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Melanie Cole: Welcome. This is UF Health Med Ed Cast with UF Health Shan's Hospital. I'm Melanie Cole and today we're discussing immunotherapy for pediatric leukemia patients. In this podcast, we'll learn the story behind the current outstanding cure rates for acute lymphoblastic leukemia. We will understand the reasons why 10% of patients still relapse. We're going to examine the awesome power of immunotherapy in relapsed patients, and learn of some current trials using immunotherapy to improve cure rates in newly diagnosed patients. Joining me is Dr. William Slayton. He's the Chief of Pediatric Hematology Oncology at UF Health Shan's Children's Hospital. Dr. Slayton, it's a pleasure to have you join us today. Please tell us a little bit about pediatric leukemia. What are the different types and how prevalent are they in the pediatric population?

Dr. Slayton: So there are really four major types of leukemia in children. The two most common types are forms of acute leukemia and these are types of leukemia that would kill you if you were not to treat them within two to four months. The most common type is acute lymphoblastic leukemia. This affects about 20 children per million children in any population. And then acute myeloid leukemia, which is about one fifth as prevalent as acute lymphoblastic. So about five per million. There are also some chronic forms of leukemia which are much more common in adults. Chronic myeloid leukemia and juvenile mylomonocytic leukemia. And those represent between two and 3% of children with leukemia. So they're very rare in children.

Host: Well then tell us the story behind the current outstanding cure rates for acute lymphoblastic leukemia Doctor.

Dr. Slayton: Well, we've gotten to the point where we can cure about 90% of the children with acute lymphoblastic leukemia. And those great improvements have come through clinical trials over the last 50 years. These include trials that were done in the 1960s and seventies at St. Jude's Children's Hospital, and between 1970 and now, a lot of clinical trials that have been done by cooperative groups like the Children's Oncology Group. These trials have tested in a very scientific way, the best known treatment and they've tested it against a new treatment that either adds a new medicine or gives an old medicine in a new way and through these trials, we've really brought the curate up to the point where nine and 10 are being cured.

Host: It is amazing, but then help us to understand the reasons why 10% of patients are still relapsing.

Dr. Slayton: Well, 10% of the patients are relapsing because it's very difficult to eliminate every cancerous cell from a person's body. You know, it's amazing that we cure as many kids as we do because all it takes is one cell to survive, and that cell becomes two cells and then four cells, and eventually through cell division it fills up the bone marrow and spills out into the blood and causes leukemia again. And so you have to be able to get rid of every last cell. Now when you give chemotherapy, it's very effective at wiping out most of the bad cells, but the cells that survive are naturally resistant to whatever chemotherapy you give. And the way we've gotten around that is by giving different blocks of chemotherapy. A block is where you give three or four different chemotherapy drugs for a period of time and then you switch to another group of drugs that you give for a period of time. And those combinations of drugs keep changing so that as the leukemia gets eliminated by one group of drugs, the cells that remain can get mopped up by the next group of drugs. And this is how we've gotten to the 90% cure rate.

Host: So then tell us a little bit about immunotherapy in relapsed patients. This is really something awesome going on right now. Tell us a little bit about it and what does the early success of T-cell immunotherapy trials represent for the future of pediatric cancer treatment?

Dr. Slayton: Well, I agree with you. I think the power of this therapy is quite awesome. And we know that the immune system will control cancer and that cancer arises in our body naturally as we grow old, and you know, these cancerous cells are eliminated by the immune system. People with HIV will develop certain types of lymphoma because their T cells are wiped out by the virus and without T cells, the other cells in the immune system can become cancerous and the T cells keep that under control. So we know the body has the ability to control cancer. There have been some recent clinical trials using the immune system to control relapsed B cell lymphoblastic leukemia, and really show the awesome power of the T cells in controlling B cell malignancy. One way that we've done that is through a technology called chimeric antigen receptor T cells. In this technology, what they're doing is they're taking the T cells from a person, they're taking them out of their body through apheresis, and they're using gene therapy to genetically modify those T cells.

So they express a T cell receptor that binds to a protein that's expressed specifically on B cells. It's expressed on all of the B cell leukemia cells. But in addition, it's expressed on normal B cells. And with those receptors, these T-cells will home to the B cells and actually bind to them and they initiate the pathways that cause the T cells to release proteins that destroy the B cells. And essentially it's a way to use these engineered cells to control leukemia in relapsed patients. This technology has been extremely effective at controlling relapsed disease. And even in patients who have relapsed several times, who really at the end of their rope in terms of their therapy, when they've given them these CAR T cells, 90% of them will respond and go into remission. And some forms of these CAR T cells will last a long time. In fact, in some of these patients, they are four or five years out from having these cells infused and the cells are still persisting in the person's body and still controlling the leukemia. And so these patients are still in remission and you know, the thinking is that they may be cured of their leukemia in spite of having relapsed several times. So that is quite a miracle.

