Long-Term Effects of CAR-T on Children’s Brains Remain Largely Unknown and More Research is Needed

Juliane Gust, MD, PhD
Credit: Seattle Children's

As chimeric antigen receptor T-cell (CAR-T) therapy still constitutes a relatively new modality in medicine, knowledge about its long-term effects on various aspects of health, such as cognition, are not well-known. This is especially true for pediatric patients. As such, more work is needed to track and document long-term outcomes for children receiving CAR-T so that future generations can make informed decisions.

Juliane Gust, MD, PhD, an assistant professor of neurology at University of Washington, Seattle Children's, gave a talk on this topic at the 2024 Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, held in San Antonio, Texas, February 21-24, 2024. Prior to her talk, CGTLive® interviewed Gust to get some insight on the main points she would be discussing and what she views as the main takeaways for the healthcare community.

CGTLive: Can you give some background info about your talk at Tandem 2024?

Juliane Gust, MD, PhD: We have been treating children with CAR T-cells for over 10 years now, but we still have very sparse data about the long-term outcome of this therapy. My interest specifically is about the neurologic outcomes in the long-term. We know that a lot of standard cancer therapy like chemotherapy, radiation, andtransplant all have neurologic long-term adverse side effects that we have documented very well over time. However, with CAR T-cells, it's a bit of a different story. We have a lot of acute toxicity that can be really severe and we really don't understand whether that affects children's neurologic development and cognitive abilities in the future. This is what this session is about—understanding where we're at with that, and how much more we have to do.

What are the main ideas you will be discussing during the session?

The main points of the session will be talking about what we know right now and how many studies there are that have looked at long-term neurocognitive outcomes. We do have a couple of good studies in adults that really show that people do well and we have no easily measurable adverse long-term effects a couple of years out from CAR-T therapy. Of course, we have no idea if that applies to children. The other point that I'm going to make is talking about what we know in children which is very little as far as cognitive studies and biomarkers of neurocognitive impairment that we are just starting to develop. Then the main part of the talk will be spent highlighting the efforts that are currently underway to improve this situation and build neurocognitive outcome studies that can be applied broadly over the pediatric CAR T-cell population.

What are the main implications that doctors and the broader healthcare community should take away from this?

We really currently have no evidence that CAR T-cells are harmful for the brain in the long term. There may be more subtle things that happen—we really have not done the work yet. But my hope is that in the end, we will find that CAR T-cells are more gentle for the brain and its development than our standard therapies that we're currently using.

Can you discuss areas of interest for further study?

The main effort that we're spending right now is to build a cognitive outcome study that could be administered remotely via a web-based cognitive assessment tool that we can give to kids before they start CAR T-cell therapy and then at periodic intervals after. The big challenges here are that a lot of our patients travel long distances and that they don't come back to the same center, they go back to their home center. Making sure that we don't lose track of them is one huge challenge. The other challenge, which is a very major challenge, is that a lot of kids go to transplant after their CAR T-cell therapy and have a lot of really complex therapeutic interventions, a lot of relapses, and many die—we lose a lot of kids. These are very sick patients that have gone through a lot and adding this extra layer of complexity of doing these studies is very challenging, but I think parents and patients will be very interested in having this data to help them make their decision about what kind of therapies to go forward with in the future.

The neurocognitive study that we're building right now is through the CARnation Consortium, which is led by the National Cancer Institute team, and a bunch of pediatric CAR T-cell programs are part of this consortium. Our whole session will talk about multiple efforts that the consortium is making to look at long-term outcomes in CAR T-cell therapy. This is one of the groups that has formed through this consortium and I'm really, really excited that we're having such excellent collaboration nationally. I'm hoping that this will spread internationally as well as more scientific centers sign on to this effort because everything is relatively rare in pediatrics and getting good numbers requires a lot of collaboration.

Is there anything else you want to share with our audience?

One thing that I could add is that in this session, we're really just talking about pediatrics. One big area of interest is toxicity of BCMA-targeting CAR T-cells, where we see a Parkinsonism syndrome emerging in some patients where they develop difficulty moving, stiffness of gait, etc. We're just starting to understand how this is related to CAR T-cells, whether this is a direct toxicity, whether this is reversible—what is the mechanism? This is something that I'm very interested in, but as a pediatric neurologist, that's not my main area of interest. So I'll be definitely looking for that kind of data to be presented [at Tandem 2024].

This transcript has been edited for clarity.

Click here for more coverage of Tandem 2024.

REFERENCES
1. Gust J. Delayed neurotoxicities following CAR T-cell therapy. Presented at: 2024 Tandem Meetings, February 21-24, San Antonio, Texas.