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

• 成果类型: Article
• 署名作者: Attianese, Greta Maria Paola Giordano; Shui, Sailan; Cribioli, Elisabetta; Triboulet, Melanie; Scheller, Leo; Hafezi, Morteza; Reichenbach, Patrick; Gainza, Pablo; Georgeon, Sandrine; Correia, Bruno E.; Irving, Melita
• 署名单位: University of Lausanne; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV); Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; Swiss Institute of Bioinformatics
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14861
• DOI: 10.1073/pnas.2405085121
• 发表日期: 2024-10-29
• 关键词: car t-cells; membrane antigen; bcl-2; apoptosis

摘要

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 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 (IFN gamma) 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 within 4 to 6 for functionally inactive T cells (no IFN gamma 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 iON & Oslash;- CAR T cells may alleviate exhaustion and hence augment persistence and long- term tumor control in patients.