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4. PCNA molecular recognition of different PIP motifs: Role of Tyr211 phosphorylation

Author

Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Ministerio de Ciencia e Innovación (MICIN). España, Junta de Andalucía, Consejo Superior de Investigaciones Científicas (CSIC), Ruiz Albor, Antonio, Chaves Arquero, Belén, Martín Barros, Inés, Guerra Castellano, Alejandra, González-Magaña, Amaia, Ibáñez de Okapua, Alain, Merino, Nekane, Ferreras Gutiérrez, Mariola, Berra, Edurne, Díaz Moreno, Irene, Blanco, Francisco J., Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Ministerio de Ciencia e Innovación (MICIN). España, Junta de Andalucía, Consejo Superior de Investigaciones Científicas (CSIC), Ruiz Albor, Antonio, Chaves Arquero, Belén, Martín Barros, Inés, Guerra Castellano, Alejandra, González-Magaña, Amaia, Ibáñez de Okapua, Alain, Merino, Nekane, Ferreras Gutiérrez, Mariola, Berra, Edurne, Díaz Moreno, Irene, and Blanco, Francisco J.

Published
2024

5. Structural analysis of ING3 protein and histone H3 binding

Author

Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Universidades (España), European Commission, Ferreras-Gutiérrez, Mariola [0000-0003-4421-3158], Chaves-Arquero, Belén [0000-0002-2761-2336], González-Magaña, Amaia [0000-0002-6007-8390], Merino, Nekane [0000-0003-0721-4813], Amusategui-Mateu, Ignacio [0000-0001-5427-1808], Huecas, Sonia [0000-0002-6419-441X], Medrano, Francisco Javier [0000-0002-8185-9751], Blanco, Francisco J. [0000-0003-2545-4319], Ferreras-Gutiérrez, Mariola, Chaves-Arquero, Belén, González-Magaña, Amaia, Merino, Nekane, Amusategui-Mateu, Ignacio, Huecas, Sonia, Medrano, Francisco Javier, Blanco, Francisco J., Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Universidades (España), European Commission, Ferreras-Gutiérrez, Mariola [0000-0003-4421-3158], Chaves-Arquero, Belén [0000-0002-2761-2336], González-Magaña, Amaia [0000-0002-6007-8390], Merino, Nekane [0000-0003-0721-4813], Amusategui-Mateu, Ignacio [0000-0001-5427-1808], Huecas, Sonia [0000-0002-6419-441X], Medrano, Francisco Javier [0000-0002-8185-9751], Blanco, Francisco J. [0000-0003-2545-4319], Ferreras-Gutiérrez, Mariola, Chaves-Arquero, Belén, González-Magaña, Amaia, Merino, Nekane, Amusategui-Mateu, Ignacio, Huecas, Sonia, Medrano, Francisco Javier, and Blanco, Francisco J.

Abstract

Proteins belonging to the ING family regulate the transcriptional state of chromatin by recruiting remodeling complexes to sites with histone H3 trimethylated at Lysine 4 (H3K4me3). This modification is recognized by the Plant HomeoDomain (PHD) present at the C-terminal region of the five ING proteins. ING3 facilitates acetylation of histones H2A and H4 by the NuA4-Tip60 MYST histone acetyl transferase complex, and it has been proposed to be an oncoprotein. The crystal structure of the N-terminal domain of ING3 shows that it forms homodimers with an antiparallel coiled-coil fold. The crystal structure of the PHD is similar to those of its four homologs. These structures explain the possible deleterious effects of ING3 mutations detected in tumors. The PHD binds histone H3K4me3 with low-micromolar, and binds the non-methylated histone with a 54-fold reduced affinity. Our structure explains the impact of site directed mutagenesis experiments on histone recognition. These structural features could not be confirmed for the full-length protein as solubility was insufficient for structural studies, but the structure of its folded domains suggest a conserved structural organization for the ING proteins as homodimers and bivalent readers of the histone H3K4me3 mark.

