CAR-T Cell-Mediated B-Cell Depletion in Central Nervous System Autoimmunity

Sasha Gupta, Milos Simic, Sharon A. Sagan, Chanelle Shepherd, Jason Duecker, Raymond A. Sobel, Ravi Dandekar, Gregory F. Wu, Wesley Wu, John E. Pak, Stephen L. Hauser, Wendell Lim, Michael R. Wilson, Scott S. Zamvil

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Background and ObjectivesAnti-CD20 monoclonal antibody (mAb) B-cell depletion is a remarkably successful multiple sclerosis (MS) treatment. Chimeric antigen receptor (CAR)-T cells, which target antigens in a non-major histocompatibility complex (MHC)-restricted manner, can penetrate tissues more thoroughly than mAbs. However, a previous study indicated that anti-CD19 CAR-T cells can paradoxically exacerbate experimental autoimmune encephalomyelitis (EAE) disease. We tested anti-CD19 CAR-T cells in a B-cell-dependent EAE model that is responsive to anti-CD20 B-cell depletion similar to the clinical benefit of anti-CD20 mAb treatment in MS.MethodsAnti-CD19 CAR-T cells or control cells that overexpressed green fluorescent protein were transferred into C57BL/6 mice pretreated with cyclophosphamide (Cy). Mice were immunized with recombinant human (rh) myelin oligodendrocyte protein (MOG), which causes EAE in a B-cell-dependent manner. Mice were evaluated for B-cell depletion, clinical and histologic signs of EAE, and immune modulation.ResultsClinical scores and lymphocyte infiltration were reduced in mice treated with either anti-CD19 CAR-T cells with Cy or control cells with Cy, but not with Cy alone. B-cell depletion was observed in peripheral lymphoid tissue and in the CNS of mice treated with anti-CD19 CAR-T cells with Cy pretreatment. Th1 or Th17 populations did not differ in anti-CD19 CAR-T cell, control cell-treated animals, or Cy alone.DiscussionIn contrast to previous data showing that anti-CD19 CAR-T cell treatment exacerbated EAE, we observed that anti-CD19 CAR-T cells ameliorated EAE. In addition, anti-CD19 CAR-T cells thoroughly depleted B cells in peripheral tissues and in the CNS. However, the clinical benefit occurred independently of antigen specificity or B-cell depletion.

Original languageEnglish
Article numbere200080
JournalNeurology: Neuroimmunology and NeuroInflammation
Volume10
Issue number2
DOIs
StatePublished - Mar 19 2023

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