Mary (00:00)
Hi everyone, welcome to the second episode of the 2025 season of the Health Tree Podcast for AML, where we connect patients with AML to the research and information they need to know about. If you've been with us before, welcome back. If this is your first time joining us, welcome. We're so happy to have you joining our AML podcast community. My name is Mary Arnett. I'm your host and AML education manager here at the Health Tree Foundation. The goal of this podcast is to make research and new information coming out about your disease easy to understand and easily accessible.

If you've ever found yourself overwhelmed by clinicaltrial.gov or a medical abstract, we're here to change that. The topic of today's podcast is pediatric AML and CAR T therapy. Specifically, we'll be pulling from the research abstract titled study of anti-CD33 chimeric antigen receptor expressing T cells in children and young adults with relapsed, refractory acute myeloid leukemia. We are going to be joined in just a few minutes by Dr. Emily Shea, a researcher on the study I just mentioned.

Before we bring her on, I want to give you a little introduction. Dr. Hsieh is a hematologist-oncologist out of the Children's Hospital of Los Angeles. Her research focuses on developing cellular therapy clinical trials for relapsed hematologic malignancies. I chose Dr. Shea and pediatric AML and CAR-T for today's episode because, as you'll hear about soon, AML isn't just a disease of older adults. I wanted us to be able to explore how treatment differs for pediatric AML patients and look at some of the promising research, including CAR-T therapy, that could change the game.

While this episode is focused on pediatric AML, and I think will provide a lot of great insights into that specific population, I think there's going to be some tidbits and information you can take away, whether you are a young adult patient or an older adult patient, as a lot of the information can be relevant to all populations with AML. So stick around until the end of the episode when I'll be back to share my final thoughts on today's interview, as well as some additional resources that you can dive into related to today's topic if you want to keep learning.

Now, without further ado, let's bring on Dr. Hsieh.

Mary (01:59)
Dr. Hsieh, thank you for joining us today. We're really excited to have you on our AML podcast.

Emily Hsieh (02:05)
Thanks for having me.

Mary (02:07)
So we are gonna get into your study here in just a minute, but I wanna give a little bit of background and context to our audience about what we're gonna be talking about today. So I wanna start with just AML in general. AML can be such a tricky disease and can be really hard to treat. So can you walk us through what makes AML such a hard disease to treat?

Emily Hsieh (02:25)
Yeah, that's a great question. think there are two major reasons why AML is such a tough disease to treat. The first one is that it is very heterogeneous. That means that there are cell surface markers and antigens on the surface of a myeloid leukemia cell that are different, and there are many of them, and they also may not be equally expressed in each leukemia cell. So this makes it difficult to develop effective therapies targeting AML because if you have one therapy that targets one specific antigen, it may not cover all AML cells. And then you compare this to ALL where the surface markers on a leukemia cell for ALL are uniformly expressed, making it easier to treat. There's also interpatient variability of AML because of genetic features of pediatric AML, which are so unique. So there's no single treatment strategy that is likely to be effective for all pediatric AML patients. And then there are markers that are on these AML cells that are also on normal healthy cells. And these cells are pretty much vital to our bone marrow being able to regenerate. And those cells are called stem cells. So if we target those leukemia cells, also target these healthy cells, making the bone marrow not able to reproduce and do its job.

Mary (03:52)
You just mentioned pediatric AML, which is what we're talking about today. AML is typically known as a disease that affects older patients, so people in their 60s and 70s. But today we're talking about pediatric AML and young adult AML. So what makes it different to treat these younger patients than what we normally see with older patients?

Emily Hsieh (04:11)
Yeah, so I think the biology of AML is very different when you compare pediatric patients to adult patients. And in fact, we can actually consider them to be distinct diseases, adult AML and pediatric AML. And there was this really interesting study that was published several years ago that looked at the origins of AML in pediatrics and adults. And what they found was that

Adult AML usually is caused by DNA mutations or alterations in the DNA that have accumulated over the course of a lifetime. Whereas when you compare it to pediatric AML, those AML cells are caused by alterations in chromosome structure. So loss, amplification, or relocation of chunks of chromosome, which can lead to what we call fusion genes and that can drive the growth of many blood cancers. And so that was found to be more common in children with AML. And then you look at even within pediatrics, there's a difference between infant AML. So AML that develops before 12 months of age and childhood and young adult AML, those also seem to be pretty distinct. And we've also learned that pediatric patients are not just little adults or smaller adults. So the dosing of medications is different and instead of know, extrapolating dosing from adults to kids that hasn't really found to be effective or worked in these young patients. And additionally, they also have different baseline health issues. So maybe less comorbidities and pediatrics and less extensive past medical history. may possibly be able to tolerate stronger chemotherapy regimens, recover from these toxicities faster, things like that.

