Neurofilament Light Chain Levels May Indicate Risk of CAR T–Related Neurotoxicity

The advent of chimeric antigen receptor (CAR) T-cell therapy expanded the cancer treatment landscape and has produced impressive outcomes in certain cancers, but a significant portion of patients experience neurotoxicity after treatment. A study published in JAMA Oncology suggests that assessing levels of neurofilament light chain (NfL) protein before CAR T-cell therapy could help identify patients who are most at risk of immune effector cell–associated neurotoxicity syndrome (ICANS) after treatment.

CAR T-cell therapy involves genetically modifying a patient’s T cells to create CAR T cells that target the individual’s specific cancer, which are then reinfused into the patient. Despite promising efficacy in hematological cancers and potential to eradicate cancer in some cases, the treatment also carries a risk of life-threatening adverse effects such as ICANS and cytokine release syndrome after treatment.

ICANS affects 40% to 60% of patients who receive CAR T-cell therapy. Identifying patients who are at the highest risk of ICANS could help facilitate early or even preventive treatment. NfL, a known marker of certain neurodegenerative and neuroinflammatory conditions, was recently identified as a possible marker for ICANS. The present study explored NfL levels in patients throughout the CAR T-cell therapy process to identify any associations with baseline NfL and posttreatment ICANS.

“Our study suggests that some patients receiving CAR-T cell therapy have previously undetected damage to neurons present at baseline, before we even begin preparing them for this treatment,” Omar Butt, MD, PhD, lead study author, professor of medicine at Washington University (WU) School of Medicine in St. Louis, and clinician at the Siteman Cancer Center at Barnes-Jewish Hospital, said in a statement. “We don’t know the origin of this damage, but it appears to predispose them to developing neurotoxic complications. If we understand who is at risk of these complications, we can take early steps to prevent it or reduce the severity.”

The study encompassed 30 patient with diffuse large B-cell lymphoma who were treated with CAR T-cell therapy at WU and Case Western Reserve University. The median patient age was 64 years, and NfL levels were measured at baseline, post lymphodepletion but before CAR T-cell infusion, and at various timepoints from days 1 to 30 after infusion.

Patients who developed ICANS of any grade, low grade (grade 1 or 2), and grade 3 or higher showed significantly elevated baseline NfL on average (mean levels of 87.6, 115.3, and 71.7 pg/m at baseline, respectively) vs patients who did not experience ICANS (mean NfL of 29.4 pg/mL at baseline). Levels of NfL also remained elevated for 30 days in patients who experienced ICANS after treatment. Baseline NfL correlated with ICANS grade, and multivariate modeling found it to be the main contributing factor to ICANS grade.

The findings suggest that testing for pretreatment NfL elevation may help identify CAR T-cell therapy recipients who are at a high risk of ICANS, although the authors note that NfL is unlikely to be the sole driver of ICANS in this patient group.

“We’re just seeing the tip of the iceberg in terms of the actual disease process, and that’s where many of our future studies are going,” Butt said. “We’re trying to get a better sense of what is causing these changes to begin with. And in later stages, even after symptoms have resolved, we still see these elevated NfL levels.”

An ongoing study at the Siteman Center aims to determine whether patients with elevated NfL levels continue to have subtle cognitive symptoms after ICANS has resolved. Further research is warranted to assess the disease process and to evaluate NfL elevation prior to CAR T-cell infusion as a biomarker for preventive treatment or early intervention for patients at a high risk of ICANS.

“We plan to continue our studies to find the origin of neuronal damage in these cancer patients,” said co-senior author Beau M. Ances, MD, PhD, professor of neurology at WU and clinician at the Center for Advanced Medicine Neuroscience Center at Barnes-Jewish Hospital. “This is a unique collaboration that was possible at WU because we have some of the top experts in CAR T-cell therapy and leading expertise in neurodegenerative diseases. It presents a great opportunity to bridge gaps and bring these fields together to try to solve a vexing problem and help patients.”

References

Butt OH, Zhou AY, Caimi PF, et al. Assessment of pretreatment and posttreatment evolution of neurofilament light chain levels in patients who develop immune effector cell-associated neurotoxicity syndrome. JAMA Oncol. Published online September 1, 2022. doi:10.1001/jamaoncol.2022.3738