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How Immunotherapy is Impacting Pediatric Cancer

September 19, 2019

Around the world, young people under the age of 20 receive a cancer diagnosis roughly every two minutes, affecting an estimated 300,000 children and adolescents every year.

In the United States, where approximately 1 of every 285 people will be diagnosed with cancer before the age of 20, cancer causes more deaths than any other disease—only traumas are responsible for more deaths in this age group. Although young people are affected by several of the same types of cancer as adults, the ways in which they develop―and the ways in which they must be treated―can be drastically different for several reasons.

The survival rates for these different types of cancers vary, but overall the majority of young people diagnosed with cancer are able to survive long-term thanks to advances in treatments over the past several decades, including immune-based therapies such as bone marrow transplants.

Already, there are five FDA-approved immunotherapy options available for children with certain types of cancer. With new immunotherapy approaches, hope now exists that we can treat young patients not only more effectively, but also―due to the specificity of the immune system―in ways that prevent the damaging side effects that can accompany conventional treatments. As of August 2019, there were more than 70 active clinical trials evaluating a number of immunotherapy approaches for children with cancer.

To better understand the current immunotherapy landscape in childhood cancer and how these immune-based approaches are starting to improve care for young patients, we spoke with Susanne Baumeister, M.D., a pediatric oncologist at Boston Children’s Hospital and Dana-Farber Cancer Institute, and an instructor in pediatrics at Harvard Medical School, in Boston, MA.

Mother Denise, patient Cole, and Dr. Susanne Baumeister. Photo by Adrianne Mathiowetz
Mother Denise, patient Cole, and Dr. Susanne Baumeister at the CRI Immunotherapy Patient Summit in Boston on July 27, 2019. Photo by Adrianne Mathiowetz

Arthur N. Brodsky, Ph.D.:

Checkpoint inhibitor immunotherapies are a type of treatment that block the “brakes” on T cells, which are some of the most powerful immune cells in the body. By doing so, these checkpoint immunotherapies—especially those that target the PD-1/PD-L1 pathway—can unleash T cells against tumors. Already, they’ve provided remarkable benefits in several types of cancers that mostly affect adults. How have these new immunotherapy treatments been applied to treating childhood cancers?

Susanne Baumeister, M.D.:

One such therapy, pembrolizumab, is approved for certain types of pediatric relapsed or refractory lymphomas, specifically primary mediastinal B cell lymphoma and classical Hodgkin lymphoma. A Phase 1 clinical trial evaluating ipilimumab, a drug inhibiting the CTLA-4 pathway, showed that immune-related toxicities were similar to those found in adults, but unfortunately did not show any objective tumor regressions in pediatric patients with melanoma or sarcoma. There are also ongoing studies using checkpoint inhibitors in pediatric patients with melanoma and certain solid tumors such as pediatric hepatocellular carcinoma. While checkpoint inhibitors have yielded good responses in certain pediatric patients, pediatric cancers generally do not appear to be as susceptible to this type of therapy compared to its success in many adult cancers. 

Arthur N. Brodsky, Ph.D.:

PD-1 checkpoint immunotherapy is also approved for children with solid cancers, as long as their tumor is “MSI-high,” which means that it has many mutations. Immunotherapy works particularly well against these tumors because mutations provide targets that the immune system recognizes and goes after to eliminate tumor cells. So, how prevalent is this MSI-high status in children with cancer?

Susanne Baumeister, M.D.:

Pembrolizumab is approved for children with unresectable or metastatic, MSI-high or mismatch repair deficient solid tumors that have progressed following prior treatment and have no satisfactory alternative options. MSI-high is relatively infrequent in pediatric cancer but can be seen in certain pediatric high-grade gliomas (brain tumors) and other solid tumors such as Ewing’s sarcoma. While not used frequently, this represents a treatment option for a select group of pediatric patients with cancer.

Arthur N. Brodsky, Ph.D.:

That makes sense. Since mutations accumulate over time, children don’t usually have heavily-mutated cancers and this could be limiting the effectiveness of checkpoint immunotherapy for young patients.

