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.

Bendamustine lymphodepletion before axicabtagene ciloleucel is safe and associates with reduced inflammatory cytokines

“…Lastly, the mechanisms underlying the differential toxicities reported for patients treated with Benda vs those treated with Flu/Cy are still unclear. Previous studies demonstrated that cytokines and serum metabolites are associated with systemic inflammation 14 , 15 and that chemotherapy can directly modify their circulating levels. 16 , 17 However, the direct contribution of LD in generating a cytokine and metabolic environment promoting the onset of CART-related toxicities has, to our knowledge, not been investigated to date.…”

Riding the storm: managing cytokine-related toxicities in CAR-T cell therapy

“…Pennisi et al modified the Endothelial Activation and Stress Index (EASIX) score, used to predict outcomes in HSCT, by replacing creatinine with CRP to create the formula lactate dehydrogenase (LDH) x CRP/platelet count and found good association between development of severe CRS and ICANS and this modified score [ 47 ]. In a unique approach, Jalota et al explored pretreatment metabolic parameters and found that higher glucose, lower glutamine, and lower cholesterol were associated with earlier onset CRS [ 48 ]. While several of these boast remarkable specificities/sensitivities, their utility in prospective risk stratification is yet to be determined.…”