Published
2023

6. A PD-L1/EGFR bispecific antibody combines immune checkpoint blockade and direct anti-cancer action for an enhanced anti-tumor response

Author

Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Fundación CRIS contra el Cáncer, Asociación Española Contra el Cáncer, Fundación la Caixa, Fundación para la Investigación Biomédica del Hospital Universitario 12 de Octubre, Universidad Francisco de Vitoria, Comunidad de Madrid, Rubio-Pérez, Laura [0000-0002-2877-6092], Lázaro-Gorines, Rodrigo [0000-0002-6885-3486], Harwood, Seandean Lykke [0000-0003-4654-8832], Compte, Marta [0000-0002-7138-9266], Navarro, Rocío [0000-0002-0083-7711], Tapia-Galisteo, Antonio [0000-0002-0507-8435], Bonet, Jaume [0000-0001-5210-4387], Blanco, Belén [0000-0001-5085-7756], Lykkemark, Simon [0000-0001-8920-6926], Ramírez-Fernández, Ángel [0000-0002-3265-6878], Ferreras-Gutiérrez, Mariola [0000-0003-4421-3158], Domínguez-Alonso, Carmen [0000-0002-0446-9629], Díez-Alonso, Laura [0000-0002-9545-6910], Segura-Tudela, Alejandro [0000-0002-5506-0153], Hangiu, Oana [0000-0002-2641-8531], Erce-Llamazares, Ainhoa [0000-0002-3656-1913], Blanco, Francisco J. [0000-0003-2545-4319], Santos, Cruz [0000-0001-5164-5050], Rodríguez-Peralto, J. L. [0000-0002-6578-7153], Sanz, Laura [0000-0002-3119-3218], Alvarez-Vallina, Luis [0000-0003-3053-6757], Rubio-Pérez, Laura, Lázaro-Gorines, Rodrigo, Harwood, Seandean Lykke, Compte, Marta, Navarro, Rocío, Tapia-Galisteo, Antonio, Bonet, Jaume, Blanco, Belén, Lykkemark, Simon, Ramírez-Fernández, Ángel, Ferreras-Gutiérrez, Mariola, Domínguez-Alonso, Carmen, Díez-Alonso, Laura, Segura-Tudela, Alejandro, Hangiu, Oana, Erce-Llamazares, Ainhoa, Blanco, Francisco J., Santos, Cruz, Rodríguez-Peralto, J. L., Sanz, Laura, Álvarez-Vallina, Luis, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Fundación CRIS contra el Cáncer, Asociación Española Contra el Cáncer, Fundación la Caixa, Fundación para la Investigación Biomédica del Hospital Universitario 12 de Octubre, Universidad Francisco de Vitoria, Comunidad de Madrid, Rubio-Pérez, Laura [0000-0002-2877-6092], Lázaro-Gorines, Rodrigo [0000-0002-6885-3486], Harwood, Seandean Lykke [0000-0003-4654-8832], Compte, Marta [0000-0002-7138-9266], Navarro, Rocío [0000-0002-0083-7711], Tapia-Galisteo, Antonio [0000-0002-0507-8435], Bonet, Jaume [0000-0001-5210-4387], Blanco, Belén [0000-0001-5085-7756], Lykkemark, Simon [0000-0001-8920-6926], Ramírez-Fernández, Ángel [0000-0002-3265-6878], Ferreras-Gutiérrez, Mariola [0000-0003-4421-3158], Domínguez-Alonso, Carmen [0000-0002-0446-9629], Díez-Alonso, Laura [0000-0002-9545-6910], Segura-Tudela, Alejandro [0000-0002-5506-0153], Hangiu, Oana [0000-0002-2641-8531], Erce-Llamazares, Ainhoa [0000-0002-3656-1913], Blanco, Francisco J. [0000-0003-2545-4319], Santos, Cruz [0000-0001-5164-5050], Rodríguez-Peralto, J. L. [0000-0002-6578-7153], Sanz, Laura [0000-0002-3119-3218], Alvarez-Vallina, Luis [0000-0003-3053-6757], Rubio-Pérez, Laura, Lázaro-Gorines, Rodrigo, Harwood, Seandean Lykke, Compte, Marta, Navarro, Rocío, Tapia-Galisteo, Antonio, Bonet, Jaume, Blanco, Belén, Lykkemark, Simon, Ramírez-Fernández, Ángel, Ferreras-Gutiérrez, Mariola, Domínguez-Alonso, Carmen, Díez-Alonso, Laura, Segura-Tudela, Alejandro, Hangiu, Oana, Erce-Llamazares, Ainhoa, Blanco, Francisco J., Santos, Cruz, Rodríguez-Peralto, J. L., Sanz, Laura, and Álvarez-Vallina, Luis