Fortunately, there have been other immunotherapy advances that have been helpful against childhood cancers. For children with B cell leukemia, the FDA has approved a bispecific antibody immunotherapy. Could you talk about this approach and how it works?

Susanne Baumeister, M.D.:

Yes, that’s a treatment called blinatumomab, which is a bispecific T cell engager—or BiTE—that targets cancer cells expressing the CD19 protein, and also binds and basically recruits T cells via the T cell co-receptor. This gets the T cells in very close contact with the leukemia cells and facilitates killing of the leukemia cell. A Phase I/II international study of blinatumomab yielded promising results in children with B cell acute lymphoblastic leukemia, or B-ALL who had relapsed or refractory disease. The complete remission rate was approximately 40 percent. This has been an important strategy to get patients into remission who did not respond well to chemotherapy. Even when ALL-patients are in remission, there may be minimal residual disease, or MRD, which can be detected by using very sensitive testing. Blinatumomab has had good success in achieving a MRD-negative disease state and is FDA-approved for children with MRD-positive B-ALL now as well.

Arthur N. Brodsky, Ph.D.:

Like the bispecific antibody approach, another immunotherapy strategy, called CAR T cell therapy, also targets the CD19 marker on cancer cells. This treatment has already been approved for children with acute lymphoblastic leukemia, and also takes advantage of patients’ existing T cells, but in a slightly different way. How do these CAR T cell therapies work?

Susanne Baumeister, M.D.:

These treatments are made by collecting a patient’s own T cells, taking them to the laboratory and inserting a new receptor, which we call a chimeric antigen receptor or CAR. This CAR typically consists of a fragment from an antibody that binds the target on cancer cells (in this case CD19), as well as some of the domains inside the T cell that normally promote T cell activation and killing. Once the patient’s T cells express this new receptor, they are administered back into the patient’s bloodstream and can now recognize and kill any cells carrying the target on their surface.

It’s basically a way to provide patients with lots of cancer-targeting T cells. They’re the patient’s own T cells but now they’re equipped with a receptor that activates these T cells once they encounter the CD19 antigen, which is expressed almost universally on B cells, including cancerous B cells. Once the T cells get activated by CD19 they divide and proliferate and then are able to mount an effective response against the leukemia.

Arthur N. Brodsky, Ph.D.:

Isn’t it true that these CAR T cell therapies have been rather successful for children with leukemia, at least as far as the initial response rates?

Susanne Baumeister, M.D.:

That’s correct. The complete remission rates from the global phase II study were around 80 percent, meaning that four of every five patients treated had their disease eliminated. These are remarkable, complete remissions that are being achieved in patients who previously had refractory disease or relapsed disease that would have been very difficult to control. The obstacle that we need to overcome now is that a number of those patients relapse after they initially achieve a complete remission. About 50 percent of patients experience a relapse at some point in the two years after receiving the CAR T cells, most of them in the first year.

This appears to be due to two reasons. On the one hand, some patients’ CAR T cells don’t persist in the body long enough to really clear everything up and provide long-term control of the leukemia. On the other hand, some patients’ leukemia cells are able to lose or modulate the expression of the CD19 protein on their surface so that the leukemia cells become unrecognizable to the CAR T cells. To address that second issue, there is ongoing research seeking to target two different surface receptors—CD19 and CD22—at the same time. Other efforts are aimed at understanding how to better keep the CAR T cells active and persisting over time so that they can provide long-term control of leukemia after they induce these complete remissions. Because of the relapse risk, many centers recommend a stem cell transplant once the leukemia is in remission, particularly in patients who have not had a transplant.

Arthur N. Brodsky, Ph.D.:

Hopefully, we will see some breakthroughs in those areas soon that will enable doctors to improve the long-term effectiveness of CAR T cells. Beyond leukemia, has there been any progress in CAR T cell therapies for other types of childhood cancers?

Susanne Baumeister, M.D.:

Yes, efforts are under way to evaluate CD19-targeting CAR T cells in pediatric patients with relapsed or refractory non-Hodgkin lymphoma, but really one big goal in the field is to expand the CAR T cell approach beyond CD19. Having established the proof of principle of what CAR T cells are able to do, the question is: can we create safe and efficacious CAR T cells for other types of leukemias or solid tumors?