Mary (05:59)
you've painted the picture. AML is very tricky and jumping from adult AML into like you just mentioned, infant childhood and young adult AML. There's such variance amongst the different diseases or versions of the disease. So

What is the treatment landscape for pediatric and AYA AMO look like? Are there a lot of studies open?

Emily Hsieh (06:23)
So looking at the treatment landscape, there have been several advancements from the 1980s until present where new chemotherapy regimens have come out and we found that bone marrow transplant is pretty much the definitive cure for AML or relapse AML. We've only kind of reached it to about 65 % cure rate. Trying to get that cure rate a little bit higher in these AML patients has been a little bit tricky.

And I think the major reasons why it's tricky in addition to what we've talked about before is that there's just been really large gaps in trying to find effective therapies for relapse refractory AML patients. And so as we learn more about the drivers of AML in children, this can lead to drug targets to turn off these drivers. And that's kind of where this field is moving toward, more targeted therapies immunotherapies that are also targeted that kind of harness a patient's own immune system to be able to fight their own leukemia. And that's kind of where CAR T-cell therapy has come in, that come into that space. And there are several trials out there looking at specific CAR T-cell therapies for AML. And so, you know, looking at the open trials for pediatric AML, I just did a quick clinical trial.gov search for childhood or pediatric AML. And really honestly, there are only about maybe 20 open clinical trials for AML out there. And then when you kind of look at adult AML, those open clinical trials approach nearly a hundred. So it's just this disparity in being able to open clinical trials specifically for children and young adults, whereas the adult populations is a lot easier, unfortunately.

Mary (08:15)
Yeah, I know we have some members in our community of AML that are both in the pediatric space and in the young adult space. there's just, from conversations with them, it's very clear that there's just different concerns that these patients have versus the more typical adult AML patient. So think it's really exciting to see, you know, the numbers are small, know, 20 is a small number of studies, but.

Emily Hsieh (08:36)
Hmm.

Mary (08:39)
It's exciting that there are studies that are being open and that there are people like yourself who are interested in trying to figure this out.

Emily Hsieh (08:46)
Yeah. We also are able to kind of maybe, let's say, play the system by having both adults and then a pediatric young adult arm into the clinical trial. you know, even though technically with this treatment be applicable to both adults and younger children, at least we can form the foundation of research for these CAR T cells, especially.

So tagging it onto the safety of adults, seeing if it's safety and safe in children, and then moving on to the efficacy part. So we've been able to kind of do that to helpfully help get these clinical trials up and running by attaching ourselves to the more adult side.

Mary (09:29)
I'm always interested, know, blood cancers in general are pretty rare and AML is even rarer and then you get into pediatric and young adult AML and get even rarer than that. So what was your drive to go into researching this specific group of people?

Emily Hsieh (09:46)
Yeah, I think because of the rarity, it's important for us to focus on rare diseases as well. So you get a lot of attention from more common diseases, breast cancer, lung cancer, but the people behind these rare diseases are people too. having the ability to help these people and move this field forward in a space that it's not very well defined or well known is something that I really wanted to do. then particularly with cellular therapy and CAR T cell therapy, I really wanted to hopefully try and translate the success that we've had with acute lymphoblastic leukemia patients, so ALL patients and their success with CAR T cells. I wanted to see if we could bring that success to the AML world where outcomes and treatment are falling behind the ALL outcomes.

Mary (10:42)
Yeah, we definitely see more in that ALL space with the similar demographic when we're talking about pediatric and young adults. So it's cool to see that there's kind of a framework for moving forward with these more acute leukemias. I think we've set a good scene for what we're going to talk about today. So let's jump into it. can you start with a brief overview or description of your study and

Emily Hsieh (10:58)
Absolutely.

