Table 1.

(a) Registered clinical trials and case reports using different CAR T-cell types for the treatment of autoimmune diseases of the CNS (b)Published results from clinical trials and case reports using different CAR T cell types for the treatment of autoimmune diseases of the CNS

Registered clinical trials and case reports using different CAR T-cell types for the treatment of neurological autoimmune diseases of the CNS
Title	Participants	Indication	NCT Number	Location	Status	Target antigen	Primary endpoints
NMOSD
Treatment of Relapsed and/or Refractory AQP4-IgG Seropositive NMOSD by Tandem CAR T Cells Targeting CD19 and CD20, phase I studyb	No information provided	AQP4-IgG seropositive NMOSD	NCT03605238	Beijing, Beijing, China	Withdrawn (recruitment failure)	CD19 and CD20	- Occurrence of AEs from baseline to 12 months post-infusion
Evaluate the Safety and Efficacy of CAR-T Cells in the Treatment of R/R NMOSD, phase I, single-arm, open-label, single-center studyb	Estimated Enrollment: n = 9	Relapsed and/or Refractory NMOSD	NCT05828212	Hangzhou, Zhejiang, China	Recruiting	CD19	- DLT from baseline to 28 days post- infusion - AE and SAE from admission to end of follow-up, up to 2 years - Maximum tolerable dose
MS
Study of KYV-101, an Autologous Fully Human Anti-CD19 CAR T-cell Therapy, in Subjects with Refractory Primary and Secondary Progressive MS (KYSA-7), phase II, open-label, randomized, multicenter studya	Estimated Enrollment: n = 120	Primary and secondary progressive MS	NCT06384976	Location not provided	Not yet recruiting	CD19	Efficacy of KYV-101 from baseline to 12 months post-infusion by rating disability on the EDSS scale
A Study to Evaluate the Safety, Tolerability, Efficacy, and Drug Levels of CC-97540 in Participants with Relapsing or Progressive Forms of MS, phase I, multicenter, single-arm studyb	Estimated Enrollment: n = 98	Relapsing and progressive MS	NCT06220201	United States, Belgium, France, Germany, Italy, Spain, United Kingdom	Recruiting	CD19A	Up to week 104 post-infusion: - Number of participants with AEs, SAEs and AESIs - Number of participants with laboratory test result abnormalities - Number of participants with imaging abnormalities - Number of participants with DLTs - Recommended Phase 2 dose based on the incidence of DLTs
A Study of Anti-CD19 CAR T-cell Therapy in Subjects with Non-relapsing and Progressive Forms of MS, a phase I, open-Label, single Center Studyb	Estimated Enrollment: n = 12	Progressive MS	NCT06138132	Palo Alto, California, United States	Recruiting	CD19	Frequency of DLT at each dose level up to 12 months post-infusion
A Study of KYV-101, a CD19 CAR T Cell Therapy, in Participants with Treatment Refractory Progressive Multiple Sclerosis, phase I, open-label, Single Center Studyb	Estimated Enrollment: n = 10	Progressive MS	NCT06451159	University of California, San Francisco, United States	Recruiting	CD19	- The presence of CAR-T cells in CSF following their peak expansion in peripheral blood up to 48 weeks post-infusion - Incidence and severity of AEs and DLTs up to 48 weeks post-infusion
Basket trials
A Study of C-CAR168 in the Treatment of Autoimmune Diseases Refractory to Standard Therapy, phase I, multicenter, open-label studyb	Estimated Enrollment: n = 30	NMOSD RRMS Mediated Necrotizing Myopathy SLE	NCT06249438	Shanghai, Shanghai, China	Recruiting	CD20 and BCMA	- Incidence of AEs throughout the first 24 months post-infusion - Recommended dose of C-CAR168 based on DLTs rates and overall safety profile
Safety and Efficacy of CT103A Cells for Relapsed/Refractory Antibody-associated Inflammatory Diseases of the Nervous System, early phase I, open-label studyb	Estimated Enrollment: n = 36	MS, AQP4-IgG seropositive NMOSD, MOGAD, AE, CIDP, IIM, MG, POEMS Syndrome	NCT04561557	Wuhan, Hubei, China	Recruiting, first results published (see below)	BCMA	- DLT from baseline to 3 months post-infusion - Incidence and severity of AEs up to 2 years post-infusion
Universal CAR-T Cells in Patients with Refractory Autoimmune Diseases of the Nervous System, early phase I, open-label, Single Center Studyb	Estimated Enrollment: n = 25	MS, NMOSD, MG, CIDP	NCT06485232	Beijing, China	Not yet recruiting	CD19 and BCMA	- Incidence of DLTs the first 28 days after infusion - Incidence of AEs and SAEs up to 12 months after infusion

