CAR T-Cell Therapy and Immunotherapy in Pediatric Cancers
Seth Rotz, MD, pediatric hematologist-oncologist and Director of the Childhood Cancer Survivorship Program at Cleveland Clinic Children's, joins the Cancer Advances podcast to talk about CAR T-cell therapies and immunotherapy in pediatric patients. Listen as Dr. Rotz explains the long-term survivorship factors to consider when using these therapies and the exciting studies that are being developed for this type of treatment.
CAR T-Cell Therapy and Immunotherapy in Pediatric Cancers
Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research in clinical advances in the field of oncology.
Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig phase I and sarcoma programs. Today I'm happy to be joined by Dr. Seth Rotz, a pediatric hematologist oncologist and director of the Childhood Cancer Survivorship Program at Cleveland Clinic Children's. In a previous episode of the Cancer Advances podcast, he discussed childhood cancer survivorship, and that episode is still available. He's here today to talk to us about CAR T-cell therapy and general immunotherapy and cellular therapies in pediatric blood cancer. So welcome back, Seth.
Seth Rotz, MD: Glad to be here. Thank you for having me.
Dale Shepard, MD, PhD: Absolutely. So remind us, what's your role here at Cleveland Clinic?
Seth Rotz, MD: As you mentioned, one of the hats I wear is our survivorship program and taking care of people that are long term survivors of pediatric cancer. But I also take care of kids with blood cancers that are undergoing active treatment, so I see kids and young adults with leukemia, lymphomas, and folks getting bone marrow transplant and cellular therapies.
Dale Shepard, MD, PhD: So let's just start off and delve into that to begin with. So we're going to really focus on CAR T therapies and cell therapies, immunotherapies. What are some of the cancers that you treat and use these treatments for?
Seth Rotz, MD: Immunotherapy is making its way into many if not all sorts of blood cancers. So one of the things you mentioned was CAR T-cell therapy, and really the furthest along regarding that treatment is for acute lymphoblastic leukemia, which is the most common type of childhood cancer. But we're also using different types of immunotherapy for Hodgkin's lymphoma as well as non-Hodgkin's lymphoma and starting to work toward some clinical trials for other types of leukemia, like acute myeloid leukemia, which doesn't currently have an FDA-approved CAR T-cell therapy.
Dale Shepard, MD, PhD: So when we think about all of these therapies, CAR T therapies, immunotherapies, sometimes it seems like there's a lag in uptake in those therapies in pediatric populations. Has that been the case with these particular treatments?
Seth Rotz, MD: When we think about drugs in general in oncology, I do think that there's a lag for pediatric patients. Most drugs when they go through trials are trialed on adults, and not until they're found to be safe or safe and efficacious in adults do you start trials in kids. That being said, Kymriah, which is the CAR T-cell therapy that's FDA approved for pre-B ALL, acute lymphoblastic leukemia, was... Those trials originally took place in kids, because there's such a large population in kids. So with CAR T-cell therapy, it was actually approved for pediatric patients before adult patients, which is not the way things usually go. But in terms of the rest of the drugs that we use, the vast array of immunotherapies, I do think that they've been tried in adults at a little bit of an earlier stage than in pediatrics. That being said, they've worked their way into the relapsed and refractory setting, so we know that they work and they're generally safe in pediatrics. And now we're really moving towards trying these different therapies in upfront clinical trials for newly diagnosed patients.
Dale Shepard, MD, PhD: What are some of the biggest challenges to using things like CAR T-cell therapies in pediatric patients?
Seth Rotz, MD: There's a variety of issues with CAR T-cell or any of our immunotherapies. So in terms of CAR T-cell therapy in particular, I think the biggest questions for us are how to use it. We know we have this really powerful tool at this point, but the question is, for whom do we give this? We, we have our current FDA indications, but we know this is a really good treatment, and trying to figure out what other populations would benefit is really our biggest challenge going forward.
From a day-to-day thing, there's a couple challenges, when you make CAR T-cells, there's a time to manufacture. So just because you want to use them doesn't mean you have them ready. It takes about four weeks or so between the time of getting your approval to harvest those cells and getting them back and infusing them. It takes about a month. So that manufacture time is an issue.
Some of these things, they're not FDA-approved for kids, and a lot of drugs aren't FDA approved for kids. In pediatric oncology, we use a lot of off-label drugs just because there hasn't been specific FDA indications. Getting those covered by insurance can be a challenge. Spending time on the phone with the insurance companies or writing letters to try to get things approved takes time.
