Back to Search
Start Over
AAV-mediated gene transfer of a checkpoint inhibitor in combination with HER2-targeted CAR-NK cells as experimental therapy for glioblastoma.
- Source :
-
Oncoimmunology [Oncoimmunology] 2022 Oct 11; Vol. 11 (1), pp. 2127508. Date of Electronic Publication: 2022 Oct 11 (Print Publication: 2022). - Publication Year :
- 2022
-
Abstract
- Glioblastoma (GB) is the most common primary brain tumor, which is characterized by low immunogenicity of tumor cells and prevalent immunosuppression in the tumor microenvironment (TME). Targeted local combination immunotherapy is a promising strategy to overcome these obstacles. Here, we evaluated tumor-cell specific delivery of an anti-PD-1 immunoadhesin (aPD-1) via a targeted adeno-associated viral vector (AAV) as well as HER2-specific NK-92/5.28.z (anti-HER2.CAR/NK-92) cells as components for a combination immunotherapy. In co-culture experiments, target-activated anti-HER2.CAR/NK-92 cells modified surrounding tumor cells and bystander immune cells by triggering the release of inflammatory cytokines and upregulation of PD-L1. Tumor cell-specific delivery of aPD-1 was achieved by displaying a HER2-specific designed ankyrin repeat protein (DARPin) on the AAV surface. HER2-AAV mediated gene transfer into GB cells correlated with HER2 expression levels, without inducing anti-viral responses in transduced cells. Furthermore, AAV-transduction did not interfere with anti-HER2.CAR/NK-92 cell-mediated tumor cell lysis. After selective transduction of HER2 <superscript>+</superscript> cells, aPD-1 expression was detected at the mRNA and protein level. The aPD-1 immunoadhesin was secreted in a time-dependent manner, bound its target on PD-1-expressing cells and was able to re-activate T cells by efficiently disrupting the PD-1/PD-L1 axis. Moreover, high intratumoral and low systemic aPD-1 concentrations were achieved following local injection of HER2-AAV into orthotopic tumor grafts in vivo . aPD-1 was selectively produced in tumor tissue and could be detected up to 10 days after a single HER2-AAV injection. In subcutaneous GL261-HER2 and Tu2449-HER2 immunocompetent mouse models, administration of the combination therapy significantly prolonged survival, including complete tumor control in several animals in the GL261-HER2 model. In summary, local therapy with aPD-1 encoding HER2-AAVs in combination with anti-HER2.CAR/NK-92 cells may be a promising novel strategy for GB immunotherapy with the potential to enhance efficacy and reduce systemic side effects of immune-checkpoint inhibitors.<br />Competing Interests: J.P.S has a consulting or advisory board membership with, or has received honoraria or travel or accommodation expenses from AbbVie, Medac, Novocure, Roche, and UCB. M.C.B has received honoraria for lectures or advisory board participation from Bristol-Myers Squibb and Gilead Sciences. All other authors report no conflict of interest.<br /> (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)
- Subjects :
- Adenoviridae genetics
Animals
B7-H1 Antigen genetics
Cell Line, Tumor
Cytokines
Immune Checkpoint Inhibitors pharmacology
Immune Checkpoint Inhibitors therapeutic use
Killer Cells, Natural metabolism
Killer Cells, Natural transplantation
Mice
RNA, Messenger
Receptor, ErbB-2 metabolism
Therapies, Investigational
Tumor Microenvironment
Glioblastoma genetics
Glioblastoma therapy
Subjects
Details
- Language :
- English
- ISSN :
- 2162-402X
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Oncoimmunology
- Publication Type :
- Academic Journal
- Accession number :
- 36249274
- Full Text :
- https://doi.org/10.1080/2162402X.2022.2127508