Over the past decade, chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment for children with acute lymphoblastic leukemia (ALL). While most patients achieve remission, the therapy can also lead to serious toxicities.
Among the most challenging is immune effector cell–associated neurotoxicity syndrome (ICANS), which can cause headaches, confusion, seizures, and—in rare cases—brain swelling and death. ICANS affects 30% to 50% of pediatric patients treated with CAR T-cell therapy, but clinicians can’t predict which children will experience it.
To address this gap, a team at Children’s Hospital Los Angeles is conducting a first-of-its-kind prospective study. Funded by a $4.5 million grant from the National Institutes of Health, the researchers aim to discover brain and biologic markers that may help predict risk for ICANS.
“If we could identify which patients are at risk, we could potentially modify their treatment, monitor them more closely, or give prophylactic drugs,” says Deepa Bhojwani, MD, a co-principal investigator on the study and Director of the Leukemia and Lymphoma Program in the Cancer and Blood Disease Institute at CHLA. “The goal is to mitigate or even prevent this complication.”
One unique aspect of the study is that it’s prospective, with the team following patients before, during, and after CAR T-cell therapy.
That design allows researchers to track how the brain and immune system change over time and to identify biomarkers that may help predict if a child is likely to develop ICANS.
“Most prior studies have been retrospective, looking back after neurotoxicity has already occurred,” explains Ravi Bansal, PhD, an investigator in the IMPACT Laboratory at CHLA and a co-principal investigator on the study. “By studying patients prospectively, we can establish a baseline before CAR T-cell therapy and follow how the brain changes.”
Now halfway through the five-year study, the team has enrolled nearly 50 patients, along with 20 healthy controls. The researchers are also preparing to expand the study to two additional local institutions.
The team’s early data suggest that children with pre-existing brain damage—possibly from prior treatments, including chemotherapy, and ongoing illness—may be most vulnerable to developing ICANS. While these findings are preliminary, they reinforce the importance of collecting detailed brain data before CAR T-cell therapy begins.
To better understand these vulnerabilities, the researchers are using advanced brain MRI methods alongside biologic data collected from cerebrospinal fluid and blood.
One area of focus is whether the blood–brain barrier—the protective layer that helps regulate what enters the brain—is disrupted in children who go on to develop neurotoxicity.
“MRI allows us to look beyond structure and begin to understand changes in brain tissue and function that aren’t visible on conventional scans,” says Bradley Peterson, MD, Chief of Psychiatry and Co-Director of the Behavioral Health Institute at CHLA and a co-principal investigator on the study. “We’re particularly interested in whether subtle differences present before treatment may help explain why some patients are more susceptible to ICANS.”
In addition to identifying risk markers, the study may also provide insights into the biology underlying ICANS—information that could further inform prevention strategies.
Importantly, the study is designed to follow children long-term. Even after ICANS resolves clinically, the team will continue to monitor patients to better understand whether there are lasting effects on brain development, cognition, or function.
If the researchers are able to identify reliable markers of ICANS risk, the next step would be to validate those markers in larger studies—and begin exploring strategies for earlier intervention.
“There is still much to be learned about ICANS,” says Dr. Bhojwani. “Our hope is that we can eventually anticipate and even prevent this neurotoxicity to make CAR T-cell therapy safer for these children.”
(Newswise/MN)