Chimeric Antigen Receptor T Cell-Mediated Neurotoxicity in Nonhuman Primates

Area of Science:

• Immunotherapy
• Oncology
• Neuroscience

Background:

• Chimeric antigen receptor (CAR) T-cell immunotherapy is effective against leukemias and lymphomas but causes toxicities like cytokine release syndrome (CRS) and neurotoxicity.
• A lack of relevant models hinders the development of therapies to prevent CAR T-cell-mediated neurotoxicity.

Purpose of the Study:

• To establish a clinically relevant nonhuman primate (NHP) model for studying CAR T-cell-induced neurotoxicity.
• To investigate the immunological mechanisms underlying CAR T-cell-mediated neurotoxicity.

Main Methods:

• Adoptive transfer of autologous CD20-specific CAR T cells into rhesus macaques (RMs) following cyclophosphamide lymphodepletion.
• Monitoring of CAR T-cell expansion, clinical toxicities (CRS and neurotoxicity), serum and cerebrospinal fluid (CSF) cytokine levels.
• Analysis of T-cell infiltration in CSF and brain parenchyma during neurotoxicity.

Main Results:

• CD20 CAR T cells expanded robustly in RMs, inducing CRS and neurotoxicity.
• Neurotoxicity was associated with elevated serum and CSF inflammatory cytokines, including IL6, IL2, GM-CSF, and VEGF.
• Both CAR T cells and non-CAR T cells infiltrated the CSF and brain parenchyma during neurotoxicity, leading to pan-T cell encephalitis.

Conclusions:

• The developed RM model is the first immunologically relevant NHP model for studying CRS and neurotoxicity associated with B cell-directed CAR T-cell therapy.
• CAR T-cell-mediated neurotoxicity involves proinflammatory CSF cytokines and a pan-T cell encephalitis characterized by T-cell infiltration in the brain.