But I think the biggest issue going forward with immunotherapy is really, hey, we got this really powerful tool right now. When do we best use it? And trying to design thoughtful clinical trials to answer some of those questions. I think that's the biggest concern for the field going forward.
Dale Shepard, MD, PhD: Certainly from a focus on things like time to treat, which has been important here at the clinic, you mentioned four weeks just from a prep time after approval, and you mentioned the administrative hurdles to get the approval. What kind of timeframe are you typically looking, see a patient in clinic, decide to move forward? What does that approval process... How long does that usually take?
Seth Rotz, MD: I guess the example I would use would be for an ALL patient getting Kymriah, the CAR T-cell therapy. Let's say you get... The patient's newly relapsed after a bone marrow transplant, so that's the first FDA approved indication. In that case, you have the relapse diagnosis. You write a letter to insurance, and approval should be coming pretty quickly, because that's a pretty straightforward indication, so probably a week there. Then it takes some time coordinating with your team for phoresis and line placement, because you got to get those T-cells out of the patient. So you can do that concurrently with getting approval from insurance, but you're looking at probably at least one to two weeks at the absolute minimum to get those T-cells harvested up and then sent out. Then you're looking at four weeks of manufacture time before you can put them back in.
During all this, though, you're dealing with somebody with a relapsed, acute leukemia, and there can be complications that come up with that. They may need other therapies in the meantime, bridging therapies to get them to the point where they can get CAR T-cell therapy. And the other thing that we're really learning about CAR T-cell therapy now is it's an excellent therapy, but just like bone marrow transplant, the less disease that you come into CAR T-cell with, the more likely you are to be cured or have a long term remission with CAR T-cell therapy. So we are using other therapies to try to get people to lower levels of disease before infusion, so that can sometimes slow things down. And really trying to like optimize what bridging chemotherapy looks like, optimize disease level going into CAR T-cell therapy, are things we're still fidgeting with a little bit and can take a lot of time and effort to get figured out.
Dale Shepard, MD, PhD: So oftentimes on the adult side, we're worried about comorbidities like diabetes or hypertension or kidney function things when we are picking between multiple types of treatment. So on the pediatric side, you're less likely to have those as factors. So what kind of factors are important when you're deciding whether to pursue a traditional chemotherapy compared to, say, a CAR T or an immunotherapy?
Seth Rotz, MD: A lot of times nowadays we have so many great treatment options for some of these diseases, we're trying to pick and choose the right one for the patient. We're really at a place where we have a lot of options and we're trying to figure out at any given time what's the best one. Oftentimes when we think about CAR T-cell therapy for ALL, we're choosing between conventional chemotherapy. We're thinking about other immunotherapies like bispecific antibodies or antibody drug-conjugates. We're thinking about bone marrow transplant.
So there are patient factors that go into that, like what is the patient's lymphocyte count? Do we think we're going to be able to adequately harvest T-cells from them? So that could be one thing. Another patient factor is, what is their disease status? Do we think we can get them down to a low level of leukemia before infusion? Because if we can't, they're going to have a little bit harder time getting a really good response from that CAR T-cell therapy.
And then we can also think about other factors in terms of the pros and cons of other therapy as well. So if we're thinking about bone marrow transplant, well, we have a large population in pediatrics of kids with Down syndrome who get a ALL, and they may be refractory to conventional chemotherapy, and we may be trying to determine what's better, a bone marrow transplant or CAR T-cell therapy. And we know from historical data that patients with Down syndrome who undergo bone marrow transplant have a really rough time with toxicity of bone marrow transplant.
Another group that we consider is really young kids, infants. So again, our traditional conditioning for BMT for ALL in pediatrics includes total body irradiation. The younger a patient is that gets radiation to their brain and their body, the more of an effect you're going to have on growth and development. So maybe somebody who's really young, you want to give CAR T-cell therapy to upfront, even if you think there's a pretty high likelihood of relapse, because you can delay that radiation perhaps until they're a little bit older. So some of those factors are there that we think about.
Dale Shepard, MD, PhD: I guess I'll piggyback on that and talking about radiation effects and your other activities from a survivorship standpoint. How does thinking ahead to survivorship issues play into choice of therapies? Are there concerns with CAR T therapies from a survivorship standpoint?
Seth Rotz, MD: Yeah, there's some. This is something we're really just starting to learn about. CAR T-cell therapy is still really young as a treatment modality, and there's some trials that are getting designed now to try to answer some of those long term survivorship questions. We do think that the toxicity of CAR T-cell therapy compared to a bone marrow transplant long term is going to be less, but there may be some unique toxicities there that we don't quite understand yet.