Mary (11:10)
the topic of today's podcast.

Emily Hsieh (11:12)
Absolutely. So the study that we're going to talk about today is basically a phase one to trial looking at the safety and feasibility of using a particular CAR T cell and we call it CD33 CAR T cell in children and adolescent and young adults with relapse refractory AML. And so this is particularly looking at a CAR T cell target called CD33 which is pretty uniformly expressed on AML cells. As we talked about, given the heterogeneous nature of AML, it's really hard to find one target that is 100 % uniformly expressed on AML cells. But I think CD33 is close, is the closest that we've gotten to uniform expression. So that's why we chose the CD33 target.

We've been trying to figure out A, are these CD33 CAR T cells even manufacturable? Can we make them from a patient's T cells? And B, are they safe to give to these types of patients? So that's one objective. We also wanted to determine what is the maximum tolerated dose of these autologous CD33 CAR T cells, meaning T cells that are derived from the patient. And how high can we push that number? Because we kind of know that the higher the dose, the more likely that dose will be effective.

Mary (12:44)
this is an open trial, right? It's recruiting. a lot of, people have a lot of questions about clinical trials and what it looks like.

Emily Hsieh (12:46)
Yes.

Mary (12:52)
want to ask a couple questions so that patients who maybe are listening and interested in participating in the trial would understand what life on this trial would look like. So how often are tests done for patients during treatment and following treatment?

Emily Hsieh (13:04)
So testing, including blood draws, are done pretty frequently. And this is basically to monitor clinical status of patients, making sure that there's no excess toxicity, monitoring the trends of lab values. so blood draws will likely be done every day to every other day for those first two weeks after the CAR T cell infusion. And then after that, if there are no significant toxicities, we space those out to weekly for the next couple weeks. And then that four week mark after CAR T cell infusion is the big marker of safety and efficacy. So we kind of look at the first four weeks, make sure there's no excess toxicity. We then check disease evaluation to see what the disease status is at that four weeks. And then after that, it's pretty much more spaced out to monthly for the next six months. And then six months, every six months until two years out would be that kind of schedule. And then if, you know, we get referrals from all sorts of different referring institutions, so not necessarily them staying locally near our hospital. So if there is a patient that comes from a different state or a different city, then we can try and arrange local evaluations and local research lab draws if the logistics work out for that. So hopefully it won't interfere too much with the patient's life after those first four weeks and then kind of get back to normal life after that.

Mary (14:43)
That's amazing that they have the opportunity to still participate, even if distance might be a potential hindrance for some other studies. That's really cool. in terms of where this study is located, is it just at your facility?

Emily Hsieh (14:51)
Absolutely. Yeah.

It is located nationwide actually, and there are six hospitals with expertise in pediatric and young adult leukemias all over the nation. So it's currently available in Washington, DC at the NIH. CHOP, Children's Hospital of Philadelphia, Boston Children's Hospital in Boston, Massachusetts.

Our location, Children's Hospital Los Angeles, and Seattle Children's, and then Children's Hospital Colorado. So all kind of scattered throughout the nation, which is nice.

Mary (15:32)
Yeah, that's really amazing. Makes some of these newer treatments accessible to a lot of patients, which is really cool, especially with what you were just talking about you know, after that first four weeks, the potential of doing some of the last pieces locally.

Emily Hsieh (15:48)
Absolutely. Yeah. We know that commitment to a clinical trial is a lot. So trying to take into account patient factors and their life being put on hold and logistics, we want to try and make sure we balance those two as well.

Mary (16:06)
what are some of the biggest inclusions or exclusions of the study for anyone who's listening and is near one of these sites or is interested in seeing if they might be right for the study?

Emily Hsieh (16:18)
Great, yeah, so I think the biggest inclusion is having an allogeneic donor that is available to donate their cells. So I talked about the autologous arm, which we accrued enough patients and I've closed that one for now, but we just opened an allogeneic arm, so meaning making CAR T cells from a different donor, not the actual patient.

