Enhancing anti-EGFRvIII CAR T cell therapy against glioblastoma with a paracrine SIRPγ-derived CD47 blocker
Abstract A significant challenge for chimeric antigen receptor (CAR) T cell therapy against glioblastoma (GBM) is its immunosuppressive microenvironment, which is densely populated by protumoral glioma-associated microglia and macrophages (GAMs). Myeloid immune checkpoint therapy targeting the CD47-...
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| Format: | Article |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54129-w |
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| author | Tomás A. Martins Deniz Kaymak Nazanin Tatari Fiona Gerster Sabrina Hogan Marie-Françoise Ritz Valerio Sabatino Ronja Wieboldt Ewelina M. Bartoszek Marta McDaid Alexandra Gerber Alicia Buck Aisha Beshirova Anja Heider Tala Shekarian Hayget Mohamed Manina M. Etter Philip Schmassmann Ines Abel Jean-Louis Boulay Yasuyuki Saito Luigi Mariani Raphael Guzman Berend Snijder Tobias Weiss Heinz Läubli Gregor Hutter |
| author_facet | Tomás A. Martins Deniz Kaymak Nazanin Tatari Fiona Gerster Sabrina Hogan Marie-Françoise Ritz Valerio Sabatino Ronja Wieboldt Ewelina M. Bartoszek Marta McDaid Alexandra Gerber Alicia Buck Aisha Beshirova Anja Heider Tala Shekarian Hayget Mohamed Manina M. Etter Philip Schmassmann Ines Abel Jean-Louis Boulay Yasuyuki Saito Luigi Mariani Raphael Guzman Berend Snijder Tobias Weiss Heinz Läubli Gregor Hutter |
| author_sort | Tomás A. Martins |
| collection | DOAJ |
| description | Abstract A significant challenge for chimeric antigen receptor (CAR) T cell therapy against glioblastoma (GBM) is its immunosuppressive microenvironment, which is densely populated by protumoral glioma-associated microglia and macrophages (GAMs). Myeloid immune checkpoint therapy targeting the CD47-signal regulatory protein alpha (SIRPα) axis induces GAM phagocytic function, but CD47 blockade monotherapy is associated with toxicity and low bioavailability in solid tumors. In this work, we engineer a CAR T cell against epidermal growth factor receptor variant III (EGFRvIII), constitutively secreting a signal regulatory protein gamma-related protein (SGRP) with high affinity to CD47. Anti-EGFRvIII-SGRP CAR T cells eradicate orthotopic EGFRvIII-mosaic GBM in vivo, promoting GAM-mediated tumor cell phagocytosis. In a subcutaneous CD19+ lymphoma mouse model, anti-CD19-SGRP CAR T cell therapy is superior to conventional anti-CD19 CAR T. Thus, combination of CAR and SGRP eliminates bystander tumor cells in a manner that could overcome main mechanisms of CAR T cell therapy resistance, including immune suppression and antigen escape. |
| format | Article |
| id | doaj-art-54d8c2ce535347fc8b97105d49f0cbda |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-54d8c2ce535347fc8b97105d49f0cbda2025-08-20T02:50:08ZengNature PortfolioNature Communications2041-17232024-11-0115112510.1038/s41467-024-54129-wEnhancing anti-EGFRvIII CAR T cell therapy against glioblastoma with a paracrine SIRPγ-derived CD47 blockerTomás A. Martins0Deniz Kaymak1Nazanin Tatari2Fiona Gerster3Sabrina Hogan4Marie-Françoise Ritz5Valerio Sabatino6Ronja Wieboldt7Ewelina M. Bartoszek8Marta McDaid9Alexandra Gerber10Alicia Buck11Aisha Beshirova12Anja Heider13Tala Shekarian14Hayget Mohamed15Manina M. Etter16Philip Schmassmann17Ines Abel18Jean-Louis Boulay19Yasuyuki Saito20Luigi Mariani21Raphael Guzman22Berend Snijder23Tobias Weiss24Heinz Läubli25Gregor Hutter26Brain Tumor Immunotherapy and Biology, Department of Biomedicine, University of BaselBrain Tumor Immunotherapy and Biology, Department of Biomedicine, University of BaselBrain Tumor Immunotherapy and Biology, Department of Biomedicine, University of BaselBrain Tumor Immunotherapy and Biology, Department of Biomedicine, University of BaselBrain Tumor Immunotherapy and Biology, Department of Biomedicine, University of BaselBrain Tumor Immunotherapy and Biology, Department of Biomedicine, University of BaselBrain Tumor Immunotherapy and Biology, Department of Biomedicine, University of