Published on August 11, 2020
Immunotherapy and Chemotherapy for Treating Childhood Acute Lymphoblastic Leukemia
Pediatric ALL expert Dr. Alison Grimes from UT Health Sciences San Antonio discusses various subsets of pediatric acute lymphoblastic leukemia (ALL) and the types of treatments available. What's the difference between pre-B ALL and T-ALL? How are they treated differently? She will also discuss immunotherapies such as BiTe and CAR T-Cell therapy.
This is part two of a five-part series, which includes:
Transcript | Immunotherapy and Chemotherapy for Pediatric ALL
You mentioned Jaden with pre B ALL. But there are other types, and if there are, how do you know what you're dealing with?
Yeah, so, the leukemia cells have, like a fingerprint. They have a very unique signature, a unique set of features that we're able to detect in the lab that allows us to determine what type of cell exactly that leukemia cell represents. So, precursor B ALL is a leukemia that's derived from very immature B-cell or precursor B-cells. And we know that based on this fingerprint signature that's detected in the lab, also called an immunophenotype. That also is able to reveal to us other types of leukemia, or if it's not derived from a B-cell. If it's a T-cell type leukemia, which is another type of immune cell.
Okay. You would treat these different types differently.
Correct. T-cell ALL is managed differently than pre B ALL. And also the outcomes that we expect for patients are different with pre-B-cell and T-cell. There are other types of leukemias as well beyond lymphoblastic leukemias. There are leukemias that derive from the myeloid type of white blood cell. You may have heard of AML, or acute myeloid leukemia. Those leukemias can occur in adults as well, but they look differently, they behave differently, and they're managed differently when they occur in young children.
Okay. Let's talk about some other treatments for a minute. So, you mentioned immunotherapy. What does that mean versus chemo?
Yeah. The idea of immunotherapy is really exciting because it's actually therapy that engages the body's own immune system in identifying, attacking and ultimately clearing the cancer cells. That's different from chemotherapy. Many chemotherapeutic drugs or agents that we use are cytotoxic, meaning they directly impact some phase of the cell cycle or some phase of replication of the leukemia cell to either stop that replication, to kill the cell, or to halt further progression. There are some other ways that chemotherapeutic agents work. But essentially the drug is intended to target the leukemia cell itself without engaging necessarily the body's own immune system in that process.
Immunotherapy is different. Immunotherapy, and I know we'll talk specifically about BiTE therapy and CAR T-cell therapy. Those are just two types of immunotherapy. There are many other types of immunotherapies, particularly used in adults, and over time some of them are making their way into childhood cancer treatment as well.
Previously, we had used immunotherapy for childhood leukemia for those types of leukemias that were just resistant to the upfront chemotherapy that most patients respond to or for the leukemia that comes back after you've initially responded to that traditional therapy. And what we've learned in managing relapsed and refractory patients over time is that the immunotherapy is so effective, that it actually can be used in combination with the chemotherapy in some subsets of patients upfront in order to reduce the total amount of chemotherapy that's needed or to improve outcomes for that subset of kids that seem to respond upfront, but are at risk for on-therapy relapses, early relapses, or that take a little bit longer to clear their disease than other children. And that's how we're now using immunotherapy, as of the last 12 months, upfront in standard-risk childhood ALL.
Wow. Okay. Let's talk about just a couple of things we've alluded to. So BiTE therapy, what is a BiTE? And where does that come in, in the treatment of children with ALL?
Sure. BiTE is an acronym and it refers to bi-specific T-cell engagers. Or B-i-T-E, BiTE. This is a class of specific drugs that allows identification of a particular marker on the surface of the leukemia cell. The first BiTE therapy that was developed targets an immunophenotypic marker, or you can think of its sort of a flag on the surface of the cell, CD19. And this drug, some may have heard of, it's called blinatumomab or Blincyto, and blinatumomab specifically targets that marker. That's important because that marker is pretty universally present on precursor B ALL cells. But you would want to know that upfront since the drug is using that as a target.
