Enhancing anti-EGFRvIII CAR T cell therapy against glioblastoma with a paracrine SIRPγ-derived CD47 blocker
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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.
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- Authors
- Martins, T. A., Kaymak, D., Tatari, N., Gerster, F., Hogan, S., Ritz, M.-F., Sabatino, V., Wieboldt, R., Bartoszek, E. M., McDaid, M., Gerber, A., Buck, A., Beshirova, A., Heider, A., Shekarian, T., Mohamed, H., Etter, M. M., Schmassmann, P., Abel, I., Boulay, J.-L., Saito, Y., Mariani, L., Guzman, R., Snijder, B., Weiss, T., Läubli, H., & Hutter, G.
- Affiliations
- University of Basel (CH)
- University of Zurich (CH)
- University Hospital of Basel (CH)
- Kobe University (JP)
- ETH Zurich (CH)
- Corresponding author
- Martins, Tomás A.
- ORCID
- Martins, Tomás A.
- Kaymak, Deniz
- Tatari, Nazanin
- Gerster, Fiona
- Hogan, Sabrina
- Ritz, Marie-Françoise
- Sabatino, Valerio
- Bartoszek, Ewelina M.
- Buck, Alicia
- Beshirova, Aisha
- Heider, Anja
- Shekarian, Tala
- Etter, Manina M.
- Schmassmann, Philip
- Boulay, Jean-Louis
- Saito, Yasuyuki
- Mariani, Luigi
- Guzman, Raphael
- Snijder, Berend
- Weiss, Tobias
- Läubli, Heinz
- Hutter, Gregor
- Venue
- Nature Communications
- Published
- 2024-11-09
- Volume
- 15
- Issue
- 1
- Pages
- 9718-9718
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC11550474
- OpenAlex
- W4404199917
- Cited by
- 54
- References
- 10
- Citations by year
- 2026: 32 · 2025: 22
- FWCI
- 9.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (PP00P3_176974, 310030_215237/1)
- Krebsliga Schweiz (KFS-5763-02-2023, KFS-4382-02-2018, KFS-5789-02-2023)
- Brain Tumour Charity (GN-000562)
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- glioblastoma, EGFRvIII, CAR T-cell therapy, CD47 blockade, SIRPα, macrophages, immunosuppressive tumor microenvironment, phagocytosis, paracrine signaling, CD19, CAR T-cell resistance, antigen escape
- MeSH terms
- Receptors, Chimeric Antigen, Animals, Antigens, Differentiation, Brain Neoplasms, Female, Glioblastoma, Humans, Macrophages, Phagocytosis, Receptors, Immunologic, T-Lymphocytes, Immunotherapy, Adoptive, Microglia, Paracrine Communication, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, CD47 Antigen, Tumor Microenvironment, ErbB Receptors
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