Expert Recognizes Major Advances in Field During Childhood Cancer Awareness Month

Tanja Gruber, MD, PhD

Pediatric patients with cancer are often underrepresented in clinical trials, which typically aim to evaluate new therapeutic options in their adult counterparts, but patient outcomes underscore the need to treat these 2 populations differently.

As the need for more research in pediatric patients with cancer becomes clearer, the role of chimeric antigen receptor (CAR) T-cell therapy continues to develop as a promising new therapeutic option. In particular, tisagenlecleucel (Kymriah) was the first CAR T-cell therapy approved by the FDA in August 2017, and this indication was for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) who are relapsed/refractory.

Since the approval of this cellular therapy, CAR T has continued to make a splash in the treatment landscape of pediatric patients with cancer. During Childhood Cancer Awareness Month, experts recognize the advancements that have been made in the field and look ahead to new research that will help optimize outcomes in this patient population.

In an interview with Targeted Oncology, Tanja Gruber, MD, PhD, chief of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Stanford Children’s Health, discussed the advances she has observed in recent years for the treatment of pediatric patients, including the evolving role of CAR T-cell therapy, and shared advice with community oncologists treating this patient population.

TARGETED ONCOLOGY: Could you discuss the current role of CAR T-cell therapy in the treatment landscape of pediatric cancer?

Gruber: The CAR T is an amazing success in the clinic. Initially, the FDA approved [this treatment] for pediatric ALL, and I think 1 of the reasons it was so successful is you had patients who had multiply-relapsed or refractory disease that was really resistant to chemotherapy, but then CAR T, in order to recognize a leukemia cell, it really just needs to recognize the protein on the surface of that cell, the so-called antigen. The initial studies were against CD19.

Leukemias that were very resistant to chemotherapy were suddenly susceptible to this treatment approach. We've learned a lot since those initial successes and, of course, resistance to CAR T can develop, either because what the drug does is it recruits the immune system to effectively eliminate the cancer. If your T cells that are being recruited to eliminate the leukemia are not as effective as they need to be, then of course the CAR T can fail, and also if the antigen isn't present on your cancer, then that's another mechanism of escape from CAR T.

It's not 100%, and we do have patients relapse that have received CAR T, but we've been able to put patients back in remission that could not be put in remission with chemotherapy alone. I think it's become a great additional tool in our arsenal. In pediatric oncology, we don't treat with a single drug. It's very much a multi-agent approach, and I consider CAR T to be another tool in the arsenal that we can use against pediatric cancer.

Now that the development of the technology has occurred, you can imagine, it's just a matter of identifying what's the right antigen for a whole host of malignancies. I think what you're going to see happening in the field is that CAR T cells are going to be developed for a variety of pediatric malignancies. In solid tumor malignancies, in particular, we've had not as much success as ALL in raising the cure rates, and so many of us are very anxious to see whether CAR T can improve outcomes in that population. There's a significant amount of effort in preclinical research to develop CAR T cells for solid tumors and brain tumors.

TARGETED ONCOLOGY: What are the biggest challenges or unmet needs in treating pediatric patients with cancer?

Gruber: We always have to think about whether or not a patient has access to state-of-the-art care. Many of the newer technologies are happening at the major pediatric hospitals throughout the country, but you can imagine if somebody is diagnosed in a rural setting and doesn't have access to health care, whether that be because they don't have insurance or what have you, it can become more difficult. There are systems in place to catch those patients and make sure they get treatment. For example, in California, we have California Children's Services, so if somebody doesn't have insurance and they're diagnosed with cancer, then the state goes ahead, Medicare comes in, and kicks in for that child to get treatment. However, I think it's important that all children that are diagnosed with cancer be able to get the best care possible. Many times, that means, traveling to a larger center as many smaller local hospitals necessarily won't be able to care for a child with cancer. That's a major component and very important.

Additionally, we have patients that have received what we call the standard of care, so the best treatment we have up front. If you have a patient that relapses on that treatment or comes back after that treatment has been completed, those relapsed patients, many times, require intensive chemotherapy or CAR T treatment in order to get them back in remission. You may have to travel quite far actually to get that type of treatment. Finding the right center that can provide the best care possible is very important in getting these kids treatment.

TARGETED ONCOLOGY: Is there any new research that is looking promising in this space?

Gruber: The field is very focused on CAR T. There are a lot of very promising targeted small molecules that are being developed in pediatric cancer. We're also continuing to work with so-called standard chemotherapy drugs and optimizing the combination of chemotherapy and the scheduled chemotherapy. When you look at ALL, at the beginning in the 1950s, everybody died, and then there was this dramatic improvement in outcomes. Most of that improvement came with optimizing combinatorial chemotherapy, with a small number of new drugs added, but physicians did an amazing job at determining the best combinations and the best sequences to optimize outcomes as much as possible.

We have to remember whenever we're evaluating drugs, it may be a study with a single drug that you don't see much response rate, but is that really how the drug should optimally be used? We're moving more towards using new agents in combination with standard chemotherapy. We evaluate them in early phase clinical studies because we don't want to stop development of a compound that could potentially benefit our patients without really assessing it and determining whether it can be effective in a multi-agent chemotherapy backbone. I think CAR T is unique in that the single agents are cellular product ready, but when you look at small molecule development and new chemotherapy drugs, then we're evaluating a multi-agent backbone.

TARGETED ONCOLOGY: What advice would you like to share with a community oncologist who comes across children with cancer in their practice?

Gruber: I think the most important thing is if they're seeing a diagnosis that they're not used to seeing or not used to treating, it's really important that they contact 1 of the larger centers that does have a high volume of pediatric oncology patients. Sometimes, it requires the patient coming to a bigger center. Sometimes, we can consult with physicians and provide recommendations in terms of treatment. In particular I specialize in infant leukemia, and while I have a study open at multiple centers, sometimes I get calls from community physicians where, for whatever reason, the patient can't come on the trial and then I work with them to help them take care of the patient in terms of what the optimal chemotherapy is and be there for them if they have any questions or are having any complications of the treatment.

I think it's important for community physicians to reach out to specialists, and 1 of the great things about the Children's Oncology Group, which is the biggest cooperative group in the United States, is that they open up their protocols in centers all across the United States, so not just the large centers but smaller centers as well, and then provide fantastic clinical trial protocols for patients to participate in it. We're very collaborative and these consortiums have allowed patients at smaller centers to get state of the art treatment that they may otherwise have difficulty getting.

TARGETED ONCOLOGY: What is the key message that you hope is taken away from Childhood Cancer Awareness Month this year?

Gruber: The most important message is that this is a very exciting time for early phase clinical trials in pediatric oncology, and we have a lot of promising drugs as we become better and better at characterizing the malignancies through next-generation sequencing approaches. Even patients that relapse with standard of care, there's still hope, and there's still a possibility of cure. I think the community, all of the pediatric oncologists, are working together very hard to cure all of our patients. I think the most important thing is that for development of new therapies, we continue to strive for cure, and we won't stop until we've cured all of our patients. There is always going to be hope.