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

doi:10.1016/j.omtm.2021.10.010

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

Mol Ther Methods Clin Dev. 2021 Oct 28:23:490-506. doi: 10.1016/j.omtm.2021.10.010. eCollection 2021 Dec 10.

Authors

Motahareh Arjomandnejad¹, Katelyn Sylvia¹, Meghan Blackwood¹, Thomas Nixon¹, Qiushi Tang¹, Manish Muhuri^{1

2}, Alisha M Gruntman^{1

3

4}, Guangping Gao^{1

2

5}, Terence R Flotte^{1

3}, Allison M Keeler^{1

3

5}

Affiliations

¹ Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
² Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
³ Department of Pediatrics, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
⁴ Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, Grafton, MA 01536, USA.
⁵ NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.

Abstract

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.

Keywords: AAV gene therapy; CAR T regulatory cells; CAR Tregs; chimeric antigen receptor T-regulatory cells; immune responses to AAV; immune responses to capsid; immune responses to transgene; immunosuppression.

Abstract

Grants and funding