Abstract

Immune checkpoint blockade (ICB) with antibodies has shown durable clinical responses in a wide range of cancer types, but the overall response rate is still limited. Other effective therapeutic modalities to increase the ICB response rates are urgently needed. New bispecific antibody (bsAb) formats combining the ICB effect and a direct action on cancer cells could improve the efficacy of current immunotherapies. Here, we report the development of a PD-L1/EGFR symmetric bsAb by fusing a dual-targeting tandem trimmer body with the human IgG1 hinge and Fc regions. The bsAb was characterized in vitro and the antitumor efficacy was evaluated in humanized mice bearing xenografts of aggressive triple-negative breast cancer and lung cancer. The IgG-like hexavalent bsAb, designated IgTT-1E, was able to simultaneously bind both EGFR and PD-L1 antigens, inhibit EGF-mediated proliferation, effectively block PD-1/PD-L1 interaction, and induce strong antigen-specific antibody-dependent cellular cytotoxicity activity in vitro. Potent therapeutic efficacies of IgTT-1E in two different humanized mouse models were observed, where tumor growth control was associated with a significantly increased proportion of CD8+ T cells. These results support the development of IgTT-1E for the treatment of EGFR+ cancers.

Published
2023

7. Trispecific T-cell engagers for dual tumor-targeting of colorectal cancer

Author

Instituto de Salud Carlos III, Comunidad de Madrid, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia e Innovación (España), Asociación Española Contra el Cáncer, Fundación CRIS contra el Cáncer, Tapia-Galisteo, Antonio [0000-0002-0507-8435], Sánchez Rodríguez, Íñigo [0000-0002-6440-0922], Aguilar-Sopeña, Óscar [0000-0002-2435-8598], Harwood, Seandean Lykke [0000-0003-4654-8832], Ferreras-Gutiérrez, Mariola [0000-0003-4421-3158], Navarro, Rocío [0000-0002-0083-7711], Corbacho, Cesáreo [0000-0002-6644-3475], Compte, Marta [0000-0002-7138-9266], Lacadena, Javier [0000-0002-7314-0333], Blanco, Francisco J. [0000-0003-2545-4319], Chames, Patrick [0000-0002-6104-6286], Roda-Navarro, Pedro [0000-0003-3799-8823], Álvarez-Vallina, Luis [0000-0003-3053-6757], Sanz, Laura [0000-0002-3119-3218], Tapia-Galisteo, Antonio, Sánchez Rodríguez, Íñigo, Aguilar-Sopeña, Óscar, Harwood, Seandean Lykke, Narbona, Javier, Ferreras-Gutiérrez, Mariola, Navarro, Rocío, Martín-García, Laura, Corbacho, Cesáreo, Compte, Marta, Lacadena, Javier, Blanco, Francisco J., Chames, Patrick, Roda-Navarro, Pedro, Álvarez-Vallina, Luis, Sanz, Laura, Instituto de Salud Carlos III, Comunidad de Madrid, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia e Innovación (España), Asociación Española Contra el Cáncer, Fundación CRIS contra el Cáncer, Tapia-Galisteo, Antonio [0000-0002-0507-8435], Sánchez Rodríguez, Íñigo [0000-0002-6440-0922], Aguilar-Sopeña, Óscar [0000-0002-2435-8598], Harwood, Seandean Lykke [0000-0003-4654-8832], Ferreras-Gutiérrez, Mariola [0000-0003-4421-3158], Navarro, Rocío [0000-0002-0083-7711], Corbacho, Cesáreo [0000-0002-6644-3475], Compte, Marta [0000-0002-7138-9266], Lacadena, Javier [0000-0002-7314-0333], Blanco, Francisco J. [0000-0003-2545-4319], Chames, Patrick [0000-0002-6104-6286], Roda-Navarro, Pedro [0000-0003-3799-8823], Álvarez-Vallina, Luis [0000-0003-3053-6757], Sanz, Laura [0000-0002-3119-3218], Tapia-Galisteo, Antonio, Sánchez Rodríguez, Íñigo, Aguilar-Sopeña, Óscar, Harwood, Seandean Lykke, Narbona, Javier, Ferreras-Gutiérrez, Mariola, Navarro, Rocío, Martín-García, Laura, Corbacho, Cesáreo, Compte, Marta, Lacadena, Javier, Blanco, Francisco J., Chames, Patrick, Roda-Navarro, Pedro, Álvarez-Vallina, Luis, and Sanz, Laura

