Overcoming CAR-Mediated CD19 Downmodulation and Leukemia Relapse with T Lymphocytes Secreting Anti-CD19 T-cell Engagers.

Autor:	Blanco B; Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain.; Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain.; Red Española de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III (RICORS, RD21/0017/0029), Madrid, Spain., Ramírez-Fernández Á; Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain.; Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain., Bueno C; Red Española de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III (RICORS, RD21/0017/0029), Madrid, Spain.; Josep Carreras Leukemia Research Institute, Barcelona, Spain.; Centro de Investigación Biomédica en Red-Oncología (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain., Argemí-Muntadas L; Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, Aarhus, Denmark., Fuentes P; Centro de Biología Molecular Severo Ochoa CSIC-UAM, Madrid, Spain., Aguilar-Sopeña Ó; Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense, Madrid, Spain.; Lymphocyte Immunobiology Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain., Gutierrez-Agüera F; Red Española de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III (RICORS, RD21/0017/0029), Madrid, Spain.; Josep Carreras Leukemia Research Institute, Barcelona, Spain., Zanetti SR; Josep Carreras Leukemia Research Institute, Barcelona, Spain., Tapia-Galisteo A; Molecular Immunology Unit, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain., Díez-Alonso L; Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain.; Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain., Segura-Tudela A; Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain.; Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain., Castellà M; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Spain., Marzal B; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Spain., Betriu S; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Spain., Harwood SL; Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, Aarhus, Denmark., Compte M; Molecular Immunology Unit, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain., Lykkemark S; Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, Aarhus, Denmark., Erce-Llamazares A; Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain.; Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain., Rubio-Pérez L; Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain.; Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain.; Chair for Immunology UFV/Merck, Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcón, Madrid, Spain., Jiménez-Reinoso A; Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain.; Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain., Domínguez-Alonso C; Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain.; Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain., Neves M; Centro de Biología Molecular Severo Ochoa CSIC-UAM, Madrid, Spain., Morales P; Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain., Paz-Artal E; Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain.; Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense, Madrid, Spain., Guedan S; Department of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain., Sanz L; Molecular Immunology Unit, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain., Toribio ML; Centro de Biología Molecular Severo Ochoa CSIC-UAM, Madrid, Spain., Roda-Navarro P; Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense, Madrid, Spain.; Lymphocyte Immunobiology Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain., Juan M; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Spain.; Servei d'Immunologia, Hospital Clínic de Barcelona, Barcelona, Spain.; Plataforma Immunoteràpia Hospital Sant Joan de Déu, Barcelona, Spain.; Universitat de Barcelona, Barcelona, Spain., Menéndez P; Red Española de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III (RICORS, RD21/0017/0029), Madrid, Spain.; Josep Carreras Leukemia Research Institute, Barcelona, Spain.; Centro de Investigación Biomédica en Red-Oncología (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain.; Department of Biomedicine, School of Medicine, Universitat de Barcelona, Barcelona, Spain.; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain., Álvarez-Vallina L; Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain.; Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain.; Red Española de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III (RICORS, RD21/0017/0029), Madrid, Spain.; Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, Aarhus, Denmark.
Jazyk:	angličtina
Zdroj:	Cancer immunology research [Cancer Immunol Res] 2022 Apr 01; Vol. 10 (4), pp. 498-511.
DOI:	10.1158/2326-6066.CIR-21-0853
Abstrakt:	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. (©2022 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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