Patient-reported outcomes and neurotoxicity markers in patients treated with bispecific LV20.19 CAR T cell therapy

• Published in: Communications medicine Vol. 2; no. 1; pp. 49 - 10
• Main Authors: Knight, Jennifer M., Szabo, Aniko, Arapi, Igli, Wu, Ruizhe, Emmrich, Amanda, Hackett, Edward, Sauber, Garrett, Yim, Sharon, Johnson, Bryon, Hari, Parameswaran, Schneider, Dina, Dropulic, Boro, Cusatis, Rachel N., Cole, Steve W., Hillard, Cecilia J., Shah, Nirav N.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.05.2022; Nature Portfolio
• Subjects: 631/67/1059/2325; 692/53/2423; 82/58; 82/79; Medicine; Medicine & Public Health; Cancer immunotherapy; Predictive markers
• ISSN: 2730-664X; 2730-664X
• DOI: 10.1038/s43856-022-00116-5

Background With the rising number of chimeric antigen receptor (CAR) T cell treated patients, it is increasingly important to understand the treatment’s impact on patient-reported outcomes (PROs) and, ideally, identify biomarkers of central nervous system (CNS) adverse effects. Methods The purpose of this exploratory study was to assess short-term PROs and serum kynurenine metabolites for associated neurotoxicity among patients treated in an anti-CD20, anti-CD19 (LV20.19) CAR T cell phase I clinical trial (NCT03019055). Fifteen CAR T treated patients from the parent trial provided serum samples and self-report surveys 15 days before and 14, 28, and 90 days after treatment. Results Blood kynurenine concentrations increased over time in patients with evidence of neurotoxicity ( p  = 0.004) and were increased in self-reported depression ( r  = 0.52, p  = 0.002). Depression improved after CAR T infusion ( p  = 0.035). Elevated 3-hydroxyanthranilic acid (3HAA) concentrations prior to cell infusion were also predictive of neurotoxicity onset ( p  = 0.031), suggesting it is a biomarker of neurotoxicity following CAR T cell therapy. Conclusions Elevated levels of kynurenine pathway metabolites among CAR T cell recipients are associated with depressed mood and neurotoxicity. Findings from this exploratory study are preliminary and warrant validation in a larger cohort. Plain language summary This study examined the impact of chimeric antigen receptor (CAR) T cell therapy—a therapy that gets immune cells to fight cancer by changing them in the lab to find and destroy cancer cells—on blood markers associated with depression, anxiety, pain, fatigue, and poor sleep. Fifteen CAR T cell patients provided blood samples and completed surveys before and three timepoints after treatment. We found that the amount of kynurenine, a normal blood constituent, and related molecules was higher in patients who experienced significant CAR T cell side effects on the brain and in patients reporting more depression. These results identify the excessive elevation of blood constituents related to the mood that may also be associated with depression and brain dysfunction following CAR T. These blood constituents could potentially be used as markers and targeted with interventions to prevent brain dysfunction. Knight et al. assess short-term patient-reported outcomes (PROs) and markers of neurotoxicity in patients with leukaemia or lymphoma treated with LV20.19 CAR T cells. In this small trial cohort, the authors report improvements in mood following CAR T infusion and identify kynurenine pathway molecules as potential markers of mood and neurotoxicity.