And this donor has to be pretty specific. It has to be, you know, a 10 out of 10 HLA matched sibling donor that is willing to donate T cells. And so this particular arm is open and recruiting. So not only do you have to have a matched sibling donor, you also have to be 16 years and older for the first several patients because we need to establish safety. And I think you know, we always want to protect pediatric patients from, you know, things that are too toxic or not effective. But I think that does hinder our ability to specifically research this pediatric population because it takes so long for us to even feel safe to open the pediatric arm. And that just kind of delays the advancements in medicine for this particular population. So.

Once we do get those several patients above 16, then we can open it to below 16 and then that will go all the way down to one year old. Yeah.

Mary (17:50)
Wow. Wow.

it shows, you know, another layer of complexity that comes in with treating this population.

Emily Hsieh (17:58)
Absolutely.

Mary (18:00)
back to the study content specifically. So this study is about CAR T. can you explain generally what is CAR T?

Emily Hsieh (18:08)
Absolutely. So CAR stands for chimeric antigen receptor, which is engineered in the lab and added to most immune cells with the most common immune cell being T cell, hence the name CAR T cell. So basically we make CAR T cells by using an inactivated virus in the lab to insert this genetic material for the CAR into the T cell which is then able to express the CAR on the surface of the cell. And so this CAR specifically targets these markers on the surface of a leukemia cell. Once they recognize that marker, they can bind to it and then use the own T cell machinery to kill that leukemia cell. And so as you can imagine, CARs can be made to target a variety of cell surface markers. Our specific study is looking at CD33, like I said.

But in leukemia, there's a CAR T cell that's FDA approved that targets CD19. And then there are other ones that are in study that can target two cell surface markers or maybe even three, or it can be used in conjunction with other therapies as well. So I think CAR T cells is really just opening up the space to be able to use a multi-pronged approach to target AML, which is what is needed.

Mary (19:36)
Yeah, Karthi has been around a little bit longer in some of the other blood cancers, but is pretty, pretty new in the AML leukemia space. Are any of these approved for pediatric or young adult AML?

Emily Hsieh (19:48)
Unfortunately not, because CAR T-cell therapy is still quite new. I think the first CAR T-cell therapy product approved for ALL was just only in 2017. So we less than 10 years experience. then kind of moving it to different blood cancers, AML especially takes time. But the good thing is, is that there are several opening and accruing clinical trials for CAR T-cells in AML patients. So looking at clinicaldraws.gov specifically for CAR T cells in AML, I think I saw about five to six actively recruiting CAR T cell clinical trials. we're all kind of doing this in parallel and hoping that as the years go on and we can accrue enough patients to do our data analysis, we can start seeing those results published in the near future and hopefully help guide next steps in this really promising therapy.

Mary (20:50)
Yeah, this is really exciting, especially as research in general is picking up in AML, but something as promising as CAR T it's exciting to see it kind of breaking into the AML space. for this study, I'm curious, what are we seeing in the research so far? Are you noticing any trends, anything you can share with us?

Emily Hsieh (21:01)
Yeah.

Yeah, so because we were able to accrue so many patients in our autologous arm, that one is now closed and we're able to analyze the data. And from that data, we're able to see that these CAR T cells are safe and don't cause severe toxicity. So we always look at things like dose limiting toxicities, the severity of toxicity that a patient experienced is to the point where we can't increase the dose level of the next cohort. So we didn't see any of that, which limited the ability to expand dose levels. So we were able to increase to the highest dose level, and that was deemed to be safe and not severely toxic. Then we were able to show that we can in fact make CAR T cells in the lab from patients who had an extensive chemotherapy treatment history.

I think there was a concern initially that what if CAR T cells can't even be made from T cells from AML patients because of their history of so much chemotherapy that really would kind of hinder the ability of the T cell to be made into a CAR T cell. And so we showed that that's not in fact the case. We can make CAR T cells from AML patients. And then they were in fact, really exciting that some patients were actually able to achieve remission of their AML from these CAR T cells and then move on to bone marrow transplant, which is the next phase of their therapy. And that is still the definitive curative therapy for AML patients. Unfortunately, this number was too small to be statistically significant. However, we are trying to look into why some of these patients were responders and why other patients were non-responders. So looking specifically at maybe the biology of the specific patient's AML or maybe the microenvironment in which the CAR T cells were able to grow in or not, or could it be the amount of disease, so the amount of AML in the patient's bone marrow or blood that, was it too much, too little, or is there a specific sweet spot of disease burden that CAR T cells are the most effective in managing.

