Pre-infusion plasma proteomics identifies an endothelial–immune priming signature predictive of severe cytokine release syndrome and neurotoxicity following CAR T-cell therapy in relapsed/refractory lymphoma

Chimeric antigen receptor (CAR) T-cell therapy has transformed treatment for relapsed /refractory(r/r) lymphoid malignancies. Yet, these cellular immunotherapies are often associated with immune-related adverse events (irAEs), namely cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), that pose significant risks to patient safety and limit broader clinical implementation of CAR T-cell therapies. In the current study, we used proteomics technology to establish circulating protein signatures that would predict severe CRS and ICANS in r/r lymphoma patients that subsequently received CAR T-cell therapy. Initial discovery was performed using plasma samples collected preceding CAR T-cell infusion from 39 r/r lymphoma patients at MD Anderson Cancer Center. A 5-marker and 8-marker protein panel was developed for predicting Grade ≥ 2 CRS and ICANS respectively, yielding respective AUCs of 0.85 [95% CI: 0.72-0.98] and 0.91 [95% CI: 0.81-1.00]. Independent testing of the CRS and ICANS panel was performed in a cohort of 59 r/r lymphoma patients from the Moffitt Cancer Center, with resultant AUCs of 0.76 [95% CI: 0.63-0.89] and 0.67 [95% CI: 0.51-0.84] for the CRS and ICANS panel, respectively. Patients were further classified into low-, intermediate-, and high-risk groups based on panel score tertiles. In the combined dataset (MDACC + Moffitt), compared to patients in the low-risk group (reference), patients in the intermediate-and high-risk groups were 3.15 [95% CI: 0.92-12.71] and 13.84 [95% CI: 4.21-56.26] more likely to have Grade ≥ 2 CRS, and 1.21 [95% CI: 0.36-4.23] and 8.59 [95% CI: 2.87-29.09] more likely to have Grade ≥2 ICANS. The protein biomarker panels provide a means to risk stratify patients who are at high risk for developing severe CRS and ICANS, to inform on the need for prophylactic interventions and improve patient outcomes.