Dual ON/OFF-switch chimeric antigen receptor controlled by two clinically approved drugs.

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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
Author(s)
Giordano Attianese GMP, Shui S., Cribioli E., Triboulet M., Scheller L., Hafezi M., Reichenbach P., Gainza P., Georgeon S., Correia B.E., Irving M.
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
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
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