Robust CD4 ⁺ CAR T cell expansion is associated with non-ICANS neurotoxicities after ciltacabtagene autoleucel in patients with multiple myeloma

Nonimmune effector cell–associated neurotoxicity syndrome neurotoxicities (NINTs) are serious, atypical toxicities associated with ciltacabtagene autoleucel (cilta-cel), a US Food and Drug Administration chimeric antigen receptor T cell (CAR T cell) therapy approved for relapsed/refractory multiple myeloma (RRMM). Risk factors contributing to the development of NINTs are poorly understood. In a cohort of 109 patients with RRMM treated with cilta-cel, we identify predisposing risk factors and propose strategies to mitigate NINTs. We show that high-peak absolute lymphocyte count is a strong NINT predictor, which directly correlates with flow cytometry–based peripheral blood CAR T cell quantitation. The observed CAR lymphocytosis was polyclonal with a bias toward CD4 ⁺ CAR T cells rich in memory marker expression. We then identified CAR lymphocytosis–associated CD4 ⁺ CAR T cell populations, which exhibited increased inflammatory pathway gene expression. Last, we characterize NINT-associated CD4 ⁺ CAR T cell populations, which are potential therapeutic targets for future exploration.