While chimeric antigen receptor (CAR) T cell therapy has shown promising outcomes among patients with hematologic malignancies, it has also been associated with undesirable side-effects such as cytokine release syndrome (CRS). CRS is triggered by CAR T-cell-based activation of monocytes, which are stimulated via the CD40L–CD40R axis or via uptake of GM-CSF to secrete proinflammatory cytokines. Mouse models have been used to model CRS, but working with them is labor-intensive and they are not amenable to screening approaches. To overcome this challenge, we established two simple cell-based CRS in vitro models that entail the co-culturing of leukemic B cells with CD19-targeting CAR T cells and primary monocytes from the same donor. Upon antigen encounter, CAR T cells upregulated CD40L and released GM-CSF which in turn stimulated the monocytes to secrete IL-6. To endorse these models, we demonstrated that neutralizing antibodies or genetic disruption of the CD40L and/or CSF2 loci in CAR T cells using CRISPR-Cas technology significantly reduced IL-6 secretion by bystander monocytes without affecting the cytolytic activity of the engineered lymphocytes in vitro. Overall, our cell-based models were able to recapitulate CRS in vitro, allowing us to validate mitigation strategies based on antibodies or genome editing.

Chimeric antigen receptor (CAR) T‐cell therapy has been investigated in neurological diseases, encompassing both central nervous system malignancies and autoimmune disorders, thereby extending its application beyond hematological cancers. This scoping review evaluates CAR T‐cell therapy applications in neurological conditions, assessing therapeutic efficacy, safety profiles, and neurotoxicity management strategies. A literature search across four databases (January 2020–December 2025) identified 33 studies meeting the inclusion criteria, encompassing original and secondary research from international centers. CAR T‐cell therapy demonstrated promising efficacy across diverse neurological conditions. In glioblastoma trials, 44% of patients ( n = 128) achieved partial or complete clinical/radiographic responses with favorable safety profiles. Moreover, compelling results emerged from neuromyelitis optica spectrum disorder studies, in which 92% of patients (11/12) achieved sustained relapse‐free remission over a median follow‐up of 5.5 months. Multiple sclerosis, myasthenia gravis, and stiff‐person syndrome cases exhibited excellent treatment tolerance without significant immune effector cell‐associated neurotoxicity syndrome (ICANS), which is a major concern affecting 27% of patients with hematological malignancies. Overall, CAR T‐cell therapy emerges as a novel therapeutic strategy in neurology, encompassing both oncological and autoimmune conditions. Toxicity profiles in neurological CAR T‐cell applications differ substantially from those observed in hematologic malignancies, underscoring the need for condition‐specific risk assessment frameworks and customized management approaches. Future research should prioritize larger multicenter trials with extended follow‐up to establish definitive efficacy and safety profiles in neurological indications.