So for instance, patients that get CAR T-cell therapy are at risk for ICANS, which is basically neurologic toxicity, in the acute setting from the CAR T-cell. Now, whether or not that may cause any long term cognitive issues or not, we don't know about so much. Some of the things we do know about is that when CAR T-cell are persistent, they're patrolling, looking for leukemia cells, and killing those off, but they're also killing off normal B cells, which make antibodies. So for most of these patients, we need to be thinking about IVIG for long term antibody replacement, as long as those CAR T-cell are circulating. You can also have other like acute toxicities of treatment that may lead to long term problems. So for example, if somebody got CAR T-cell therapy and had really, really bad CRS and maybe ended up on a ventilator or needed dialysis in the ICU in the acute setting, some of those things can lead to long term issues. Again, how frequently we don't know. But those are potential risk factors there. But we generally think about CAR T-cell therapy as having less long term toxicity than bone marrow transplant.
Dale Shepard, MD, PhD: In addition to CAR T therapies, some of the other immunotherapies that you discussed, what's on the horizon that excites you for pediatric cancers?
Seth Rotz, MD: Yeah. I mean, CAR T-cells are certainly one of the most talked about therapies, but where we've come in terms of immunotherapy in the last couple of years is really just incredible. I mean, we have so many classes of drugs that we're have available to us and now trying to figure out the best way to use them. It's just really an exciting time.
I was at the Children's Oncology Group meeting in Texas. This was 2018, when they were unveiling or showing the new generation of acute leukemia clinical trials that were going to be opening soon. Those trials are open now. And I remember texting one of my mentors. I said, "This is really exciting stuff. In the past, when people were showing new trials with conventional chemotherapy, were people as excited about this? And he said, "No, absolutely not. This is a whole different level of excitement, knowing that we have totally new ways of treating these diseases."
I think some current studies that are being developed or are underway that we're waiting to get some results on, I think that'll be helpful. There is a study through the BMT Clinical Trials Network that's getting developed called the CAR Cure Study. So this is going to be a trial for patients that get CAR T-cell therapy. And then we're trying to be able to predict who's going to relapse. Right now, there's a lot of controversy in the field. You get your CAR T-cell therapy. Do you need a bone marrow transplant after that? Or can CAR T-cell therapy be curative?
And this CAR Cure Study is going to be looking at two things to predict relapse. One is, do you lose B-cell aplasia? Meaning, do the B cells come back, a sign that you're losing your CAR T-cell graft? Or two, can we use next-generation sequencing to pick up really low levels of leukemia in the peripheral blood? We know from other trials that these things tend to predict relapse. This study will basically say, "You're going to get your CAR T-cell therapy, and then we're going to watch for any of these warning signs. If you see a warning sign, you're going to go to transplant." And we're going to find out if that's an effective strategy to minimize the amount of people that need transplants but also maximize the amount of people that are cured by therapy. So that's a really interesting trial that I'm excited to see in development.
We also have new CAR T-cells in development for other targets. So this CD19 target, which we use for pre-B ALL and diffuse large B-cell lymphoma, that's just one of many potential targets. It seems to work really well. But our options for relapse T-cell leukemia are somewhat limited, and people are developing anti-CD7 CAR therapies. There's one being developed here by Dr. Gupta and Dr. Hill. I believe there's also some phase I trials open at other institutions. So having something for the T-cell patients is going to be really important. And I think developing immunotherapies for AML is going to be really important. To date, those have had much more modest results than the ALL studies. And these are patients that generally fare worse than patients with ALL and are really in need of new therapies.
Dale Shepard, MD, PhD: And we have another episode of this Cancer Advances podcast that I spoke with Dr. Melenhorst, and he had talked to us about those developments in AML, so it's a pretty exciting field.
Seth Rotz, MD: Yeah. Yeah, absolutely.
Dale Shepard, MD, PhD: If you were to consider the biggest gaps, where do we need to go from here? How do we improve either the current therapies or tolerance to therapies, response? Where do you think is the biggest need for change?
Seth Rotz, MD: I think the biggest thing is, again, figuring out who, what, and where do we use these therapies? So we have all this potential right at our fingertips, and we use them right now in the relapsed and refractory setting, when we know patients are really sick and maybe have limited other potential treatment options. But trying to move these therapies into the frontline setting where we think they may improve survival and decrease toxicity is really the next step. I mean, it's like you have this invention that you know is important, but you don't know exactly how it's going to be important or why. It's like, "Okay, we got the internet now. Yeah, that seems pretty cool. What can it do?" Well, it can probably do a lot of things, but knowing exactly what it's going to do remains to be seen.
