Enhancing anti-EGFRvIII CAR T cell therapy against glioblastoma with a paracrine SIRPγ-derived CD47 blocker
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 and
Gregor Hutter ()
Additional contact information
Tomás A. Martins: University of Basel
Deniz Kaymak: University of Basel
Nazanin Tatari: University of Basel
Fiona Gerster: University of Basel
Sabrina Hogan: University of Basel
Marie-Françoise Ritz: University of Basel
Valerio Sabatino: University of Basel
Ronja Wieboldt: University of Basel
Ewelina M. Bartoszek: University of Basel
Marta McDaid: University of Basel
Alexandra Gerber: University of Basel
Alicia Buck: ETH Zurich
Aisha Beshirova: University of Basel
Anja Heider: University of Zurich
Tala Shekarian: University of Basel
Hayget Mohamed: University of Basel
Manina M. Etter: University Hospital Basel
Philip Schmassmann: University of Basel
Ines Abel: University of Basel
Jean-Louis Boulay: University of Basel
Yasuyuki Saito: Kobe University Graduate School of Medicine
Luigi Mariani: University Hospital Basel
Raphael Guzman: University Hospital Basel
Berend Snijder: ETH Zurich
Tobias Weiss: University Hospital Zurich
Heinz Läubli: University of Basel
Gregor Hutter: University of Basel
Nature Communications, 2024, vol. 15, issue 1, 1-25
Abstract:
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.
Date: 2024
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54129-w
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DOI: 10.1038/s41467-024-54129-w
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