AAV-mediated gene transfer of a checkpoint inhibitor in combination with HER2-targeted CAR-NK cells as experimental therapy for glioblastoma
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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | OncoImmunology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2022.2127508 |
| _version_ | 1797995666086035456 |
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| author | M.I. Strecker K. Wlotzka F. Strassheimer B. Roller G. Ludmirski S. König J. Röder C. Opitz T. Alekseeva J. Reul L. Sevenich T. Tonn W.S. Wels J.P. Steinbach C.J. Buchholz M.C. Burger |
| author_facet | M.I. Strecker K. Wlotzka F. Strassheimer B. Roller G. Ludmirski S. König J. Röder C. Opitz T. Alekseeva J. Reul L. Sevenich T. Tonn W.S. Wels J.P. Steinbach C.J. Buchholz M.C. Burger |
| author_sort | M.I. Strecker |
| collection | DOAJ |
| description | 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+ 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. |
| first_indexed | 2024-04-11T10:05:19Z |
| format | Article |
| id | doaj.art-94d82fff92f741b8ae2df7293f6ae1d4 |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-04-11T10:05:19Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-94d82fff92f741b8ae2df7293f6ae1d42022-12-22T04:30:15ZengTaylor & Francis GroupOncoImmunology2162-402X2022-12-0111110.1080/2162402X.2022.2127508AAV-mediated gene transfer of a checkpoint inhibitor in combination with HER2-targeted CAR-NK cells as experimental therapy for glioblastomaM.I. Strecker0K. Wlotzka1F. Strassheimer2B. Roller3G. Ludmirski4S. König5J. Röder6C. Opitz7T. Alekseeva8J. Reul9L. Sevenich10T. Tonn11W.S. Wels12J.P. Steinbach13C.J. Buchholz14M.C. Burger15Senckenberg Institute of Neurooncology, Goethe University, Frankfurt, GermanySenckenberg Institute of Neurooncology, Goethe University, Frankfurt, GermanySenckenberg Institute of Neurooncology, Goethe University, Frankfurt, GermanySenckenberg Institute of Neurooncology, Goethe University, Frankfurt, GermanySenckenberg Institute of Neurooncology, Goethe University, Frankfurt, GermanySenckenberg Institute of Neurooncology, Goethe University, Frankfurt, GermanyFrankfurt Cancer Institute, Goethe University, Frankfurt, GermanyInstitute for Transfusion Medicine, German Red Cross Blood Donation Service North-East and Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, GermanyFrankfurt Cancer Institute, Goethe University, Frankfurt, GermanyPaul-Ehrlich-Institut, Molecular Biotechnology and Gene Therapy, Langen, GermanyGerman Cancer Consortium (DKTK), partner site Frankfurt/Mainz, Frankfurt, GermanyInstitute for Transfusion Medicine, German Red Cross Blood Donation Service North-East and Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, GermanyGerman Cancer Consortium (DKTK), partner site Frankfurt/Mainz, Frankfurt, GermanySenckenberg Institute of Neurooncology, Goethe University, Frankfurt, GermanyFrankfurt Cancer Institute, Goethe University, Frankfurt, GermanySenckenberg Institute of Neurooncology, Goethe University, Frankfurt, GermanyGlioblastoma (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+ 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.https://www.tandfonline.com/doi/10.1080/2162402X.2022.2127508Immunotherapytumor targetingcheckpoint inhibitionCAR-NK celladeno-associated virusHER2 |
| spellingShingle | M.I. Strecker K. Wlotzka F. Strassheimer B. Roller G. Ludmirski S. König J. Röder C. Opitz T. Alekseeva J. Reul L. Sevenich T. Tonn W.S. Wels J.P. Steinbach C.J. Buchholz M.C. Burger AAV-mediated gene transfer of a checkpoint inhibitor in combination with HER2-targeted CAR-NK cells as experimental therapy for glioblastoma OncoImmunology Immunotherapy tumor targeting checkpoint inhibition CAR-NK cell adeno-associated virus HER2 |
| title | AAV-mediated gene transfer of a checkpoint inhibitor in combination with HER2-targeted CAR-NK cells as experimental therapy for glioblastoma |
| title_full | AAV-mediated gene transfer of a checkpoint inhibitor in combination with HER2-targeted CAR-NK cells as experimental therapy for glioblastoma |
| title_fullStr | AAV-mediated gene transfer of a checkpoint inhibitor in combination with HER2-targeted CAR-NK cells as experimental therapy for glioblastoma |
| title_full_unstemmed | AAV-mediated gene transfer of a checkpoint inhibitor in combination with HER2-targeted CAR-NK cells as experimental therapy for glioblastoma |
| title_short | AAV-mediated gene transfer of a checkpoint inhibitor in combination with HER2-targeted CAR-NK cells as experimental therapy for glioblastoma |
| title_sort | aav mediated gene transfer of a checkpoint inhibitor in combination with her2 targeted car nk cells as experimental therapy for glioblastoma |
| topic | Immunotherapy tumor targeting checkpoint inhibition CAR-NK cell adeno-associated virus HER2 |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2022.2127508 |
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