Neetu Gupta, Ph.D., MSc, BSc from the Cleveland Clinic speaks about the ASH 2020 abstract – 1447 Unbiased Metabolomic Screening Reveals Pre-Existing Plasma Signatures in Large B-Cell Lymphoma Patients Treated with Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cells: Association with Cytokine Release Syndrome (CRS) and Neurotoxicity (ICANS).
Context:
The FDA has approved CAR T-cells that target CD19 for the treatment of relapsed/refractory large B cell lymphoma (r/r LBCL). The advantage of this strategy is also complicated by potentially serious toxicities, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome, despite clinical effectiveness in chemo-refractory patients (ICANS). The physiological basis of these limitations remains poorly understood and reflects a therapeutic need that has not been met. Metabolomics is a global approach that can be used to classify diverse biochemical entities with a broad variety of roles that are low molecular weight. We used an untargeted metabolomics method in this research to classify novel plasma metabolites in patients treated with CAR T-cell therapy that are correlated with clinical outcomes and treatment toxicity.
Methodology:
Peripheral blood samples from 41 r/r LBCL patients treated with Axicabtagene Ciloleucel (Axi-cel; n=31) and Tisagenlecleucel (Tisa-cel; n=10) were obtained at the time of apheresis. For all patients, baseline clinical characteristics and descriptions of previous care were captured. Response results and grading of toxicity as calculated for CRS and ICANS by ASTCT consensus criteria were registered. Using a commercial Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectrometry platform, plasma was extracted from blood and analysed for metabolites. Using ordinal logistic regression, association analysis was performed to classify the metabolites whose plasma abundance correlated with ICANS and CRS grade at the time of apheresis (FDR 0.2). In addition, to classify disruptions of biologically important pathways associated with grade CRS/ICANS, substantial metabolites were used.
Outcomes:
With 25 (61 percent) males, the median age of patients surveyed was 61 (range 25-77). Both patients have had R-CHOP or R-EPOCH treated previously. At baseline, 20 (48.8 percent) patients had high or high-intermediate IPI. Until CAR T-cell therapy, patients had undergone a median of 3 (range, 2-6) lines of therapy, with 21 (51.22 percent) having received previous autologous stem cell transplantation. Answer assessment was available for 28 Axi-cel recipients and 10 Tisa-cel recipients at the 3-month time point. In 16 (57 percent) and 2 (20 percent) patients, objective response was seen and death was reported in 3 (11 percent) and 2 (20 percent) patients, respectively, in the Axi-cel and Tisa-cel classes. A total of 1,241 metabolites identified in positive, negative, and polar modes, of which 1,011 were called, were discovered by untargeted metabolomics. These involve lipids, amino acids, xenobiotics, nucleotides, compounds, cofactors, and vitamins that have been partly characterized. Three metabolites whose abundance was negatively correlated with ICANS grade (FDR ⇠0.2) were identified while analyzing the toxicity of CAR-T cell care, suggesting that a high abundance of these metabolites was associated with a reduced risk of (i.e. safety from) ICANS at the time of apheresis. CRS was also associated with plasma metabolites, with 23 associated with an increased risk (i.e. predisposition to CRS and 204 associated with a reduced risk i.e. safety from CRS. Caffeine metabolism, glycine, serine, and threonine metabolism, arginine biosynthesis, and aminoacyl-tRNA biosynthesis were classified as the most significantly represented pathways, using a hypergeometric test for over-represented metabolites in the KEGG metabolic pathways (FDR 0.2).
The Conclusion:
At the time of apheresis, pre-existing biochemical signatures present in plasma are closely correlated with toxicity observed in response to commercial CD19 CAR T-cell therapy. These endogenous metabolites may be used as biomarkers to monitor the risk of toxicity associated with the treatment of CD19 CAR T cells and provide insight into rational clinical approaches to reduce these risks.