Mary (23:34)
That's so interesting. it opens up a lot of questions, a lot of potential, yes, a lot of new pathways to explore. How do you see the results for this study impacting the future of AML treatment?

Emily Hsieh (23:38)
Absolutely. I'm talking more questions than answers.

My hope is that it really bursts open the door to be able to research more different types of CAR T cells for AML. So I hope that these results can prove that CAR T cells can be made to treat patients with AML and that they are safe. And then this can potentially be added to the arsenal of personalized therapy for these patients. You know, it may not necessarily be that magic bullet we were all hoping for but it may be a useful tool in our so-called multi-pronged approach to treating pediatric patients with AML. I feel like because the biology is so different and then the actual AML cells are so heterogeneous, I think it has to be different targeted therapies from attacking on different pathways and from different angles for us to really be able to get a hold of treating AML. And I really believe that CAR T cells can be that one strong arm to be able to be an effective treatment for AML.

Mary (24:54)
one of the things we're seeing the more we get into treating AML, and like you explained at the beginning, just how incredibly complex this disease can be that it takes a lot. It takes a lot of different approaches. even for the same patient, it can take a lot of different approaches to receive, the kind of results that we're looking for. what, if any, are some expected challenges you're seeing of trying to get CAR-T approved for these younger patients?

Emily Hsieh (25:11)
Yeah. man, that is a tough question. And I think it's more tough because of the realities of the world that we live in. So basically it's time and funding. because like we all know pediatric AML just represents such a small population of patients, AML is rare to begin with, but of course it's more common in adult...

Mary (25:29)
Yeah.

Emily Hsieh (25:45)
AML, then you take a rare disease and then put it specifically to pediatrics. It's such an even smaller population. So it not only takes time to crew the necessary patients to evaluate both safety and efficacy of CAR T cells. It also, that time could sometimes last five years, seven years, 10 years. And that sometimes is too long because within the field of medicine, the science is changing so quickly.

Mary (25:51)
Right.

Emily Hsieh (26:14)
So sometimes clinical trials can't move quickly enough to adapt to the scientific advancements, right? Because there are so many safeguards in place, which are so necessary, but because of those safeguards and because of those regulations, it takes a long time to develop protocols for first in human trials for pediatric patients. So it's just another barrier that needs to be overcome, which may contribute to the delay in getting these CAR T cells out into the open. And then the second one is funding. And it always goes back to the money, unfortunately, but as we know, pediatric cancer is such a small population, it's not quite that marketable for large pharmaceutical companies to pick up these novel therapies, which are quite expensive, and then scale them to what is needed and to invest in FDA approvals. And so,

That is kind of the reality we live in in pediatrics. Unfortunately, we are such an important population, right? Children deserve to be treated. But in the eyes of people who look at things and just like profits and losses, it's not profitable to invest in pediatric research. So we're trying to like flip the script and see, do we even need to depend on these large pharmaceutical companies to,

Mary (27:18)
Yes.

Emily Hsieh (27:39)
advanced these such vital therapies in the pediatric space. Can we just cut them out altogether and then figure out a way to advance these therapies on our own? And so that is still in very early, early discussions, talks. It's something that's been on a lot of pediatric oncologists' minds. So we're hoping that our collective voice would be able to kind of move the needle forward in terms of not depending on profits to be able to treat these patients.

Mary (28:11)
you brought up so many incredible points there about the length of time clinical trials can take and with how fast medicine happens these days and how fast advancements happen. It's so hard to keep up. And the money piece, that's always so tricky. It sounds like a very, very lofty mountain you guys are looking at.

Emily Hsieh (28:35)
Yeah. And I think in pediatrics, we've kind of had to, that's kind of where we, that's our baseline. We've always had to surmount these mountains because we're so tiny. But I think what we've been able to learn from being a small but mighty section of medicine that we have been able to utilize our ability to lobby our ability to like gain more public attention on pediatric funding in particular, and then be able to really just say, these are not just numbers, these are people, these are humans that still deserve equal chance and equal ability to have effective treatments. so having the opportunity to be able to talk about this in an honest and open environment and be able to know the challenges that we're facing really sets us up for being able to face those challenges head on and then try and think of solutions to be able to move forward.

