Host metabolome predicts the severity and onset of acute toxicities induced by CAR T-cell therapy

Abstract

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is a highly effective treatment option for patients with relapsed/refractory large B cell lymphoma (r/r LBCL). However, widespread use is deterred by development of clinically significant acute inflammatory toxicities, including cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS), that induce significant morbidity and require close monitoring. Identification of host biochemical signatures that predict the severity and time-to-onset of CRS and ICANS may assist patient stratification to enable timely mitigation strategies. Here, we report pre-treatment host metabolites that are associated with CRS and ICANS induced by Axicabtagene Ciloleucel or Tisagenlecleucel therapy. Both untargeted metabolomics analysis and validation using targeted assays revealed significant association between the abundance of specific pre-treatment biochemical entities and an increased risk and/or onset of clinically significant CRS (q<.1) and ICANS (q<.25). Higher pre-treatment levels of plasma glucose, and lower levels of cholesterol and glutamate were associated with faster onset of CRS. On the other hand, low baseline levels of amino acids proline and glycine and secondary bile acid isoursodeoxycholate were significantly correlated with clinically significant CRS. Lower concentration of the amino acid hydroxyproline was associated with higher grade and faster onset of ICANS, whereas low glutamine was negatively correlated with faster development of ICANS. Overall, our data indicate that the pre-treatment host metabolome has biomarker potential in determining the risk of clinically significant CRS and ICANS, and may be useful in risk stratification of patients prior to anti-CD19 CAR T-cell therapy.