2. Academic Validation
  3. Chimeric antigen receptor macrophages target and resorb amyloid plaques

Chimeric antigen receptor macrophages target and resorb amyloid plaques

  • JCI Insight. 2024 Feb 6;9(6):e175015. doi: 10.1172/jci.insight.175015.
Alexander B Kim 1 2,  Qingli Xiao 3 4,  Ping Yan 3 4,  Qiuyun Pan 1 2,  Gaurav Pandey 1 2,  Susie Grathwohl 3 4,  Ernesto Gonzales 3 4,  Isabella Xu 3 4,  Yoonho Cho 3 4,  Hans Haecker 5,  Slava Epelman 6,  Abhinav Diwan 3 4 7 8,  Jin-Moo Lee 3 4,  Carl J DeSelm 1 2
Affiliations

Affiliations

  • 1 Department of Radiation Oncology.
  • 2 Bursky Center for Human Immunology and Immunotherapy.
  • 3 Department of Neurology, and.
  • 4 Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA.
  • 5 Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
  • 6 Department of Medicine, Division of Cardiology, Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
  • 7 Departments of Medicine, Cell Biology and Physiology, Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri, USA.
  • 8 Medicine Service, St. Louis VA Medical Center, St. Louis, Missouri, USA.
PMID: 38516884 DOI: 10.1172/jci.insight.175015
Abstract

Substantial evidence suggests a role for immunotherapy in treating Alzheimer's disease (AD). While the precise pathophysiology of AD is incompletely understood, clinical trials of Antibodies targeting aggregated forms of β amyloid (Aβ) have shown that reducing amyloid plaques can mitigate cognitive decline in patients with early-stage AD. Here, we describe what we believe to be a novel approach to target and degrade amyloid plaques by genetically engineering macrophages to express an Aβ-targeting chimeric antigen receptor (CAR-Ms). When injected intrahippocampally, first-generation CAR-Ms have limited persistence and fail to significantly reduce plaque load, which led us to engineer next-generation CAR-Ms that secrete M-CSF and self-maintain without exogenous cytokines. Cytokine secreting "reinforced CAR-Ms" have greater survival in the brain niche and significantly reduce plaque load locally in vivo. These findings support CAR-Ms as a platform to rationally target, resorb, and degrade pathogenic material that accumulates with age, as exemplified by targeting Aβ in AD.

Keywords

Aging; Alzheimer disease; Immunotherapy; Macrophages; Therapeutics.

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