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oai:recercat.cat:2072/4739352025-04-03T10:24:19Zcom_2072_98col_2072_378192

Overcoming CAR-Mediated CD19 Downmodulation and Leukemia Relapse with T Lymphocytes Secreting Anti-CD19 T-cell Engagers Blanco, Belén Ramírez-Fernández, Ángel Bueno, Clara Argemí-Muntadas, Lidia Fuentes, Patricia Aguilar-Sopeña, Óscar Gutierrez-Agüera, Francisco Zanetti, S. R Tapia-Galisteo, Antonio Díez-Alonso, Laura Segura-Tudela, Alejandro Castellà, Maria Marzal, Berta Betriu-Méndez, Sergi Harwood, Seandean L. Compte, Marta Lykkemark, Simon Erce-Llamazares, Ainhoa Rubio-Pérez, Laura Jiménez-Reinoso, Anaïs Domínguez-Alonso, Carmen Neves, Maria Morales, Pablo Paz-Artal, Estela Guedan, Sonia Sanz, Laura Toribio, Maria L. Roda-Navarro, Pedro Juan, Manel Menéndez Bujan, Pablo Álvarez-Vallina, Luis 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. 2022 Article https://ddd.uab.cat/record/289379 urn:10.1158/2326-6066.CIR-21-0853 urn:oai:ddd.uab.cat:289379 urn:scopus_id:85127179043 urn:articleid:23266074v10n4p498 urn:pmid:35362043 urn:pmc-uid:7612571 urn:pmcid:PMC7612571 urn:oai:pubmedcentral.nih.gov:7612571 eng Ministerio de Ciencia e Innovación SAF2016-75656-P European Commission 646903 European Commission 811220 Ministerio de Ciencia e Innovación RTC-2017-5944-1 Agencia Estatal de Investigación SAF2017-89437-P Agencia Estatal de Investigación PID2019-105623RB-I00 Instituto de Salud Carlos III PI20/01030 Instituto de Salud Carlos III PI20/00822 Ministerio de Economía y Competitividad PI16/00357 Instituto de Salud Carlos III PI19/00132 Instituto de Salud Carlos III DTS20/00089 Cancer Immunology Research ; Vol. 10 Núm. 4 (april 2022), p. 498-511 open access Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades. https://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf