dc.creator | García-Guerrero, Estefanía | es |
dc.creator | Rodríguez-Lobato, Luis G. | es |
dc.creator | Sierro-Martínez, Belén | es |
dc.creator | Danhof, Sophia | es |
dc.creator | Bates, Stephan | es |
dc.creator | Frenz, Silke | es |
dc.creator | Pérez Simón, José Antonio | es |
dc.creator | Prommersberger, Sabrina R. | es |
dc.date.accessioned | 2024-02-06T16:37:33Z | |
dc.date.available | 2024-02-06T16:37:33Z | |
dc.date.issued | 2023 | |
dc.identifier.citation | García-Guerrero, E., Rodríguez-Lobato, L.G., Sierro-Martínez, B., Danhof, S., Bates, S., Frenz, S.,...,Prommersberger, S.R. (2023). All-trans retinoic acid works synergistically with the γ-secretase inhibitor crenigacestat to augment BCMA on multiple myeloma and the efficacy of BCMA-CAR T cells. HAEMATOLOGICA, 108 (2), 568-580. https://doi.org/10.3324/haematol.2022.281339. | |
dc.identifier.issn | 0390-6078 | es |
dc.identifier.uri | https://hdl.handle.net/11441/154736 | |
dc.description.abstract | B-cell maturation antigen (BCMA) is the lead antigen for chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma
(MM). A challenge is inter- and intra-patient heterogeneity in BCMA expression on MM cells and BCMA downmodulation
under therapeutic pressure. Accordingly, there is a desire to augment and sustain BCMA expression on MM cells in patients
that receive BCMA-CAR T-cell therapy. We used all-trans retinoic acid (ATRA) to augment BCMA expression on MM cells
and to increase the efficacy of BCMA-CAR T cells in pre-clinical models. We show that ATRA treatment leads to an increase
in BCMA transcripts by quantitative reverse transcription polymerase chain reaction and an increase in BCMA protein expression by flow cytometry in MM cell lines and primary MM cells. Analyses with super-resolution microscopy confirmed
increased BCMA protein expression and revealed an even distribution of non-clustered BCMA molecules on the MM cell
membrane after ATRA treatment. The enhanced BCMA expression on MM cells after ATRA treatment led to enhanced
cytolysis, cytokine secretion and proliferation of BCMA-CAR T cells in vitro, and increased efficacy of BCMA-CAR T-cell
therapy in a murine xenograft model of MM in vivo (NSG/MM.1S). Combination treatment of MM cells with ATRA and the γsecretase inhibitor crenigacestat further enhanced BCMA expression and the efficacy of BCMA-CAR T-cell therapy in vitro
and in vivo. Taken together, the data show that ATRA treatment leads to enhanced BCMA expression on MM cells and consecutively, enhanced reactivity of BCMA-CAR T cells. The data support the clinical evaluation of ATRA in combination with
BCMA-CAR T-cell therapy and potentially, other BCMA-directed immunotherapies. | es |
dc.format | application/pdf | es |
dc.format.extent | 13 p. | es |
dc.language.iso | eng | es |
dc.publisher | Ferrata Storti Foundation | es |
dc.relation.ispartof | HAEMATOLOGICA, 108 (2), 568-580. | |
dc.rights | Atribución-NoComercial 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc/4.0/ | * |
dc.title | All-trans retinoic acid works synergistically with the γ-secretase inhibitor crenigacestat to augment BCMA on multiple myeloma and the efficacy of BCMA-CAR T cells | es |
dc.type | info:eu-repo/semantics/article | es |
dc.type.version | info:eu-repo/semantics/publishedVersion | es |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | es |
dc.contributor.affiliation | Universidad de Sevilla. Instituto de Biomedicina de Sevilla (IBIS) | es |
dc.contributor.affiliation | Universidad de Sevilla. Departamento de Medicina | |
dc.relation.projectID | PFIS - FI12/00189 | es |
dc.relation.projectID | PI20/01792 | es |
dc.relation.publisherversion | https://haematologica.org/article/view/haematol.2022.281339 | es |
dc.identifier.doi | 10.3324/haematol.2022.281339 | es |
dc.journaltitle | HAEMATOLOGICA | es |
dc.publication.volumen | 108 | es |
dc.publication.issue | 2 | es |
dc.publication.initialPage | 568 | es |
dc.publication.endPage | 580 | es |
dc.contributor.funder | Instituto de Salud Carlos III | es |