With respect to acute myeloid leukemia, or AML, which is a pediatric leukemia that can be difficult to treat, there are a couple different targets that are in preclinical or early clinical development. One of them is CD33, another is CD123. Here at the Dana-Farber Cancer Institute, we completed a study of CAR T cells targeting NKG2D-ligands in adults with AML.

One of the challenges in AML and in malignancies other than acute lymphoblastic leukemia is that it is hard to find a target that is as suitable as CD19 is for ALL. An ideal CAR T cell target is found on the surface of all of the cancer cells, but not on any essential healthy cells in the body. CD19 is found on healthy B cells, but the body can tolerate the loss of B cells if we substitute their role in protecting against infections by giving patients infusions of antibodies, or immunoglobulins.  

However, if cells in critical organs share the same marker that’s targeted by CAR T cells, we may not be able to tolerate the side effects. For the myeloid leukemias such as AML, some of the targets found on the surface of the AML cells can also be found on healthy precursors of blood cells that we don’t want to eliminate or would need to replace with a stem cell transplant if they are eliminated. So, these CAR T cell strategies have been a little bit slower to develop, but I’m happy to say that a few pediatric cancer centers in the country, including Dana-Farber/Boston Children’s are getting ready to open a trial of CD33-targeting CAR T cells for pediatric patients with AML.

Arthur N. Brodsky, Ph.D.:

Moving beyond blood cancers, the ultimate goal would seem to be to apply these CAR T cells to patients with solid cancers. One type of solid cancer that is common in children is neuroblastoma, which affects the nervous system. Are there any CAR T cells being investigated in this cancer type?

Susanne Baumeister, M.D.:

There are definitely some CAR T cell approaches being explored in neuroblastoma, the most prominent being those that target GD2. GD2 is a molecule that is highly expressed on the surface of neuroblastoma cells, and the incorporation of antibodies directed against GD2 into the treatment regimen for high-risk neuroblastoma has significantly improved overall survival and is now standard.  

So, this is certainly a promising target. There have been several clinical trials exploring CAR T cells directed against GD2. Those have been safe, but so far clinically significant tumor clearance or control has been limited. The same is true for clinical trials of CAR T cells targeting L1-CAM, an adhesion molecule that is expressed in neuroblastoma.

One of the hurdles with CAR T cells in solid tumors is that, as you might imagine, it’s much easier for T cells to encounter and kill leukemia cells that are everywhere in the blood or in the bone marrow. It’s harder to get T cells to find their way into a solid tumor. To do so, they have to come out of the bloodstream and make their way into the solid tumor tissue, where there’s often a tumor microenvironment that suppresses immune activity. It’s much harder for the CAR T cells to go find the target, multiply, and completely eliminate the cancer cells that express it.

A lot of research focuses on how to overcome these challenges in solid tumors. Newer versions of CAR T cells are being tested, including those that produce additional molecules that help them find their way into the solid tumor as well as immune-boosting cytokines that can improve their survival and function in the tumor microenvironment.

Arthur N. Brodsky, Ph.D.:

Obviously, these CAR T cells are very powerful weapons against cancer. However, sometimes they can become overactive, and it can cause a serious side effect known as cytokine release syndrome (CRS) or cytokine storm. Have there been any advances in our understanding of cytokine release syndrome, or in our ability to prevent or manage it?

Susanne Baumeister, M.D.:

We’ve learned a lot about the timeline, markers, and clinical parameters that are part of cytokine release syndrome, which, as you said, is basically a sign of a high level of activation of the immune system, which can resemble signs of a serious infection and can make kids pretty sick while they go through it. It’s a bit tricky, because we’re happy to see the CAR T cells working and eliminating the cancer, but obviously we don’t want patients to get too sick. Fortunately, there are now well-established guidelines on how to recognize and manage different stages of cytokine release syndrome. We have learned that there are certain cytokines that play a big role in cytokine release syndrome, such as interleukin-6, or IL-6, and that we can treat patients with antibodies that block the signaling of the IL-6 pathway.

