Dual ON/OFF-switch chimeric antigen receptor controlled by two clinically approved drugs.
Details
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State: Public
Version: Final published version
License: CC BY-NC-ND 4.0
State: Public
Version: Final published version
License: CC BY-NC-ND 4.0
Serval ID
serval:BIB_D70C09408C95
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Dual ON/OFF-switch chimeric antigen receptor controlled by two clinically approved drugs.
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN
1091-6490 (Electronic)
ISSN-L
0027-8424
Publication state
Published
Issued date
29/10/2024
Peer-reviewed
Oui
Volume
121
Number
44
Pages
e2405085121
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Abstract
The ability to remotely control the activity of chimeric antigen receptors (CARs) with small molecules can improve the safety and efficacy of gene-modified T cells. Split ON- or OFF-switch CARs involve the dissociation of tumor-antigen binding from T cell activation (i.e., CD3ζ) on the receptor (R-) and signaling (S-) chains, respectively, that either associate or are disrupted in the presence of a small molecule. Here, we have developed an inducible (i)ON-CAR comprising the anti-apoptotic B cell lymphoma protein 2 protein in the ectodomain of both chains which associate in the presence of venetoclax. We showed that inducible ON (iON)-CAR T cells respond to target tumors cells in the presence of venetoclax or the BH3 mimetic navitoclax in a dose-dependent manner, while there is no impact of the drugs on equivalent second generation-CAR T cells. Within 48 h of venetoclax withdrawal, iON-CAR T cells lose the ability to respond to target tumor cells in vitro as evaluated by Interferon-gamma (IFNγ) production, and they are reliant upon the presence of venetoclax for in vivo activity. Finally, by fusing a degron sequence to the endodomain of the iON-CAR S-chain we generated an all-in-one ON/OFF-switch CAR, the iONØ-CAR, down-regulated by lenalidomide within 4 to 6 for functionally inactive T cells (no IFNγ production) within 24 h. We propose that our remote-control CAR designs can reduce toxicity in the clinic. Moreover, the periodic rest of iON and iONØ-CAR T cells may alleviate exhaustion and hence augment persistence and long-term tumor control in patients.
Keywords
Receptors, Chimeric Antigen/immunology, Receptors, Chimeric Antigen/metabolism, Humans, Sulfonamides/pharmacology, Animals, T-Lymphocytes/immunology, T-Lymphocytes/drug effects, Mice, Bridged Bicyclo Compounds, Heterocyclic/pharmacology, Cell Line, Tumor, Antineoplastic Agents/pharmacology, Immunotherapy, Adoptive/methods, Proto-Oncogene Proteins c-bcl-2/metabolism, Xenograft Model Antitumor Assays, Receptors, Antigen, T-Cell/metabolism, Receptors, Antigen, T-Cell/immunology, Lymphocyte Activation/drug effects, Interferon-gamma/metabolism, Interferon-gamma/immunology, Aniline Compounds, T cell, cancer, chimeric antigen receptor, synthetic biology
Pubmed
Open Access
Yes
Create date
01/11/2024 14:15
Last modification date
02/11/2024 7:22