A computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy

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dc.contributor.authorGiordano-Attianese, Gretako
dc.contributor.authorGainza, Pabloko
dc.contributor.authorGray-Gaillard, Eliseko
dc.contributor.authorCribioli, Elisabettako
dc.contributor.authorShui, Sailanko
dc.contributor.authorKim, Seonghoonko
dc.contributor.authorKwak, Mi-Jeongko
dc.contributor.authorVollers, Sabrinako
dc.contributor.authorOsorio, Angel De Jesus Corriako
dc.contributor.authorReichenbach, Patrickko
dc.contributor.authorBonet, Jaumeko
dc.contributor.authorOh, Byung-Hako
dc.contributor.authorIrving, Melitako
dc.contributor.authorCoukos, Georgeko
dc.contributor.authorCorreia, Bruno E.ko
dc.date.accessioned2020-10-20T02:56:01Z-
dc.date.available2020-10-20T02:56:01Z-
dc.date.created2020-02-18-
dc.date.issued2020-04-
dc.identifier.citationNATURE BIOTECHNOLOGY, v.38, no.4, pp.426 - 432-
dc.identifier.issn1087-0156-
dc.identifier.urihttp://hdl.handle.net/10203/276712-
dc.description.abstractThe activity of CAR-T cells is reversibly halted with a small-molecule drug. Approaches to increase the activity of chimeric antigen receptor (CAR)-T cells against solid tumors may also increase the risk of toxicity and other side effects. To improve the safety of CAR-T-cell therapy, we computationally designed a chemically disruptable heterodimer (CDH) based on the binding of two human proteins. The CDH self-assembles, can be disrupted by a small-molecule drug and has a high-affinity protein interface with minimal amino acid deviation from wild-type human proteins. We incorporated the CDH into a synthetic heterodimeric CAR, called STOP-CAR, that has an antigen-recognition chain and a CD3 zeta- and CD28-containing endodomain signaling chain. We tested STOP-CAR-T cells specific for two antigens in vitro and in vivo and found similar antitumor activity compared to second-generation (2G) CAR-T cells. Timed administration of the small-molecule drug dynamically inactivated the activity of STOP-CAR-T cells. Our work highlights the potential for structure-based design to add controllable elements to synthetic cellular therapies.-
dc.languageEnglish-
dc.publisherNATURE PUBLISHING GROUP-
dc.titleA computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy-
dc.typeArticle-
dc.identifier.wosid000510822200003-
dc.identifier.scopusid2-s2.0-85079899789-
dc.type.rimsART-
dc.citation.volume38-
dc.citation.issue4-
dc.citation.beginningpage426-
dc.citation.endingpage432-
dc.citation.publicationnameNATURE BIOTECHNOLOGY-
dc.identifier.doi10.1038/s41587-019-0403-9-
dc.contributor.localauthorOh, Byung-Ha-
dc.contributor.nonIdAuthorGiordano-Attianese, Greta-
dc.contributor.nonIdAuthorGainza, Pablo-
dc.contributor.nonIdAuthorGray-Gaillard, Elise-
dc.contributor.nonIdAuthorCribioli, Elisabetta-
dc.contributor.nonIdAuthorShui, Sailan-
dc.contributor.nonIdAuthorVollers, Sabrina-
dc.contributor.nonIdAuthorOsorio, Angel De Jesus Corria-
dc.contributor.nonIdAuthorReichenbach, Patrick-
dc.contributor.nonIdAuthorBonet, Jaume-
dc.contributor.nonIdAuthorIrving, Melita-
dc.contributor.nonIdAuthorCoukos, George-
dc.contributor.nonIdAuthorCorreia, Bruno E.-
dc.description.isOpenAccessN-
dc.type.journalArticleArticle-
dc.subject.keywordPlusMEMBRANE ANTIGEN-
dc.subject.keywordPlusBH3-ONLY PROTEINS-
dc.subject.keywordPlusB-CELL-
dc.subject.keywordPlusPROSTATE-
dc.subject.keywordPlusINHIBITOR-
dc.subject.keywordPlusBINDING-
dc.subject.keywordPlusSYSTEM-
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