This drug has been shown to mitigate the cytokine release syndrome and improve patients’ clinical status without impacting the efficacy of the CAR T cells. In some cases, we use that in combination with systemic steroids, to dampen down the immune response and make sure patients recover from CRS.

In addition to cytokine release syndrome, there are some neurologic symptoms that can also be seen in pediatric patients. These often occur after cytokine release syndrome or at the tail end of it. In pediatric patients this typically resolves on its own, although it can be scary for patients and families when it occurs.

Arthur N. Brodsky, Ph.D.:

What do we currently know about the potential long-term side effects of these immunotherapies, both the checkpoint immunotherapies and CAR T cell therapies?

Susanne Baumeister, M.D.:

Checkpoint inhibitors can cause immune-related adverse events that can resemble autoimmune diseases and cause inflammation in healthy tissues. While this can be treated successfully, it has the potential to be very serious and may affect the function of important organs. An example is thyroid dysfunction requiring the use of thyroid replacement medication.

So long as anti-CD19 CAR T cells persist, they also attack healthy B cells, which puts a patient at risk of infection if they do not receive immunoglobulin replacement regularly.

CAR T cell therapies against other targets might have very different short- or long-term side effects. Thankfully, the method of introducing the gene for the chimeric receptor into T cells has proven to be very safe to date.

Because immunotherapy is still relatively young, we don’t have comprehensive data on long-term side effects in children, yet. However, depending on the type of treatment, conventional treatments with chemotherapy or radiation can significantly affect organ function in pediatric patients during their life and, at least preliminarily, immunotherapy looks very favorable in comparison.    

Arthur N. Brodsky, Ph.D.:

So, we’ve been talking about these different approaches for childhood cancers, but we haven’t explicitly mentioned that all of these treatments were first tested—or still are being tested—in clinical trials. I know that there are some misconceptions out there as far as clinical trials, which could be preventing some patients from enrolling in studies that could potentially benefit them immensely. How important are clinical trials when it comes to advancing the medical field and creating better treatments for children with cancer?

Susanne Baumeister, M.D.:

Clinical trials are critically important when it comes to advancing the treatments that we can offer patients. Particularly in pediatrics they are very important because, thankfully, there are far fewer children with cancer than adults.

To really evaluate whether a drug is working or is better than an existing treatment, it’s important to look at it rigorously in a clinical trial. This can help us understand if it’s effective, across a defined cohort of patients. We can also determine if there are any side effects and how common they are.

I would also stress that we would never offer a patient with cancer a placebo instead of a legitimate treatment. These are carefully designed trials that look at the best available existing therapy that would be offered to a patient and see if we can make improvements by adding a new therapy or modify the existing therapy. In the case of very new treatments (such as when CD19-CAR T cells were first tested), patients are only eligible to participate if they didn’t respond to other standard chemotherapy. It’s a way to offer a new treatment to patients that could help them, doing it as safely as possible and rigorously learning from it, so that it can improve therapies in the future. Especially in early phase trials, we don’t know if the new treatment will benefit a participating patient, but without other patients having participated in clinical trials before them, we would not be able to achieve the outcomes in pediatric oncology we have today.

So, it’s critically important to carefully conduct clinical trials and to ensure that they include and are made available to children with cancer early on, especially if they look to be relatively safe and have shown an efficacy signal in adults.

Arthur N. Brodsky, Ph.D.:

Definitely. Finally, I wanted to touch on a non-scientific issue related to childhood cancer. Having cancer is obviously tough for anyone, but especially so for children. And in addition to the stress of the treatments themselves, being stuck in a hospital and away from their friends during this formative period in their lives can also exact a toll. So in that light, what advice do you give to parents and children with cancer as they begin their care?

Susanne Baumeister, M.D.:

That’s a good question. I think just being supportive and positive throughout the treatment and explaining what is happening to children in an age-appropriate way is key. Children are remarkably resilient, and I think it helps them to maintain a sense of structure and to be able to continue activities they enjoy, to the extent possible. Most centers have a comprehensive care team consisting not only of the medical providers, but also psychosocial support and child-life specialists that can help navigate this difficult time. I think it is critical for patients and parents to understand their treatment options, to be active participants in their medical care, and to feel that they can raise and have any concerns taken seriously.

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