Modulating immune responses to AAV by expanded polyclonal T-regs and capsid specific chimeric antigen receptor T-regulatory cells

Motahareh Arjomandnejad; Katelyn Sylvia; Meghan Blackwood; Thomas Nixon; Qiushi Tang; Manish Muhuri; Alisha M. Gruntman; Guangping Gao; Terence R. Flotte; Allison M. Keeler

Molecular Therapy: Methods & Clinical Development (Dec 2021)

Modulating immune responses to AAV by expanded polyclonal T-regs and capsid specific chimeric antigen receptor T-regulatory cells

Motahareh Arjomandnejad,
Katelyn Sylvia,
Meghan Blackwood,
Thomas Nixon,
Qiushi Tang,
Manish Muhuri,
Alisha M. Gruntman,
Guangping Gao,
Terence R. Flotte,
Allison M. Keeler

Affiliations

Motahareh Arjomandnejad: Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
Katelyn Sylvia: Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
Meghan Blackwood: Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
Thomas Nixon: Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
Qiushi Tang: Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
Manish Muhuri: Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
Alisha M. Gruntman: Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; Department of Pediatrics, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, Grafton, MA 01536, USA
Guangping Gao: Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
Terence R. Flotte: Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; Department of Pediatrics, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
Allison M. Keeler: Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; Department of Pediatrics, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; Corresponding author: Allison M. Keeler, PhD, Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.

Journal volume & issue: Vol. 23
pp. 490 – 506

Abstract

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Immune responses to adeno-associated virus (AAV) capsids limit the therapeutic potential of AAV gene therapy. Herein, we model clinical immune responses by generating AAV capsid-specific chimeric antigen receptor (AAV-CAR) T cells. We then modulate immune responses to AAV capsid with AAV-CAR regulatory T cells (Tregs). AAV-CAR Tregs in vitro display phenotypical Treg surface marker expression, and functional suppression of effector T cell proliferation and cytotoxicity. In mouse models, AAV-CAR Tregs mediated continued transgene expression from an immunogenic capsid, despite antibody responses, produced immunosuppressive cytokines, and decreased tissue inflammation. AAV-CAR Tregs are also able to bystander suppress immune responses to immunogenic transgenes similarly mediating continued transgene expression, producing immunosuppressive cytokines, and reducing tissue infiltration. Taken together, AAV-CAR T cells and AAV-CAR Tregs are directed and powerful immunosuppressive tools to model and modulate immune responses to AAV capsids and transgenes in the local environment.

Published in Molecular Therapy: Methods & Clinical Development

ISSN: 2329-0501 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Biology (General): Genetics; Science: Biology (General): Cytology
Website: http://www.cell.com/molecular-therapy-family/methods/latest-content

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