmm. You know, one thing I'm reflecting on listening to you, you know, I mean this, this, it sounds like this field is just as evidence, you're talking 300 investigational new drugs out there is is just exploding. And certainly there are centers, you know, like your own laboratory that are doing a lot of this work.

You know, our listeners may be in a whole variety of different situations. They may not necessarily have a CAR T facility at their hospital, but certainly everybody, including our student listeners will be, you know, can, you know, look at articles that are published in in journals, right? That's a common practice for probably most of our audience, you know, as an expert in this field, you know, are there a few things that you look for when you read an article that's reporting about CAR T cells?

Because I think maybe the more broader public, you know, professional healthcare, public, you know, it's, it's a new field. We may not understand how to critically read this literature. Do you have a couple pointers on on what you kind of pay attention to or what you look for with these?

- Yeah, and I, I would have to admit I'm a little more jaded than the the general public because obviously I work in a GMP facility and our, and our, you know, goal is to be able to translate these things in the clinic. So when I'm looking at it, I'm looking at more at can we do this? Is this something we can manufacture? Because that's, you know, that's obviously an issue translating from the bench to the bedside, which is what we do. But you know, definitely other things to look at.

I mean there some targets are useful and some aren't. I mean if, if you think about a solid tumor, anytime that grows, you know, over a specific size, you don't have vasculature in there. So it's difficult to see how you're gonna kill a solid tumor unless you have something else going along with it.

So there is, you know, studies out there that look at say like delivering a payload or something that help penetrate a tumor more or when they engage with a solid tumor, they're gonna, you know, put off some, some perforins or something that's gonna kill cells. So definitely looking at the strategies and how they kill them because as we know, there's a lot of things that can kill tumor cells in a dish or you know, even in, you know, even in a mouse model that aren't gonna do it in a human.

So that's kinda the lens I put on it, which probably isn't what, you know, most, most people would look at. But definitely looking at the, the feasibility of, you know, I can put an art artificial, you know, CAR T in there

and kill a tumor if expressing what I need to, but is it gonna be useful in the long run? Because if it's not, then, I mean it's just like anything, if you give a high enough dose of a, of any kind of drug, you're gonna kill all the cells. But is there a therapeutic window there? - You know, I, I think that's a brilliant answer for our audience to, to hear, right? This idea and, and you know, I'm grateful you kind of share this, just this perspective of practicality, right?

Because I think everybody can kind of relate to that and I think that can instantly make this literature a lot more accessible to people that are reading it to reflect on and, and think about these things about, yeah, I heard you talk about, you know, access, talking about really feasibility of things and then you, you mentioned targets, right? Right. And there you're talking about, you know, what are we engineering the t-cell to go after?

Which as I understand it, that's kind of been a limiting thing because of, I guess I hear it described as off target effects. Can you kind of explain what what that is? - Yeah, and that's really a therapeutic window because if you find a target that's on the, the tumor but also on healthy cells, you're gonna be killing those as well. So there are a few ways around that and, and some things which kind of try to deal with that, such

as logic gated CAR T cells where you're looking at a specific mutation along with a target. So you really want our on target effects without the off-target toxicity, which, which is difficult to, to come by if you don't have a good tumor target. So I think that's what a lot of the, the basic, basic research is trying to flush out some of these targets that that can be expressed on the surface of the cell, that, that are easy hits.

I think we've found a lot of those, so it's getting more difficult as we go along. But like I said, the low-hanging fruit we've gotten, it's, it's just getting more complicated now as we look for that ther therapeutic window where it's expressed on the tumor and not normal healthy cells. - Maybe this is a good time to kind of slip into this kind of, you know, I think CAR T is getting out there enough that, I mean I certainly we're getting into interview season right now as we're recording this.

It's kind of late October and you know, we, we get certainly a percentage of our applicant's pathology programs are applying to pathology and expressing an interest in in CAR T. So you know, there this has really kind of established itself. And so I'm curious, you know, what's really the new work in CAR T cells that you guys are, are really kind of working on right now? Or are, I'm sorry, not working right now, but what's, what are some of the new things that have come out recently?

- Yeah, I've kind of hinted at a few of those, but really we know there's a major push towards living a more healthy CAR T-cell to make them more persistent in the body. That means avoiding exhaustion while encouraging long-term

growth because studies are showing if we can keep the CAR T in the body and healthy for longer periods of time, people have better responses. So there's many ways to do that. Shorter growth times actually using the body as the incubator, so putting in less cells and and allowing them to grow up within the body.

So we're also expressing different, you know, different receptors on there such as a, a membrane bound cytokine receptor, which causes the CAR T to grow so it gets in the body and grows from there. So we can deliver low lower doses, which theoretically equals, you know, less toxicities and side effects while making sure that the CAR T grows while it's in there. There's also pushes towards, you know, allo CAR T products. We have something off the shelf.

