Mostrar el registro sencillo del ítem
Overcoming CAR-Mediated CD19 Downmodulation and Leukemia Relapse with T Lymphocytes Secreting Anti-CD19 T-cell Engagers.
dc.contributor.author | Blanco, Belén | |
dc.contributor.author | Rubio Pérez, Laura | |
dc.contributor.author | Álvarez-Vallina, Luis | |
dc.date.accessioned | 2023-03-31T08:43:31Z | |
dc.date.available | 2023-03-31T08:43:31Z | |
dc.date.issued | 2022 | |
dc.identifier.issn | 2326-6066 | spa |
dc.identifier.uri | https://hdl.handle.net/10641/3310 | |
dc.description.abstract | Chimeric antigen receptor (CAR)–modified T cells have revolutionized the treatment of CD19-positive hematologic malignancies. Although anti-CD19 CAR-engineered autologous T cells can induce remission in patients with B-cell acute lymphoblastic leukemia, a large subset relapse, most of them with CD19-positive disease. Therefore, new therapeutic strategies are clearly needed. Here, we report a comprehensive study comparing engineered T cells either expressing a second-generation anti-CD19 CAR (CART19) or secreting a CD19/CD3-targeting bispecific T-cell engager antibody (STAb-T19). We found that STAb-T19 cells are more effective than CAR-T19 cells at inducing cytotoxicity, avoiding leukemia escape in vitro, and preventing relapse in vivo. We observed that leukemia escape in vitro is associated with rapid and drastic CAR-induced internalization of CD19 that is coupled with lysosome-mediated degradation, leading to the emergence of transiently CD19-negative leukemic cells that evade the immune response of engineered CAR-T19 cells. In contrast, engineered STAb-T19 cells induce the formation of canonical immunologic synapses and prevent the CD19 downmodulation observed in anti- CD19 CAR-mediated interactions. Although both strategies show similar efficacy in short-term mouse models, there is a significant difference in a long-term patient-derived xenograft mouse model, where STAb-T19 cells efficiently eradicated leukemia cells, but leukemia relapsed after CAR-T19 therapy. Our findings suggest that the absence of CD19 downmodulation in the STAb-T19 strategy, coupled with the continued antibody secretion, allows an efficient recruitment of the endogenous T-cell pool, resulting in fast and effective elimination of cancer cells that may prevent CD19-positive relapses frequently associated with CAR-T19 therapies. | spa |
dc.language.iso | eng | spa |
dc.publisher | Cancer Immunology Research | spa |
dc.rights | Atribución-NoComercial-SinDerivadas 3.0 España | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/es/ | * |
dc.title | Overcoming CAR-Mediated CD19 Downmodulation and Leukemia Relapse with T Lymphocytes Secreting Anti-CD19 T-cell Engagers. | spa |
dc.type | journal article | spa |
dc.type.hasVersion | AM | spa |
dc.rights.accessRights | open access | spa |
dc.description.extent | 1691 KB | spa |
dc.identifier.doi | 10.1158/2326-6066.CIR-21-0853 | spa |
dc.relation.publisherversion | https://aacrjournals.org/cancerimmunolres/article/10/4/498/689536/Overcoming-CAR-Mediated-CD19-Downmodulation-and | spa |
Ficheros en el ítem
Este ítem aparece en la(s) siguiente(s) colección(ones)
-
MEDICINA [819]