Mary (29:39)
thank you so much for helping us to understand pediatric AML and the incredible work that you're doing and that all of the pediatric hematologists are working on right now. It's truly inspiring and it's really incredible. And I'm thinking about, you know, the audience who's listening to this episode and thinking about, you know, the parents of children or family members and friends or, you know, a young adult themselves listening and looking for the hope and looking for what's new, what's coming. do you have any anything you'd want to say or any advice or anything you'd want to give these patients or these family members and friends?

Emily Hsieh (30:17)
Yeah, so I think reaching out is so important. So I think sometimes it's hard to know what is out there and your platform and your ability to disseminate information I think is huge. So being able to know what resources are available and what resources can be trusted is so important and never being afraid to reach out to whoever. you know, I...

My contact information is on clinicaltrials.gov for this specific clinical trial. So if you ever have any questions about any clinical trial, going to that website is great. And it has a wealth of information about eligibility, where these trials are located and where they're open, and then contact information if you wanna get more information about it. I hope that if there is interest and if there is more questions that come out of this podcast to be able to contact me, it's totally fine. I'm totally willing to be able to hopefully answer more questions or direct to any other place that may be more useful. So reaching out I think is very, important.

Mary (31:41)
A lot of people don't know that there are resources out there. So just taking that step and looking and then, you know, if someone's information is available, it's because they want it to be available. So going ahead and reaching out and, you know, not worrying about

Emily Hsieh (31:51)
Yes,

Mary (31:56)
Am I bothering this doctor by reaching out no reach out?

Emily Hsieh (31:57)
Yes.

Exactly. I 100 % agree. We are busy, but the whole reason why we got into medicine is to help patients and treat patients. So if there are questions or if there's any sort of concerns or anything, we are always more than happy to help out and respond to questions.

Mary (32:15)
I can say on behalf of the patients that I talk to and the patients that we work with, they're so incredibly grateful for all of the work that their doctors are doing and for the work that researchers are doing to move the space forward so that they have better choices and better options for their treatment. So thank you for all the work that you're doing and for the time that you dedicate to these patients and to making their lives better.

Emily Hsieh (32:40)
You're so welcome. It's been my pleasure.

Mary (32:43)
Wow, I am so grateful for Dr. Shea and all of the incredible insights and research she shared with us today. AML, as we know, is a rare disease and pediatric AML is even rarer. It's so exciting to see work being done in this space that can really make the lives of these young patients better. For the parents, family, or community members listening, I hope you remember Dr. Shea's advice and tips for advocating for your loved ones, as well as the importance Dr. Shea expressed that researchers place on making sure that the young patients they're treating and involving in clinical trials are safe and closely monitored. If you want to keep learning, we have a couple additional resources you can look into. One is Health Tree University, the video learning program I mentioned last week. We have a unit on pediatric AML that goes over the basics of AML and how it affects pediatric patients. We also have a unit coming soon on transplants for pediatric patients that we just filmed in New York City And that will be available on the platform soon. So keep an eye out.

The other resource I wanted to mention is an article that our team published earlier this year about recent advances in pediatric AML treatment. It's a quick but informational read that provides a good overview of some of the new treatments and what's available for pediatric patients currently. I also wanted to mention that we are actively working to expand our resources and support this pediatric population. So we are putting together an advisory board of pediatric patient caregivers to help us inform how we develop resources and how we really get into this space to make sure we're supporting these patients and their families in the best way possible. If this is something you're interested in being a part of, please send me an email and I can set up a time for us to meet virtually and explain the opportunity a bit more if it's something that you might be a good fit for. If any of these resources piqued your interest, I'm going to link them in the episode description so you can check them out. Thank you so much for joining us today on our episode of the Health Tree Podcast for AML. I hope you learned something new. Next week, we're to be diving into another unique population in AML, young adults.

Dr. Erin Feliciano walks us through the challenges and barriers to care that are unique to this age group through some of the research that she's done recently. Her insights into this demographic shine a light on issues and potential solutions that could benefit not only this AYA population, but any patient with AML. I would love to hear any thoughts you have about today's episode, so share them with me in a comment or send them to me in an email. You can find my email in the episode description. Until next time.