Research Propels Forward With CAR T-Cell Therapy in Pediatric ALL

Christine N. Duncan, MD

CAR T-cell therapy has changed the face of pediatric acute lymphoblastic leukemia (ALL), said Christine N. Duncan, MD, providing patients with a historically poor survival renewed hope for the future.

“CAR T-cell therapy is a complete paradigm shift,” said Duncan. “It started with CD19, which is a specific form of pediatric ALL. Now that it has expanded, we're learning a lot more about the obstacles to therapy and how we need to pick the right patients so that we can move forward.”

In August 2017, the FDA approved the anti-CD19 CAR T-cell therapy tisagenlecleucel (Kymriah) for pediatric and young adult patients ≤25 years of age with B-cell precursor ALL that is refractory or in second or later relapse. Although investigators have come a long way since the inception of the first CD19-targeted CAR T-cell therapy, Duncan explained that the field is still focused on fostering a greater understanding of the long-term toxicities of treatment, developing potential methods of prevention, and ultimately expanding the therapy to other high-risk populations.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Duncan, a senior physician at Dana-Farber Cancer Institute, assistant professor of pediatrics, Harvard Medical School, discussed the current components of CAR T-cell therapy in pediatric ALL.

OncLive: How is CAR T-cell therapy evolved the pediatric ALL space?

Duncan: Pediatric CAR T-cell therapy is used for children who have relapsed or refractory high-risk ALL. In general, the success of ALL therapy has been tremendous. In the early 1970s, the survival rate was about 58%. From the 1990s to now, the survival rate is over 90%. It almost makes you wonder why we need CAR T-cell therapy. The problem is that children who relapse or are refractory to therapy do quite poorly, with survival rates at around 28%. Much of the CAR T-cell therapy research grew out of the pediatric space and has now expanded to many other diseases.

Could you speak to the advances that have been made in the pediatric space?

Many of the advances in pediatric leukemia are similar to those made in adult leukemia with regard to specific drugs. Monoclonal antibody therapies have really helped us target the disease more specifically; that approach has been incredibly important. The closest thing we have to compare CAR T-cell therapy to is allogeneic stem cell transplant, which has pros and cons as well as many toxicities we worry about. There is a lot of focus on CAR T cells because, in many cases, it uses an autologous product. That way, patients don’t need intense chemotherapy or radiation therapy as is common in ALL. The big advances are targeted therapies and monoclonal therapies.

How is patient selection being approached?

Patients are diagnosed upfront based on their clinical presentation. We used to consider age and clinical features at the time of diagnosis. Now, it's much more advanced. We're looking at cytogenetic changes and response to therapy at a molecular level in ways we could never do before. Rather than only looking at who they are at the time of diagnosis, we're looking at who they are, what their cancer looks like molecularly, and how they respond to therapy on a molecular level. That’s how we're stratifying patients for therapy.

Are there specific challenges with this stratification process?

Generally, it works quite well. However, not everyone's cancer goes by the book. We’ve gotten very good at trying to figure out how to respond to patients who don't follow that expected plan. We're thinking about CAR T-cell therapy and allogeneic stem cell transplant.

We’re trying to figure out how to use new technologies correctly. There are some patients who could receive CAR T-cell therapy or transplant. There are also patients who have had CAR T-cell therapy and go to transplant or vice versa. We don't yet know how to predict who the right patients are for those strategies. It's not due to a lack of effort, but rather because the technology has moved very quickly. There's a lot that we still need to figure out in this space. We need collaborative efforts and consortia. Pediatric ALL therapy has a long history of clinical trial- and research-based treatments. In fact, that's how the majority of patients are treated. I'm very optimistic we'll be able to figure this out.

Are there any CAR T-cell therapy trials that you're excited about?

It is exciting to see CAR T-cell therapy expand beyond B-cell ALL. Over time, what you see is patients with CD19-targeted disease who had been treated with CD19-directed CAR T-cell therapy will relapse with CD19-negative disease. The work coming from laboratories and clinicians has shown us that we can use CAR T cells that target both CD19 and CD22. Beyond that, there's a population of patients who have relapsed T-cell ALL, and up until recently they haven't been able to receive CAR T-cell therapy. Those patients have a dismal survival rate, after relapse, of about 28% or less. It's exciting to see CAR T-cell studies developing and expanding to very high-risk patient populations. We're very hopeful that CAR T-cell therapy will expand to entirely new populations.

What are some unanswered questions that need to be addressed?

There are so many. One of the most important questions is, “Who are the right patients?” “Should CAR T-cell therapy be used as a bridge to get to a stem cell transplant, or is this an alternative to stem cell transplant?” The community is extraordinarily divided on that. Moreover, how do we treat associated toxicities appropriately? Some toxicities can be intense and life-threatening. We're still trying to learn how to predict who is going to develop those toxicities, the best way to treat them, and how to prevent them from happening altogether.

Also, we know nothing about the long-term effects of this therapy independent of transplant or in combination with transplant. The paradigm shift happened very quickly. It took many years to figure out how to correctly follow patients who received a stem cell transplant. Now, we're trying to figure out how to follow patients who received CAR T-cell therapy. This is something we'll learn over time. There are probably more unanswered questions than answered questions in this space right now.

Where should future research be focused?

As a clinician, I would like us to focus on some of the toxicities and long-term effects of this therapy. Even more than that, how do we prevent relapse? How can we predict who should receive CAR T-cell therapy and those who are at high-risk for relapse after that? The number one reason children die after CAR T-cell therapy isn't due to the toxicity of the therapy, it's because they relapse. We still need to figure out how to predict relapse and how to prevent it.

Are there any studies in particular that are looking at this?

There's a lot of work dedicated to understanding the mechanisms by which leukemia cells survive or adapt. Researchers are trying to predict who is relapsing, but these are still relatively small numbers of patients [included in these trials]. These studies need to be done in larger settings. Then, there's the issue that one CAR T-cell product is not necessarily the same as another CAR T-cell product. There are certainly similarities, but they don't necessarily have the same outcomes or toxicities. There is a need for collaborative work. Everyone is so excited about the therapy they're using, but there are not as many consortia trials [as there should be]. Consortia trials are really important in this field, and [more are] coming.

Are there challenges with CAR T-cell therapy that are specific to pediatric patients?

I've only treated pediatric and young adult patients. Pediatric patients generally tolerate therapy better than adult patients, so you can provide greater intensity of therapy. Child and young adult patients will survive toxicity that older adults will not survive. There are many reasons to be optimistic about the therapies we have in pediatrics.

The flip side of that is that we're talking about curing patients for 70 or 80 more years of life. We need to think about what happens next in terms of their development, their organ function, and their long-term side effects. It's a slightly different lens to view therapy through. We also have to think about treating the entire family. That is true in adult cancer care as well, but it is a slightly different flavor when you're talking about a parent of a 5-year-old than perhaps a spouse of an adult patient. Ultimately, there are lots of differences, but all the same goals.