2026-06-30T03:14:13Zhttps://docta.ucm.es/rest/oai/request

oai:docta.ucm.es:20.500.14352/1200882025-08-20T15:39:34Zcom_20.500.14352_14col_20.500.14352_15

00925njm 22002777a 4500 dc Roda Navarro, Pedro author Blanco, Belén author Ramírez-Fernández, Ángel author Aguilar-Sopeña, Óscar author Díez-Alonso, Laura author Segura-Tudela, Alejandro author Erce-Llamazares, Ainhoa author Rubio-Pérez, Laura author Jiménez Reinoso, Anaïs author Domínguez-Alonso, Carmen author Morales, Pablo author Paz Artal, Estela Natividad author Álvarez-Vallina, Luis author 2022 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 (CAR-T19) 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. Blanco B, Ramírez-Fernández Á, Bueno C, Argemí-Muntadas L, Fuentes P, Aguilar-Sopeña Ó, Gutierrez-Agüera F, Zanetti SR, Tapia-Galisteo A, Díez-Alonso L, Segura-Tudela A, Castellà M, Marzal B, Betriu S, Harwood SL, Compte M, Lykkemark S, Erce-Llamazares A, Rubio-Pérez L, Jiménez-Reinoso A, Domínguez-Alonso C, Neves M, Morales P, Paz-Artal E, Guedan S, Sanz L, Toribio ML, Roda-Navarro P, Juan M, Menéndez P, Álvarez-Vallina L. Overcoming CAR-Mediated CD19 Downmodulation and Leukemia Relapse with T Lymphocytes Secreting Anti-CD19 T-cell Engagers. Cancer Immunol Res. 2022 Apr 1;10(4):498-511. doi: 10.1158/2326-6066.CIR-21-0853. PMID: 35362043; PMCID: PMC7612571. 2326-6074 10.1158/2326-6066.CIR-21-0853 https://hdl.handle.net/20.500.14352/120088 https://doi.org/10.1158/2326-6066.CIR-21-0853 35362043 https://aacrjournals.org/cancerimmunolres Overcoming CAR-Mediated CD19 Downmodulation and Leukemia Relapse with T Lymphocytes Secreting Anti-CD19 T-cell Engagers.