Abstract

Retargeting of T lymphocytes toward cancer cells by bispecific antibodies has demonstrated its therapeutic potential, with one such antibody approved for the treatment of acute lymphoblastic leukemia (blinatumomab) and several other in clinical trials. However, improvement of their efficacy and selectivity for solid tumors is still required. Here, we describe a novel tandem T-cell recruiting trispecific antibody for the treatment of colorectal cancer (CRC). This construct, termed trispecific T-cell engager (TriTE), consists of a CD3-specific single-chain Fv (scFv) flanked by anti-epidermal growth factor receptor (EGFR) and anti-epithelial cell adhesion molecule (EpCAM) single-domain VHH antibodies. The TriTE was well expressed in mammalian and yeast cells, bound the cognate antigens of the three parental antibodies, and enabled the specific cytolysis of EGFR- and/or EpCAM-expressing cancer cells, without inducing T cell activation and cytoxicity against double-negative (EGFR−EpCAM−) cancer cells. Bivalent bispecific targeting of double-positive HCT116 cells by TriTE improved in vitro potency up to 100-fold compared to single-positive cells and significantly prolonged survival in vivo. In addition, it was less efficient at killing single-positive target cells than the corresponding bispecific controls, leading to potentially enhanced tumor specificity. Moreover, dual targeting of two tumor-associated antigens may contribute toward preventing the tumor escape by antigen loss caused by selective pressures from conventional single-targeting T-cell engagers, and may help to overcome antigenic heterogeneity.

Published
2022

8. A PD-L1/EGFR bispecific antibody combines immune checkpoint blockade and direct anti-cancer action for an enhanced anti-tumor response

Author

Rubio-Pérez, Laura, primary, Lázaro-Gorines, Rodrigo, additional, Harwood, Seandean L., additional, Compte, Marta, additional, Navarro, Rocío, additional, Tapia-Galisteo, Antonio, additional, Bonet, Jaume, additional, Blanco, Belén, additional, Lykkemark, Simon, additional, Ramírez-Fernández, Ángel, additional, Ferreras-Gutiérrez, Mariola, additional, Domínguez-Alonso, Carmen, additional, Díez-Alonso, Laura, additional, Segura-Tudela, Alejandro, additional, Hangiu, Oana, additional, Erce-Llamazares, Ainhoa, additional, Blanco, Francisco J., additional, Santos, Cruz, additional, Rodríguez-Peralto, José L., additional, Sanz, Laura, additional, and Álvarez-Vallina, Luis, additional

Published
2023
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9. Trispecific T-cell engagers for dual tumor-targeting of colorectal cancer

Author

Antonio Tapia-Galisteo, Íñigo Sánchez Rodríguez, Oscar Aguilar-Sopeña, Seandean Lykke Harwood, Javier Narbona, Mariola Ferreras Gutierrez, Rocío Navarro, Laura Martín-García, Cesáreo Corbacho, Marta Compte, Javier Lacadena, Francisco J. Blanco, Patrick Chames, Pedro Roda-Navarro, Luis Álvarez-Vallina, Laura Sanz, Hospital Universitario Puerta de Hierro-Majadahonda [Madrid, Spain], Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Aarhus University [Aarhus], Centro de Investigaciones Biológicas Margarita Salas, Leadartis Sl, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU), Hospital Universitario 12 de Octubre [Madrid], Chames, Patrick, Instituto de Salud Carlos III, Comunidad de Madrid, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia e Innovación (España), Asociación Española Contra el Cáncer, Fundación CRIS contra el Cáncer, Tapia-Galisteo, Antonio, Sánchez Rodríguez, Íñigo, Aguilar-Sopeña, Óscar, Harwood, Seandean Lykke, Ferreras-Gutiérrez, Mariola, Navarro, Rocío, Corbacho, Cesáreo, Compte, Marta, Lacadena, Javier, Blanco, Francisco J., Roda-Navarro, Pedro, Álvarez-Vallina, Luis, Sanz, Laura, Tapia-Galisteo, Antonio [0000-0002-0507-8435], Sánchez Rodríguez, Íñigo [0000-0002-6440-0922], Aguilar-Sopeña, Óscar [0000-0002-2435-8598], Harwood, Seandean Lykke [0000-0003-4654-8832], Ferreras-Gutiérrez, Mariola [0000-0003-4421-3158], Navarro, Rocío [0000-0002-0083-7711], Corbacho, Cesáreo [0000-0002-6644-3475], Compte, Marta [0000-0002-7138-9266], Lacadena, Javier [0000-0002-7314-0333], Blanco, Francisco J. [0000-0003-2545-4319], Chames, Patrick [0000-0002-6104-6286], Roda-Navarro, Pedro [0000-0003-3799-8823], Álvarez-Vallina, Luis [0000-0003-3053-6757], and Sanz, Laura [0000-0002-3119-3218]

Subjects
Mammals, cancer immunotherapy, T-Lymphocytes, [SDV]Life Sciences [q-bio], single-domain antibodies, Immunology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, colorectal cancer, RC581-607, Epithelial Cell Adhesion Molecule, Lymphocyte Activation, scFv, scfv, ErbB Receptors, singledomain antibodies, [SDV] Life Sciences [q-bio], Oncology, Trispecific antibodies, tandem antibodies, Animals, Immunology and Allergy, Immunologic diseases. Allergy, Colorectal Neoplasms, trispecific antibodies, RC254-282
Abstract

14 p.-6 fig., Retargeting of T lymphocytes toward cancer cells by bispecific antibodies has demonstrated its therapeutic potential, with one such antibody approved for the treatment of acute lymphoblastic leukemia (blinatumomab) and several other in clinical trials. However, improvement of their efficacy and selectivity for solid tumors is still required. Here, we describe a novel tandem T-cell recruiting trispecific antibody for the treatment of colorectal cancer (CRC). This construct, termed trispecific T-cell engager (TriTE), consists of a CD3-specific single-chain Fv (scFv) flanked by anti-epidermal growth factor receptor (EGFR) and anti-epithelial cell adhesion molecule (EpCAM) single-domain VHH antibodies. The TriTE was well expressed in mammalian and yeast cells, bound the cognate antigens of the three parental antibodies, and enabled the specific cytolysis of EGFR- and/or EpCAM-expressing cancer cells, without inducing T cell activation and cytoxicity against double-negative (EGFR−EpCAM−) cancer cells. Bivalent bispecific targeting of double-positive HCT116 cells by TriTE improved in vitro potency up to 100-fold compared to single-positive cells and significantly prolonged survival in vivo. In addition, it was less efficient at killing single-positive target cells than the corresponding bispecific controls, leading to potentially enhanced tumor specificity. Moreover, dual targeting of two tumor-associated antigens may contribute toward preventing the tumor escape by antigen loss caused by selective pressures from conventional single-targeting T-cell engagers, and may help to overcome antigenic heterogeneity., This study was funded by grants from Instituto de Salud Carlos III PI16/00357, PI19/00132), partially supported by the European Regional Development Fund (ERDF), Comunidad Autónoma de Madrid (S2010-BMD-2312), and Ministerio de Economía y Competitividad (RTC-2016-5118-1) to L.S.; and from Ministerio de Ciencia e Innovación (SAF2017-89437-P and PID2020-117323RB-I00), partially supported by ERDF, the Spanish Association Against Cancer (AECC 19084) and the CRIS Cancer Foundation FCRIS-2018-0042, FCRIS-2021-0090 (FCRIS-2018-0042 and FCRIS-2021-0090) to L.A-V. A.T-G. was supported by a predoctoral fellowship from Comunidad Autónoma de Madrid (PEJD-2018-PRE/BMD-8314);Spanish Ministry of Science and Innovation [SAF2017-89437-P, PID2020-117323RB-I00].

