Localized PD-1 CAR T therapy reprograms neuroinflammation

Area of Science:

• Neuroimmunology
• Single-cell genomics
• Cellular therapy

Background:

• B cell-depleting therapies show efficacy in multiple sclerosis (MS) but patient relapse necessitates novel therapeutic targets.
• Understanding the specific immune cell interactions within the central nervous system (CNS) is crucial for developing precise MS interventions.

Purpose of the Study:

• To create a comprehensive single-cell RNA sequencing (scRNA-seq) atlas of the CNS and blood in MS and related neuroinflammatory diseases.
• To identify novel cellular targets and immune circuits implicated in MS pathogenesis.
• To develop and evaluate a novel cell-based therapy for MS.

Main Methods:

• Generation of an scRNA-seq atlas from cerebrospinal fluid (CSF), brain, and blood of controls and patients with MS or other neuroinflammatory diseases.
• Unbiased analysis to identify disease-associated cell populations.
• Development and testing of PD-1-directed chimeric antigen receptor (CAR) T cells in preclinical neuroinflammation models.

Main Results:

• Disease-associated enrichment of class-switched IgG+ B cells and plasma cells was observed in MS CSF.
• Identification of a rare, disease-enriched subset of activated, PD-1+ T follicular helper-like cells with B cell-recruiting properties.
• PD-1 CAR T cells selectively depleted pathogenic PD-1+ CD4 T cells, released IL-10, attenuated CNS inflammation, and improved clinical outcomes in murine models.

Conclusions:

• A CNS-localized adaptive immune circuit involving specific T and B cell subsets is implicated in MS.
• Programmable PD-1 CAR T cells represent a promising therapeutic strategy to disrupt this circuit and treat MS.