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

Details

Ressource 1Download: 38828721.pdf (2493.63 [Ko])
State: Public
Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_36EE50DF7CA8
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Combining SiRPα decoy-coengineered T cells and antibodies augments macrophage-mediated phagocytosis of tumor cells.
Journal
The Journal of clinical investigation
Author(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
Publication state
Published
Issued date
23/04/2024
Peer-reviewed
Oui
Volume
134
Number
11
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
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.
Keywords
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
Yes
Create date
13/06/2024 15:04
Last modification date
20/08/2024 6:22
Usage data