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

• Published in: Molecular therapy. Methods & clinical development Vol. 23; pp. 490 - 506
• Main Authors: Arjomandnejad, Motahareh, Sylvia, Katelyn, Blackwood, Meghan, Nixon, Thomas, Tang, Qiushi, Muhuri, Manish, Gruntman, Alisha M., Gao, Guangping, Flotte, Terence R., Keeler, Allison M.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 10.12.2021; American Society of Gene & Cell Therapy; Elsevier
• Subjects: 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; Original; AAV gene therapy; CAR Tregs; immune responses to AAV; immune responses to capsid; chimeric antigen receptor T-regulatory cells; CAR T regulatory cells; immunosuppression; immune responses to transgene
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2021.10.010

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. [Display omitted] We herein utilized AAV-CAR Tregs to create tolerogenic environments suppressing both capsid and AAV-delivered transgene responses allowing for continued transgene expression from transduced cells. This induced local immune tolerance may ultimately be safer clinically than systemic, broad-spectrum immune suppression.