CAR+ extracellular vesicles predict ICANS in patients with B cell lymphomas treated with CD19-directed CAR T cells

Area of Science:

• Immunology
• Neuroscience
• Biomarker Discovery

Background:

• Predicting immune effector cell-associated neurotoxicity syndrome (ICANS) following CAR T cell infusion remains a significant clinical challenge.
• Current methods lack reliable biomarkers, as CAR T cells are scarce and undetectable shortly after infusion when ICANS typically develops.

Purpose of the Study:

• To investigate CAR+ extracellular vesicles (CAR+EVs) as early biomarkers for predicting ICANS in patients receiving CD19.CAR T cell therapy.
• To explore the role of CAR+EVs in the pathogenesis of ICANS.

Main Methods:

• Assessed CAR+EV release from CD19.CAR T cells co-cultured with CD19+ target cells in vitro.
• Quantified plasma CAR+EV levels in 100 patients with B cell lymphoma undergoing CD19.CAR T cell infusion.
• Utilized induced pluripotent stem cell-derived neural cells to model CAR+EV-induced neurotoxicity.

Main Results:

• CAR+EVs were released within 1 hour of target engagement in vitro and were detectable in patient plasma 1 hour post-infusion.
• Specific plasma CAR+EV concentrations at hour +1 and day +1 post-infusion accurately predicted ICANS onset up to 4 days in advance, outperforming existing predictors.
• ENO2+ nanoparticles, released by neural cells upon CAR+EV exposure, were elevated in ICANS patients' plasma.

Conclusions:

• Plasma CAR+EVs serve as an immediate indicator of CD19.CAR T cell activation.
• CAR+EVs are effective predictive biomarkers for ICANS, enabling early intervention.
• CAR+EVs may play a direct role in the development of ICANS pathogenesis.