Host:

Well, it certainly is. And like many cancer therapies, CAR T can cause several worrisome and sometimes serious side effects. What are some of the risks and the benefits and as you're discussing that Dr. Slayton, are you using these as additions to, in some cases, alternatives to traditional treatment modalities? How is h that all working together?

Dr. Slayton: Well, yes, so it's true that there are side effects of the CAR T cells and a lot of it has to do with the programs that are activated by a T cell that is recognizing a leukemia cell and the fact that, that stimulates a massive inflammatory response. And so what they've learned over time is patients who have a lot of leukemia around will have what's called a cytokine storm. Cytokines are chemicals that our immune system produces in order to activate immune response. And like when you have the flu, the cytokines are what make you feel rotten. They give you fever and they give you body aches, and you know when you activate too much inflammation you can end up causing the liver to become inflamed. And even you can make the liver fail or you can cause somebody to hallucinate. These are our responses that all occur because of cytokines that are being released.

And when they discovered this, they discovered ways to target that reaction using specific drugs that target the cytokines. And that's a way to treat the side effect of the CAR T's. The other thing that they realized is if you give somebody medicines to reduce the amount of leukemia in their body, but maybe not give them enough to cure them, and then you give them the CAR T's. The CAR T's will then mop up whatever's left but not cause the huge cytokine storm. So what happens now is most patients get some chemotherapy that's very well tolerated, mild chemotherapy, and they do that. And then about three weeks to a month later, they get their CAR T cells, they call that cyto reduction. And that, that really reduces the chance of a bad cytokine storm.

Host: Well, thank you for explaining that. So you're using combination therapy, but if these therapies have shown potent efficacy in their own right, are you looking at clinical grade reagents that could be given concurrently to enhance the effects? Tell us what's going on right now in clinical trials and how you envision your research translating to patient care?

Dr. Slayton: Well, there are other agents besides the CAR T therapy that harness the immune system. These are things like bicistronic antibodies or bytes, these are proteins that essentially bind to the T cells, but also have another receptor on them that will bind to the B cells and get the two cells to stick together. And without genetically engineering the T cells, the T cells get activated and they kill the B cells. There's a medicine called blinatumomab that is a byte that is specifically for a protein on the B cells, and has been very effective at getting relapsed patients back into remission without having to engineer their T cells. This is using the T cells that are still in a person's body. You know, after their leukemia treatment, those T cells can be forced to interact with the B cells and leukemia cells through these byte antibodies and those T cells will destroy the leukemia. There are other antibodies that will carry chemotherapy right to the cancer cells. These are medicines like eputusamab amatuximab that carry a chemotherapy payload, but the antibody that's bound to the chemotherapy allows the chemotherapy to accumulate in the cancerous cells but maybe not affect the normal cells quite as much, and those are other drugs that we're using that have been shown to be very effective in relapse patients.

Host: That's absolutely fascinating. Dr. Slayton, as we wrap up, how rewarding is it for you to be a part of this really burgeoning awesome immunotherapy treatments for pediatric leukemia patients and when would you like other physicians to refer? When is it important that they look to the experts at UF Health Shan's hospital?

Dr. Slayton: We want to cure every single kid with leukemia and these immunotherapeutic drugs will allow us to provide additional therapy to patients who are likely to relapse and that will narrow that 10% gap of patients who do not get cured to the point where it will be very, very, very rare that a patient relapses. We've moved these immunotherapy treatments into the upfront therapy of children with leukemia, but we reserve the immunotherapy for patients who may be responding more slowly to their chemotherapy. We're also using immunotherapy in patients with Down syndrome because patients with Down syndrome have a harder time with the traditional chemotherapy. They have more problems with side effects, and some of these children actually die from the side effects even though they're responding to the chemotherapy.

They died from infection because the chemotherapy is so harsh. Some types of immunotherapy are a lot less harsh than the standard chemotherapy, and through clinical trials from the children's oncology group, we're providing the kids with downs, immunotherapy as part of their clinical trial. So we're interested in caring for any child in the state of Florida or in our region who has acute lymphoblastic leukemia. We have a phenomenal center and we're very good at identifying the children who need additional therapy. We're very creative at designing therapy for relapse patients who may have maybe one or two additional chances of being cured. We will look to find the best possible pathway forward for these patients and we'll combine immunotherapy and other targeted approaches to cure these patients.

Host: Thank you so much Dr. Slayton. What an absolutely fascinating topic. Thank you so much for all the great work that you're doing and for joining us today. That concludes today's episode of UF Health Med Ed cast with UF Health Shan's Hospital. You can visit UFhealth.org/pediatrics for more information on immunotherapy for pediatric leukemia patients, or to learn more about this and other healthcare topics at UF Health Shan's Hospital, please visit UHhealth.org/medmatters to get connected with one of our providers. Please remember to subscribe, rate, and review this podcast and all the other UF Health Shan's Hospital podcasts. I'm Melanie Cole.