So moving these drugs into frontline clinical trials is the most important thing at this point. And a lot of these drugs are working their way into that. So they started in the multiply relapsed setting. Okay, they work there. Well, why don't we try it for first relapse? Okay, that improves, the outcomes. Now it's really trying these drugs in combination with our standard of care to see if they're going to improve outcomes or if we can use them. We've used the, for example, in the Hodgkin's lymphoma setting to decrease the toxicity of conventional chemotherapy and still get excellent results. So really developing these frontline trials for pediatrics and young adults to find out what is the optimal role for these drugs, that's the next step here.
Dale Shepard, MD, PhD: It seems like incorporating some of these off-the-shelf CAR Ts or things might be important for that, because you might not have the six or eight weeks lead time when somebody shows up with a leukemia.
Seth Rotz, MD: Yeah, yeah. And people are certainly working on that, matching limited HLA antigens. In terms of off-the-shelf stuff, there's also other cool things happening. For example, we have viral specific T-cells that are off-the-shelf that can treat patients with viral reactivation after bone marrow transplant or solid organ transplant. But we also have some of these that are EVV specific for treating EVV-associated malignancies like PTLD, for example, and these are off-the-shelf therapies. So getting that going, trying to shorten the manufacture time is important as well.
Dale Shepard, MD, PhD: All right. So Seth, we've primarily focused on CAR T therapies. What other types of immunotherapies are available for these pediatric patients with hematologic cancers?
Seth Rotz, MD: Yeah. So the different immunotherapies really run the gamut. So starting off with the most basic thing, we have just antibody therapies that target some antigen on a hemalignancy. So you could have, for example, rituximab, which targets CD20. In adults that's used in ALL, but certainly in non-Hodgkin's lymphomas.
Then you can spice up your antibodies by adding a drug to it, so you have your antibody drug-conjugate, so an antibody to a specific target linked to some type of chemotherapy. So this is a way of really trying to be specific in terms of getting your chemotherapy to the target and limiting off-target toxicity. So CD30 antibody drug-conjugates, brentuximab, which is used in Hodgkin's lymphoma, or gemtuzumab, which is used in AML.
Then you have things like bispecific antibodies like blinatumomab. So this is two antibodies that are attached back-to-back. On one end, you're targeting your antigen, like CD19 on an ALL cell. And on the other end, you're targeting CD3. So you're bringing an immune cell, a T-cell, into contact with your hemalignancy cell, with the idea that that cell is going to go and eat up the malignant cell.
We also have checkpoint inhibitors. So these are monoclonal antibodies that target signals that are made by tumors that tell the immune system to go away. And by blocking these signals, you can get an anti-tumor response. So those are things like nivolumab, which is working its way into the treatment for Hodgkin's lymphoma, as well as many, many other solid tumors.
We have CAR T-cells, which we've already talked about to some degree. And then you have the most tried and true immunotherapy, which is a bone marrow transplant, where you rely on a graft versus leukemia effect. And sometimes with a bone marrow transplant, you even do things like a donor lymphocyte infusion afterwards, where you're giving the recipient the donor's immune cells. And different people are working on different cellular therapies around BMT, adding in different cells, like adding in donor NK cells that are specifically trained to target specific things. So there's really this whole range of therapies, from something that's just a naked antibody to really detailed cell therapies.
Dale Shepard, MD, PhD: So if you were to have the availability of a crystal ball, which one of those therapies do you think has the potential to make that next big leap either in its current form or some iteration?
Seth Rotz, MD: Yeah, that's a great question, Dr. Shepherd. You know, I don't know for sure. There's a lot of cool CAR T-cell therapies being worked on, but I haven't seen anything that's as exciting as the original Kymriah at this point. There's pretty cool Hodgkin's stuff out there with really exciting results, but Hodgkin's is, generally speaking, a really treatable malignancy, so in terms of moving the field forward, I think we have less work to do there in Hodgkin's than we do in AML. And in AML, those cell therapies have been a little bit less exciting to date, although that may change.
But I think moving forward, the biggest question is, how do we move these drugs into the upfront setting, and how do we best use them so that we can improve outcomes overall, but also so that we can limit toxicity of conventional chemotherapy? So for example, with CAR T-cell therapy, when can we use that to avoid a bone marrow transplant in patients? With blinatumomab, can we use that to match some of the intensity of conventional chemotherapies that have more long term side effects? So those, I think, are the more modest but also important next steps for the field.
Dale Shepard, MD, PhD: Very good. Well, you're doing some very interesting work. We appreciate your insights today. Thanks for being with us.
Seth Rotz, MD: Yeah. Thank you so much.
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