Enhancing anti-EGFRvIII CAR T cell therapy against glioblastoma with a paracrine SIRPγ-derived CD47 blocker

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 re...

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Published in:	Nature communications Vol. 15; no. 1; pp. 9718 - 25
Main Authors:	Martins, Tomás A., Kaymak, Deniz, Tatari, Nazanin, Gerster, Fiona, Hogan, Sabrina, Ritz, Marie-Françoise, Sabatino, Valerio, Wieboldt, Ronja, Bartoszek, Ewelina M., McDaid, Marta, Gerber, Alexandra, Buck, Alicia, Beshirova, Aisha, Heider, Anja, Shekarian, Tala, Mohamed, Hayget, Etter, Manina M., Schmassmann, Philip, Abel, Ines, Boulay, Jean-Louis, Saito, Yasuyuki, Mariani, Luigi, Guzman, Raphael, Snijder, Berend, Weiss, Tobias, Läubli, Heinz, Hutter, Gregor
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 09-11-2024 Nature Publishing Group Nature Portfolio
Subjects:	13 13/109 13/31 13/51 14/63 38/77 42 49 59 59/5 631/67/1059/2325 631/67/1922 631/67/327 64 64/60 82/1 82/58 82/80 96 96/109 96/35 Animal models Antigens Bioavailability Biocompatibility Brain tumors CD19 antigen Cell culture Cell therapy Chimeric antigen receptors Effector cells Engineers Glioblastoma Glioma Glioma cells Growth factors Humanities and Social Sciences Immune checkpoint Immunosuppressive agents Lymphocytes Lymphocytes T Lymphoma Macrophages Microenvironments Microglia multidisciplinary Paracrine signalling Phagocytes Phagocytosis Population density Proteins Receptors Science Science (multidisciplinary) Signal regulatory protein-α Solid tumors Therapy Toxicity Tumor cells Tumors
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Summary:	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. EGFRvIII-targeted CAR T cells have been proposed as a therapeutic option for patients with glioblastoma (GBM), however, clinical responses remain suboptimal. Here the authors engineer anti-EGFRvIII CAR T cells to secrete an optimized SIRPγ-derived CD47 blocker, showing that combining CAR T cell effector functions with enhanced macrophage-mediated tumor cell phagocytosis improves anti-tumor efficacy in preclinical models.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-024-54129-w