Published results
Title	Participants	Indication	Target antigen	Primary endpoints	Exploratory outcomes	Adverse events	Laboratory results
Clinical trials
Anti-BCMA CAR T-cell therapy (CT103A) in relapsed or refractory AQP4-IgG seropositive neuromyelitis optica spectrum disorders: phase I trial interim results, CARTinNS, 01/2023, from trial NCT04561557,b [46]	n = 12	AQP4-IgG seropositive NMOSD	BCMA	- DLT after CT103A cells infusion up to 3 months post-infusion - Incidence and severity of AEs up to 2 years post-infusion	- No relapse reported in 11 of 12 patients (92%) at 5.5 months. - All corticosteroids and immunosuppressants were discontinued. - Disabilities and quality-of-life outcomes improved in all patients	- Grade 1–2 CRS reported in all patients. - Grade 3 or higher AEs occurred including neutropenia (n = 12), anemia (n = 6), and thrombocytopenia (n = 3). - Infections (n = 7), including 3 with serious CMV infections and 1 with pneumonia	- Serum AQP4-IgG for all participants decreased after infusion, and was negative by 12 weeks in 7/10 patients (70%), and by 6 months in 5/6 patients (83%). - Serum BCMA levels reduced below the lower limit of detection within 1-month post-infusion and returned to baseline levels by 6 months. - Significant decrease in total serum immunoglobin after infusion in all patients
Case studies
CD19-targeted chimeric antigen receptor T-cell therapy in two patients with MS, Hamburg, Germany, 01/2024,e [44]	n = 2	MS	CD19	–	- Pat. 1: EDSS score increased to 6.0 before returning to baseline (4.5) by day 29 and remaining stable. Walking distance increased from 400 m at baseline to 700 m at day 100 post-infusion. - Pat. 2: EDSS remained stable. - Other neurological assessments including timed 25-ft walk, 9-hole peg test, and 6-min walking distance matched pre-infusion scores in both patients	- Pat. 1: CRS grade 1, with facial and neck swelling and transient increase in transaminases. - Pat. 2: transient increase of transaminases (CTCAE grade 3) which improved with ursodeoxycholic acid. - No other adverse events occurred	- Pat. 1: OCBs decreased from 13 to 6 on day 14 after infusion and were sustained through day 64. - Pat. 2: Number of OCBs and intrathecal immunoglobulin levels remained stable - The residual B-cell population of patient 1 was depleted by day 2 post-infusion and has not reconstituted as of day 100. B-cell population of Pat. 2 was already depleted prior to CAR T-cell infusion. - Reduced serum immunoglobulin G was observed in both patients at day 14 post-infusion
Successful use of anti-CD19 CAR T cells in severe treatment-refractory stiff-person syndrome, Germany, 06/2024,e [47]	n = 1	SPS	CD19	–	- Reduced pain and leg stiffness in a 5-month follow-up. - Walking speed increase over 100%. - Daily walking distance improvement from < 50 m to > 6 km within 3 months - GABAergic medication (benzodiazepines) was reduced by 40%. - No immunotherapy was administered post-CAR T cell infusion	- Grade 2 CRS with fever (maximum of 38.3 °C) and transient hypotension successfully treated with paracetamol, dexamethasone, and tocilizumab. - Sore throat and cervical lymph node swelling were observed on day + 9 after CAR T-cell infusion. - Transient increase of transaminases (spontaneously reversible)	- Anti-GAD65 titers in serum decreased from 1:3.200 at baseline to 1:1.000 at day + 56 and to 1:320 by day + 144. - B-cell levels were low following previous immunotherapy and remained low

Results from ClinicalTrials.gov: CAR T cells + multiple sclerosis: 7 results, CAR T cells + NMOSD = 5 results (3 duplicates), CAR T cells + MOG = 1 result (duplicate), and CAR T cells + autoimmune encephalitis: 1 result (duplicate)

MS multiple sclerosis, RRMS relapsing–remitting MS, MG myasthenia gravis, NMOSD neuromyelitis optica spectrum disorders, MOGAD myelin oligodendrocyte glycoprotein antibody-associated disease, SPS stiff-person syndrome, CAR chimeric antigen receptor, BCMA B-cell maturation antigen, AQP4 Aquaporin-4, IgG immunoglobulin G, CRS cytokine release syndrome, ICANS immune effector cell-associated neurotoxicity syndrome, CSF cerebrospinal fluid, SLE systemic lupus erythematosus, CIPD chronic inflammatory demyelinating polyneuropathy, IIM idiopathic inflammatory myopathy, EDSS expanded disability status scale, OCB oligoclonal bands, CTCAE common terminology criteria for adverse events, AE adverse events, DLT dose-limiting toxicity, SAE serious adverse events, AESIs adverse events of special interest

^ANEX-T CAR T cells; a process designed to shorten manufacturing time and improve the potency and phenotypic attributes of the CAR T-cell drug product to enhance depth and durability of response [49]

^a–eQuality Rating Scheme for Studies and Other Evidence: ^aProperly powered and conducted randomized clinical trial; systematic review with meta-analysis, ^bWell-designed controlled trial without randomization; prospective comparative cohort trial, ^cCase–control studies; retrospective cohort study, ^dCase series with or without intervention; cross-sectional study, ^eOpinion of respected authorities; case reports.