BaselCancer Immunotherapy, Department of Biomedicine, University of BaselMicroscopy Core Facility, Department of Biomedicine, University of BaselBrain Tumor Immunotherapy and Biology, Department of Biomedicine, University of BaselBrain Tumor Immunotherapy and Biology, Department of Biomedicine, University of BaselInstitute of Molecular Systems Biology, ETH ZurichExperimental Immunology, Department of Biomedicine, University of BaselSwiss Institute of Allergy and Asthma Research, University of ZurichBrain Tumor Immunotherapy and Biology, Department of Biomedicine, University of BaselBrain Tumor Immunotherapy and Biology, Department of Biomedicine, University of BaselDepartment of Neurosurgery, University Hospital BaselBrain Tumor Immunotherapy and Biology, Department of Biomedicine, University of BaselBrain Tumor Immunotherapy and Biology, Department of Biomedicine, University of BaselBrain Tumor Immunotherapy and Biology, Department of Biomedicine, University of BaselDivision of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of MedicineDepartment of Neurosurgery, University Hospital BaselDepartment of Neurosurgery, University Hospital BaselInstitute of Molecular Systems Biology, ETH ZurichDepartment of Neurology, Clinical Neuroscience Center, University Hospital ZurichCancer Immunotherapy, Department of Biomedicine, University of BaselBrain Tumor Immunotherapy and Biology, Department of Biomedicine, University of BaselAbstract A significant challenge for chimeric antigen receptor (CAR) T cell therapy against glioblastoma (GBM) is its immunosuppressive microenvironment, which is densely populated by protumoral glioma-associated microglia and macrophages (GAMs). Myeloid immune checkpoint therapy targeting the CD47-signal regulatory protein alpha (SIRPα) axis induces GAM phagocytic function, but CD47 blockade monotherapy is associated with toxicity and low bioavailability in solid tumors. In this work, we engineer a CAR T cell against epidermal growth factor receptor variant III (EGFRvIII), constitutively secreting a signal regulatory protein gamma-related protein (SGRP) with high affinity to CD47. Anti-EGFRvIII-SGRP CAR T cells eradicate orthotopic EGFRvIII-mosaic GBM in vivo, promoting GAM-mediated tumor cell phagocytosis. In a subcutaneous CD19+ lymphoma mouse model, anti-CD19-SGRP CAR T cell therapy is superior to conventional anti-CD19 CAR T. Thus, combination of CAR and SGRP eliminates bystander tumor cells in a manner that could overcome main mechanisms of CAR T cell therapy resistance, including immune suppression and antigen escape.https://doi.org/10.1038/s41467-024-54129-w |
| spellingShingle | Tomás A. Martins Deniz Kaymak Nazanin Tatari Fiona Gerster Sabrina Hogan Marie-Françoise Ritz Valerio Sabatino Ronja Wieboldt Ewelina M. Bartoszek Marta McDaid Alexandra Gerber Alicia Buck Aisha Beshirova Anja Heider Tala Shekarian Hayget Mohamed Manina M. Etter Philip Schmassmann Ines Abel Jean-Louis Boulay Yasuyuki Saito Luigi Mariani Raphael Guzman Berend Snijder Tobias Weiss Heinz Läubli Gregor Hutter Enhancing anti-EGFRvIII CAR T cell therapy against glioblastoma with a paracrine SIRPγ-derived CD47 blocker Nature Communications |
| title | Enhancing anti-EGFRvIII CAR T cell therapy against glioblastoma with a paracrine SIRPγ-derived CD47 blocker |
| title_full | Enhancing anti-EGFRvIII CAR T cell therapy against glioblastoma with a paracrine SIRPγ-derived CD47 blocker |
| title_fullStr | Enhancing anti-EGFRvIII CAR T cell therapy against glioblastoma with a paracrine SIRPγ-derived CD47 blocker |
| title_full_unstemmed | Enhancing anti-EGFRvIII CAR T cell therapy against glioblastoma with a paracrine SIRPγ-derived CD47 blocker |
| title_short | Enhancing anti-EGFRvIII CAR T cell therapy against glioblastoma with a paracrine SIRPγ-derived CD47 blocker |
| title_sort | enhancing anti egfrviii car t cell therapy against glioblastoma with a paracrine sirpγ derived cd47 blocker |
| url | https://doi.org/10.1038/s41467-024-54129-w |
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