A lot of the patients that receive CAR T in heme malignancies are, are in dire straits by the time they reach us. They only have a matter of, of a short time. So if we could come up with something off the shelf, an allogeneic CAR T that would be useful, could, - Could we take a little bit of a deeper dive into that? 'cause I think, you know, I, I think I, I get where you're going, but I just wanna make sure our listeners appreciate.

Yeah. You know, when you we're talking about CAR T so far we've been talking about allo autologous or from the patient's own self, but you just said allogeneic, so from a different person and you used the kind of phrase off the shelf ready to go.

Can you kind of maybe go back what's involved with creating your typical CAR T what's that timeline look like and then that contrasted with this off the shelf idea? - Yeah, so there's, there's now six commercially approved CAR Ts by the FDA that can be prescribed and they take anywhere from three to four weeks, sometimes even a little bit more. And there is competition for those slots. So an off the shelf would be ready to go, but it's also a non-self.

So as soon as it goes into the body, the body recognizes that a as T cell that came from somebody else and it's gonna attack it. So some of the strategies are knocking down, say some of the, the, you know, the MHC class molecules so the body doesn't recognize it. So I, I think people are working towards that, but it's still, still the low hanging fruit is the, you know, the alt autologous, but it also has the drawbacks, you know, of it takes some time to manufacture and at a significant cost.

So. Hmm. - So what do you see the, the future of, of CAR T cells going? Do you, do you think it's going to, you know, progress along this pathway of developing, you know, autologous constructs that are gonna be more effective against solid tumor

and you know, we're gonna figure out more of that access feasibility or, you know, do you think of more of this, you know, off the shelf is gonna be, you know, further perfected or, you know, is there some kind of a combination where an off the shelf is kind of like some, you know, in case of emergency break glass kind of product, right? But, but you know, some of the autologous, what's, what are your thoughts on the future for the field?

- Yeah, and you've hit on a, on a huge debate in the field right now of, of where this gonna move. Because, you know, as I said, there, there is a limited manufacturing of these and that's, that's a huge barrier to it. So if we get to the allogeneic, it'll be great.

I think there's significant obstacles, both, you know, mechanistically as well as logistically and, and, and regulatory context because when you're genetically modifying a cell and, and, and in this case, you know, you'd use CRISPR to knock something out so it doesn't, you know, it's,

it not, it's recognized itself. So that creates a whole nother layer of regulations as far as the FDA's concerned. So I, I think we may get there someday, but it is more of that kind of the dream of getting to that someday where we can take somebody's healthy t-cells as opposed to somebody that's been heavily pretreated and, and you know, use those for manufacturing. But I, I think there's, there's gonna be a lot of strides made in the, in, in reducing the side effects

as we, we get more effective and put healthier cells in. So

- Is is part of, I was just reflecting as you're talking about, you know, when we're talking about transplantation, right? Which is another strategy that's used for patients with some heme malignancies. And when we talk about transplantation, a lot of times there are pretty significant, you know, inequalities, non-equity among different ethnic backgrounds because we don't have many like minority donors in the National Marrow Donor program, for example.

Is access and that kind of, is this a more equitable kind of product that we're seeing or are there still some struggles with, with getting equity for different populations with CAR T? - Yeah, sadly, no, it's not a very equitable treatment modality because really because one of the largest barriers is, is cost. And, and we know, you know, from other, other data that, you know, if you're socioeconomically disadvantaged or minority, the cost is a seriously prohibitive factor.

So I think that's one thing that people are looking at. And there's, there's entire companies now that are founded on, on trying to make it a more equitable, not just for, for the, you know, people in the US but people outside of the US. 'cause you know, we're, you know, US, Europe, some of the Asian countries and Australia are really the only ones that have, you know, broad access, what we call broad access, which is still very limited.

So I, I think that is a, a huge issue moving forward, you know, which is in healthcare in general, there's inequities and this one really magnifies that because of the sheer cost of delivering a CAR T product. - And is, is the promise of an off the shelf, not just the emergency, but could that be a cheaper option? - Yeah, I think much cheaper option because I mean, if you think about it, this is a one patient, one product manufacturing.

So we're collecting the raw material from the patient, you know, sending it off to a, a manufacturing facility, which, you know, significant resources to, to have a facility like that they manufacture and then send it back. So the, the commercial car ts at this point are somewhere between four and $500,000 for one dose. So it's a, it's a significant cost to patients.

- Yeah. Yeah. Yeah. Well we've been rounding with Dr. Wiltshire talking about the importance of CAR T for healthcare professionals. Dr. Wiltshire, thank you for really, I think you've gotten given our audience a lot to think about a better understanding of how to read this literature and then also to continue to kind of highlight some of the inequities in our current system. I think hopefully for our student listeners, this really kind of sparks some thoughts from them.

- Yeah. Thank you so much Dr. Kreuter. - And to our listeners, thank you for joining us today. We invite you to share your thoughts and suggestions via email to [email protected]. If you've enjoyed this podcast, please subscribe until our next rounds together. We encourage you to continue to connect lab medicine in the clinical practice through educational conversations.