{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Blanco B"],"funding":["Carlos III Health Institute","Spanish Ministry of Science and Innovation under a Ramon y Cajal grant","CatSalut, Fundació La Caixa","Portuguese Foundation for Science and Technology","ISCIII","European Research Council","Spanish Ministry of Science and Innovation","Comunidad Autónoma de Madrid","Spanish Association Against Cancer","CRIS Cancer Foundation"],"pagination":["498-511"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC7612571"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["10(4)"],"pubmed_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 (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."],"journal":["Cancer immunology research"],"pubmed_title":["Overcoming CAR-Mediated CD19 Downmodulation and Leukemia Relapse with T Lymphocytes Secreting Anti-CD19 T-cell Engagers."],"pmcid":["PMC7612571"],"funding_grant_id":["811220","SAF2017-89437-P","FCRIS-IFI-2018","CP042702","SFRH/BD/136574/2018","SAF-2019-108160-R","PIE13/33","AECC CICPF18030TORI","PI20/01030","AECC 19084","CoG-2014-646903","646903","PI19/00132","PID2020-117323RB-100","RTC-2017-5944-1","PI13/676","PEJD-2018- PRE/BMD-8314","PoC-2018-811220","PI16/00357","PI20/00822","PI18/775","PDC2021-121711-100","SAF2016-75656-P","PRE2018-083445","CM20/00004","957466","PID2019-105623RB-I00","PICI14/122","FCRIS-IFI-2020","RYC2018-024442-I","DTS20/00089"],"pubmed_authors":["Rubio-Perez L","Ramirez-Fernandez A","Paz-Artal E","Fuentes P","Harwood SL","Tapia-Galisteo A","Sanz L","Betriu S","Lykkemark S","Argemi-Muntadas L","Blanco B","Menendez P","Morales P","Dominguez-Alonso C","Juan M","Gutierrez-Aguera F","Diez-Alonso L","Alvarez-Vallina L","Aguilar-Sopena O","Toribio ML","Jimenez-Reinoso A","Marzal B","Compte M","Zanetti SR","Roda-Navarro P","Bueno C","Erce-Llamazares A","Castella M","Segura-Tudela A","Neves M","Guedan S"],"additional_accession":[]},"is_claimable":false,"name":"Overcoming CAR-Mediated CD19 Downmodulation and Leukemia Relapse with T Lymphocytes Secreting Anti-CD19 T-cell Engagers.","description":"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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Apr","modification":"2026-06-21T03:09:56.373Z","creation":"2025-04-05T18:23:20.984Z"},"accession":"S-EPMC7612571","cross_references":{"pubmed":["35362043"],"doi":["10.1158/2326-6066.CIR-21-0853"]}}