Published
2022
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10. A PD-L1/EGFR bispecific antibody combines immune checkpoint blockade and direct anti-cancer action for an enhanced anti-tumor response

Author

Laura Rubio-Pérez, Rodrigo Lázaro-Gorines, Seandean L. Harwood, Marta Compte, Rocío Navarro, Antonio Tapia-Galisteo, Jaume Bonet, Belén Blanco, Simon Lykkemark, Ángel Ramírez-Fernández, Mariola Ferreras-Gutiérrez, Carmen Domínguez-Alonso, Laura Díez-Alonso, Alejandro Segura-Tudela, Oana Hangiu, Ainhoa Erce-Llamazares, Francisco J. Blanco, Cruz Santos, José L. Rodríguez-Peralto, Laura Sanz, Luis Álvarez-Vallina, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Fundación CRIS contra el Cáncer, Asociación Española Contra el Cáncer, Fundación 'La Caixa', Fundación de Investigación Biomédica Hospital 12 de Octubre, Universidad Francisco de Vitoria, Comunidad de Madrid, Rubio-Pérez, Laura, Lázaro-Gorines, Rodrigo, Harwood, Seandean Lykke, Compte, Marta, Navarro, Rocío, Tapia-Galisteo, Antonio, Bonet, Jaume, Blanco, Belén, Lykkemark, Simon, Ramírez-Fernández, Ángel, Ferreras-Gutiérrez, Mariola, Domínguez-Alonso, Carmen, Díez-Alonso, Laura, Segura-Tudela, Alejandro, Hangiu, Oana, Erce-Llamazares, Ainhoa, Blanco, Francisco J., Santos, Cruz, Rodríguez-Peralto, J. L., Sanz, Laura, and Alvarez-Vallina, Luis

Subjects
combination, cancer immunotherapy, family, receptor, Immunology, persistent activity, bispecific antibody, igg1, Oncology, cetuximab, cells, Immunology and Allergy, activation, escape, Cancer immunotherapy, bispecific antibody, Dual action, Immune checkpoint blockade, Epithelial growth factor receptor
Abstract

Immune checkpoint blockade (ICB) with antibodies has shown durable clinical responses in a wide range of cancer types, but the overall response rate is still limited. Other effective therapeutic modalities to increase the ICB response rates are urgently needed. New bispecific antibody (bsAb) formats combining the ICB effect and a direct action on cancer cells could improve the efficacy of current immunotherapies. Here, we report the development of a PD-L1/EGFR symmetric bsAb by fusing a dual-targeting tandem trimmer body with the human IgG1 hinge and Fc regions. The bsAb was characterized in vitro and the antitumor efficacy was evaluated in humanized mice bearing xenografts of aggressive triple-negative breast cancer and lung cancer. The IgG-like hexavalent bsAb, designated IgTT-1E, was able to simultaneously bind both EGFR and PD-L1 antigens, inhibit EGF-mediated proliferation, effectively block PD-1/PD-L1 interaction, and induce strong antigen-specific antibody-dependent cellular cytotoxicity activity in vitro. Potent therapeutic efficacies of IgTT-1E in two different humanized mouse models were observed, where tumor growth control was associated with a significantly increased proportion of CD8+ T cells. These results support the development of IgTT-1E for the treatment of EGFR+ cancers., L.A-V. was supported by grants from the MCIN/AEI/10.13039/ 501100011033 (PID2020-117323RB-100 and PDC2021-121711-100), the Instituto de Salud Carlos III (DTS20/00089), the CRIS Cancer Foundation (FCRIS-2021-0090), the Spanish Association Against Cancer (PROYE19084ALVA), the Fundación ‘‘La Caixa’’ (HR21-00761 project IL7R_LungCan) and the Fundación de Investigación Biomédica 12 de Octubre Programa Investiga (2022-0082). B.B and L.S. were supported by grants PI20/01030 and PI19/00132 from the Instituto de Salud Carlos III (PI20/01030). FJB and MF-G were supported by grants PID2020- 113225GB-I00 and PRE2018-085788 funded by MCIN/AEI/10.13039/ 501100011033. L.R-P. was supported by a predoctoral fellowship from the Immunology Chair, Universidad Francisco de Vitoria/Merck. C. D-A. was supported by a predoctoral fellowship from the MCIN/AEI/ 10.13039/501100011033 (PRE2018-083445). L.D-A. was supported by a Rio Hortega fellowship from the Instituto de Salud Carlos III (CM20/ 00004). O.H. was supported by an industrial PhD fellowship from the Comunidad de Madrid (IND2020/BMD-17668). AE-L was supported industrial PhD fellowship from the Instituto de Salud Carlos III (IFI18/ 00045)

Published
2023
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