Chimeric Antigen Receptor T Cell-Mediated Neurotoxicity in Non-Human Primates [Research Articles]

Chimeric Antigen Receptor (CAR) T cell immunotherapy has revolutionised the treatment of refractory leukemias and lymphomas, but is associated with significant toxicities, namely cytokine release syndrome (CRS) and neurotoxicity. A major barrier to developing therapeutics to prevent CAR T cell-mediated neurotoxicity is the lack of clinically relevant models. Accordingly, we developed a rhesus macaque (RM) model of neurotoxicity via adoptive transfer of autologous CD20-specific CAR T cells. Following cyclophosphamide lymphodepletion, CD20 CAR T cells expand to 272-4450 cells/µl after 7-8 days and elicit CRS and neurotoxicity. Toxicities are associated with elevated serum IL-6, IL-8, IL-1RA, MIG and I-TAC levels, and disproportionately high cerebrospinal fluid (CSF) IL-6, IL-2, GM-CSF and VEGF levels. During neurotoxicity, both CD20 CAR and non-CAR T cells accumulate in the CSF and in the brain parenchyma. This RM model demonstrates that CAR T cell-mediated neurotoxicity is associated with pro-inflammatory CSF cytokines and a pan-T cell encephalitis.

http://ift.tt/2IHDXJS