Nemours Children’s Health Medical Director of the Pediatric Bone Marrow Transplant and Cellular Therapy program, Michael Joyce, MD, PhD talks about CAR T-cells being a new therapy for B-cell lymphoma in a young patient.
Interview conducted by Ivanhoe Broadcast News in 2022.
So let’s talk about immunotherapy. It seems like that is the way everything is going right now.
JOYCE: So immunotherapy is the culmination of years of research. So there’s a couple of different components. One are the by-antibodies that by specific antibodies wanted to MAB for childhood ALL and there’s some other by-antibodies for other diseases and it’s been revolutionary. So instead of giving children chemotherapy, which has a lot of side effects, the immunotherapy has been effective therapy and the antibodies have been approved, I think since 2018. More recently, people have developed chimeric antigen receptor T-cells, which called commonly called CAR T-cells. And in the current CAR T-cell that’s approved for children is called Kymriah, made by Novartis and that you take the patient’s own peripheral blood stem cells, you isolate their T-lymphocytes and they genetically re-engineer them with a receptor for CD19, which is one of the molecules on the surface of childhood acute lymphocytic leukemia, which is the most common cancer in children. We then infuse these cells back into the patient and those cells attack the leukemia cells. And so it’s been approved for children who have relapsed acute lymphocytic leukemia who failed two lines to treatment. So I’ve had front-line therapy and neither had refractory disease and failed the second line, so that’s commercially available in the United States and we were approve to give that to patients. And it is shown to put about 75-80 percent of the children in complete remission but most of those remissions, some can be long term. Some children will relapse, some children will get a second dose of CAR T. Some children will have to go on and get a transplant if their disease comes back.
You said, right now, it’s not the first line of therapy. Do you see that this is going to go towards the first-line therapy?
JOYCE: I think that the future clinical trials that are going to be in pediatric is probably going to use that for a subset of patients who are at more high risk for relapse than standard. Fortunately with a childhood acute lymphocytic leukemia, for a standard or feeble risk with cure rates are over 90% with front-line therapy. The CAR T-cell therapy is very effective therapy but also has significant risks of side effects. So one is the cytokine release syndrome, and the other one is the neurotoxicity called ICANS, immune effector cell associated neurotoxicity. But we have all gone through special training to be able to treat the children who develop those side effects and watch very closely for the first week or two after the CAR T.
When you think about side effects and you think about front-line therapy is it chemotherapy?
JOYCE: Yes.
And then you think about these side effects and which one outweighs the other?
JOYCE: Well, all children with leukemia are at risk for developing opportunistic infection whether they’re being treated or not. So with the chemotherapy in the first few months of ALL therapy, the therapy is more intensive so there’s a higher risk of infection when you’re in the later part and maintenance therapy, there’s a lower risk of infection because your blood counts generally aren’t dropping. But the CAR T-cell therapy there is a risk of infection. We use prophylaxis with antiviral, and anti-fungal, and sometimes bacterial antibiotics for preventing infections but usually the it’s a little bit different. I think the CAR T, the side effects are sooner after the CAR T and don’t last as long and so it’s mixing. But children who need the CAR T therapy to cure their disease, it’s worth the risk. There is clearly a benefit versus that risk of infection.
What makes these stem cells different that when you take them out and put them back in, they’re going to attack the cancer to where they wouldn’t before. Is that right?
JOYCE: So they put in a specific receptor for the CD19, which is one of the proteins on the surface of the leukemia cells. Those cells go into body and they proliferate and start to divide and attack any residual leukemia cells. You try and do some bridging chemotherapy before you give the CAR T and there’s what’s called lymphoma depleting chemotherapy, which has given a few days before the CAR T-cell therapy to decrease the disease burden because you don’t want to have the child in florid leukemia relapse because that would increase the risk of side effects.
Will this work and other cancers then?
JOYCE: They are. So the other Kymriahs also approve for children with certain types of non-Hodgkin’s lymphoma and in adults there are several products using the same CD19 CAR T. Other companies have made CAR T therapy that had been approved for relapsed or refractory lymphomas. These are generally B-cell malignancies, but they are currently trying to develop CAR T-cells for acute myeloid leukemia. They’ve recently attended the transplant meetings and they are developing, they had abstracts and developing CAR T-cells for some brain tumors. They’re trying to develop them for solid tumors. So there are some technical challenges, but I think you’re going to see in the future, we’re not going to be using as much chemotherapy, but more what we call targeted therapy and immunotherapy to treat the diseases that we currently don’t have success with.
I think it also just makes people feel better. Chemo has had such a bad reputation because of the side effects and how hard it is to make it through that we are using something from your own body to heal yourself.
JOYCE: Yes, it’s generally, we hope that in time will have less side effects that CAR T, they are also trying to develop what’s called off-the-shelf CAR T, which are more CAR T natural killer cells and so that they can try and develop them or they can just take them off the shelf and so if you have refractory ALL or refractory non-Hodgkin’s lymphoma, we don’t have to manufacture them and harvest your own peripheral blood stem cells, but we can just use that as an immunotherapy.
Are there any lasting effects from this?
JOYCE: Well, there can be short-term effects. So some of the children will develop because the B cells make antibodies, we have to monitor their antibody level and sometimes give them intravenous immunoglobulin to keep their antibody level, it’s safe. And sometimes there can be dropping their counts transiently. So sometimes they knew we needed some growth factors. But several studies for typically the non-Hodgkin’s lymphoma as though they’ve shown that the remission rates they get one dose and lot of the patients, about half of the patients will stay in long-term remission.
So in these kids, this is their last therapy, right?
JOYCE: Well, it’s probably the last cured if ill. For the children who are getting CAR T, it’s the last curative therapy or they may also get a transplant. So a lot of times for children, and particularly for some of the very high-risk leukemias like in Philadelphia, like ALL they’re now recommended if they get in remission. Some people are given the CAR T and then doing sequential transplant. So I think for very high-risk group patients, they may be getting CAR T and may need an allergenic bone marrow transplant after that. That is some of the newer protocols are recommending that.
How long does it take? Is it the same day where you take the stem cells?
JOYCE: No. So right now, initially it took about two months to harvest the, to manufacture the cells, but now they’re getting it down to six weeks and there was some of the new improvements are talking about having them in 3-4 weeks.
How many stem cells would you say it would take?
JOYCE: Well, we’re actually looking at the CD3, the number of lymphocytes. So we need about two to five million lymphocytes per kilo body weight.
Anything we’re missing on this one? You’ve come a long way in this hospital, but it seems like you’ve probably come a long way in the treatment of this.
JOYCE: Well, when I started in oncology, we cured about 60 to 70% of ALL and overtime with the randomized clinical trials. Now we’re curing over 90% of ALL, which is really satisfying.
END OF INTERVIEW
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