So then the drug is able to target that marker on the surface of the leukemia cells. It's like taking a highlighter and highlighting all of those cells with that marker, the leukemia cells in the body, and then the body's immune system suddenly says, "A-ha, you're not longer hidden. I see you, you're foreign, and I want to get rid of you." So, it triggers the body's own innate immune system, that then mount an attack, kind of like you would to an infection. And your immune system then can find, because those cells are now highlighted bound to the drug, can find those abnormal leukemia cells, and then can clear them as if you're clearing an infection.
Now, how is this drug delivered? I understand it may be different than going to the hospital and having chemotherapy. I've heard if some people would like a little fanny pack or something and it can be infused, but over many days.
That's exactly right. It's given in a series of cycles. The first cycle of the medication you are going to spend more time in the hospital. But it's a 28-day infusion, at least blinatumomab is a 28-day infusion. Just like any other medication that you've never had before, and certainly a medication that's going to turn on your immune system, you really want to monitor a child that's receiving that medication for the first time in the hospital. So usually they spend at least a week, through day eight, sometimes longer on the infusion to make sure they tolerated the starting dose, and then there's a ramp-up that occurs on day eight. Only in cycle one.
If everything is tolerated well, then your cancer treatment team is going to coordinate with an outpatient infusion center or nursing facility for that patient to continue to receive replacement bags of the medication. And yeah, it's placed in a little backpack or fanny pack that you then carry around. And that infusion just continues to go. As each bag is running out, it's changed out with a combination of teaching with the parents and a nurse that comes to the home. And at the end of the 28 days, it's done, and the infusion can be turned off in a clinic setting.
Then that patient proceeds with the rest of their therapy until the next cycle of blinatumomab is due. And when it is due, usually you only have to spend the first day or two, the next, your subsequent times around in the hospital for monitoring, and then you go home to complete the rest of the 28 days.
Wow. Okay. So mobile treatment.
Okay. Well, I'm sure, I know the Leihsings are listening. That hasn't been the therapy that they've had, but they're hearing about the progress, so I'm going to ask about one other. CAR T-cell therapy, chimeric antigen receptor T-cell therapy has been approved, I believe, for ALL for kids. So, what is it? And when does it come in?
So, CAR T-cell therapy is also a form of immunotherapy. There are different types of CAR T-cell therapy, just like BiTE therapy. CAR T operates a little bit differently though because you have to have a piece of the immune system. What's interesting about CAR T-cell therapy it is not currently used upfront for pediatric ALL, it's used in relapse or progressed disease, or refractory cases where children aren't responding to typical therapy, or the disease just keeps coming back. It has also been very effective in teens and young adults in these settings as well. And it's a therapy that's used even into older adulthood.
So for children, if you're in that situation where the disease keeps coming back, or you're not responding to upfront therapy, CAR T-cell therapy can be considered. And what has to be done for CAR T therapy to proceed is, usually it's given by a transplant team, many children's cancer centers have a cancer treatment team and a children's bone marrow transplant team jointly. Others may only have one and you may need to go elsewhere for either bone marrow transplant or to receive something like CAR T-cell therapy.
However, there are many institutions throughout the US that offer it. So that child then would present to the transplant physician team, they would have an evaluation of their immune system, including their T-cells. And then, the child would, it's like they're getting a blood donation. Blood would need to be saved and then processed in the lab, so that the T-cells, which are one of the immune cells that we all produce can be trained and they are trained meaning in the lab they're activated to identify a particular target.
And I just talked about this in a setting blinatumomab, where that medication is looking for a particular target on leukemia cells, this is what the T-cells in CAR T therapy are being trained to do in the lab. So you activate them against a particular target. That target may be CD19 or it may be another marker that's highly prevalent on the surface of those immune cells.
Once they're trained, then the child re-presents to get their own T-cells that are now activated and ready for battle infused back into them. And those T-cells then go on a hunt. They're activated, they're primed just like what happens when you have an infection that you've had before, that you're now ready to respond to. And the CAR T-cells are then engaged to identify and clear those abnormal leukemia blasts.