Combining SiRPα decoy-coengineered T cells and antibodies augments macrophage-mediated phagocytosis of tumor cells.

Détails

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Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_36EE50DF7CA8
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Combining SiRPα decoy-coengineered T cells and antibodies augments macrophage-mediated phagocytosis of tumor cells.
Périodique
The Journal of clinical investigation
Auteur⸱e⸱s
Stefanidis E., Semilietof A., Pujol J., Seijo B., Scholten K., Zoete V., Michielin O., Sandaltzopoulos R., Coukos G., Irving M.
ISSN
1558-8238 (Electronic)
ISSN-L
0021-9738
Statut éditorial
Publié
Date de publication
23/04/2024
Peer-reviewed
Oui
Volume
134
Numéro
11
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: epublish
Résumé
The adoptive transfer of T cell receptor-engineered (TCR-engineered) T cells (ACT) targeting the HLA-A2-restricted cancer-testis epitope NY-ESO-1157-165 (A2/NY) has yielded favorable clinical responses against several cancers. Two approaches to improve ACT are TCR affinity optimization and T cell coengineering to express immunomodulatory molecules that can exploit endogenous immunity. By computational design we previously developed a panel of binding-enhanced A2/NY-TCRs including A97L, which augmented the in vitro function of gene-modified T cells as compared with WT. Here, we demonstrated higher persistence and improved tumor control by A97L-T cells. In order to harness macrophages in tumors, we further coengineered A97L-T cells to secrete a high-affinity signal regulatory protein α (SiRPα) decoy (CV1) that blocks CD47. While CV1-Fc-coengineered A97L-T cells mediated significantly better control of tumor outgrowth and survival in Winn assays, in subcutaneous xenograft models the T cells, coated by CV1-Fc, were depleted. Importantly, there was no phagocytosis of CV1 monomer-coengineered T cells by human macrophages. Moreover, avelumab and cetuximab enhanced macrophage-mediated phagocytosis of tumor cells in vitro in the presence of CV1 and improved tumor control upon coadministration with A97L-T cells. Taken together, our study indicates important clinical promise for harnessing macrophages by combining CV1-coengineered TCR-T cells with targeted antibodies to direct phagocytosis against tumor cells.
Mots-clé
Animals, Humans, Mice, Antigens, Differentiation/immunology, Antigens, Neoplasm/immunology, CD47 Antigen/immunology, Cell Line, Tumor, HLA-A2 Antigen/immunology, HLA-A2 Antigen/genetics, Immunotherapy, Adoptive, Macrophages/immunology, Macrophages/metabolism, Phagocytosis, Receptors, Antigen, T-Cell/immunology, Receptors, Antigen, T-Cell/metabolism, Receptors, Immunologic/immunology, Receptors, Immunologic/metabolism, Receptors, Immunologic/genetics, T-Lymphocytes/immunology, Xenograft Model Antitumor Assays, Male, Female, Cancer immunotherapy, Immunology, Innate immunity, T cells, Therapeutics
Pubmed
Web of science
Open Access
Oui
Création de la notice
13/06/2024 15:04
Dernière modification de la notice
20/08/2024 6:22
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