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1. PVR (CD155) epigenetic status mediates immunotherapy response in multiple myeloma

Author

Martinez-Verbo, Laura, Veselinova, Yoana, Llinàs-Arias, Pere, García-Prieto, Carlos A., Noguera-Castells, Aleix, Pato, Miguel L., Bueno-Costa, Alberto, Campillo-Marcos, Ignacio, Villanueva, Lorea, Oliver-Caldes, Aina, Cardus, Oriol, Salsench, Sergi V., García-Ortiz, Almudena, Valeri, Antonio, Rojas, Elizabeta A., Barrena, Naroa, Gutiérrez, Norma C., Prósper, Felipe, Agirre, Xabier, Fernández de Larrea, Carlos, Martínez-López, Joaquín, Ferrer, Gerardo, and Esteller, Manel

Published
2024
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2. Abstract P22: PVR (CD155) epigenetic status mediates adoptive cell therapy and anti-TIGIT response in Multiple Myeloma

Author

Martinez-Verbo, Laura, primary, Villanueva, Lorea, additional, Llinàs-Arias, Pere, additional, García-Prieto, Carlos A., additional, Piñeyro, David, additional, Oliver-Caldes, Aina, additional, García-Ortiz, Almudena, additional, Valeri, Antonio, additional, de Larrea, Carlos Fernández, additional, Martínez-López, Joaquín, additional, Ferrer, Gerardo, additional, and Esteller, Manel, additional

Published
2024
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3. Corrigendum: Personalized monitoring of circulating tumor DNA with a specific signature of trackable mutations after chimeric antigen receptor T-cell therapy in follicular lymphoma patients

Author

Jiménez-Ubieto, Ana, primary, Martín-Muñoz, Alejandro, additional, Poza, María, additional, Dorado, Sara, additional, García-Ortiz, Almudena, additional, Revilla, Enrique, additional, Sarandeses, Pilar, additional, Ruiz-Heredia, Yanira, additional, Baumann, Tycho, additional, Rodríguez, Antonia, additional, Calbacho, María, additional, Sánchez, Pilar Martínez, additional, Pina, José María Sánchez, additional, García-Sancho, Alejandro Martín, additional, Figaredo, Gloria, additional, Gil-Alós, Daniel, additional, Rufián, Laura, additional, Rodríguez, Margarita, additional, Carneros, Laura, additional, Martínez-Laperche, Carolina, additional, Bastos-Oreiro, Mariana, additional, Wang, Chongwu, additional, Cedena, María-Teresa, additional, Rapado, Inmaculada, additional, de Toledo, Paula, additional, Gallardo, Miguel, additional, Valeri, Antonio, additional, Ayala, Rosa, additional, Martínez-López, Joaquín, additional, and Barrio, Santiago, additional

Published
2024
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4. NKG2D-CAR-transduced natural killer cells efficiently target multiple myeloma

Author

Leivas, Alejandra, Valeri, Antonio, Córdoba, Laura, García-Ortiz, Almudena, Ortiz, Alejandra, Sánchez-Vega, Laura, Graña-Castro, Osvaldo, Fernández, Lucía, Carreño-Tarragona, Gonzalo, Pérez, Manuel, Megías, Diego, Paciello, María Liz, Sánchez-Pina, Jose, Pérez-Martínez, Antonio, Lee, Dean A., Powell, Jr., Daniel J., Río, Paula, and Martínez-López, Joaquín

Published
2021
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6. OA-02 α-NKG2A blockade overcomes multiple myeloma resistance to BCMA and NKG2D CAR-NKAE cells

Author

Encinas, Jessica, primary, García-Ortiz, Almudena, additional, Maroto-Martín, Elena, additional, Castellano, Eva, additional, Oliva, Raquel, additional, Alonso, Rafael, additional, Cedena, Teresa, additional, Leivas, Alejandra, additional, García, Laura García, additional, Martín-Antonio, Beatriz, additional, Suñe, Guillermo, additional, Lee, Dean, additional, Prabhala, Rao, additional, Jr., Daniel Powell, additional, Río, Paula, additional, Martinez-Lopez, Joaquín, additional, and Valeri, Antonio, additional

Published
2023
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7. Corrigendum: Personalized monitoring of circulating tumor DNA with a specific signature of trackable mutations after chimeric antigen receptor T-cell therapy in follicular lymphoma patients

Author

Jiménez-Ubieto, Ana, primary, Martín-Muñoz, Alejandro, additional, Poza, María, additional, Dorado, Sara, additional, García-Ortiz, Almudena, additional, Revilla, Enrique, additional, Sarandeses, Pilar, additional, Ruiz-Heredia, Yanira, additional, Baumann, Tycho, additional, Rodríguez, Antonia, additional, Calbacho, María, additional, Sánchez, Pilar Martínez, additional, Pina, José María Sánchez, additional, García-Sancho, Alejandro Martín, additional, Figaredo, Gloria, additional, Rufián, Laura, additional, Rodríguez, Margarita, additional, Carneros, Laura, additional, Martínez-Laperche, Carolina, additional, Bastos-Oreiro, Mariana, additional, Wang, Chongwu, additional, Cedena, María-Teresa, additional, Rapado, Inmaculada, additional, de Toledo, Paula, additional, Gallardo, Miguel, additional, Valeri, Antonio, additional, Ayala, Rosa, additional, Martínez-López, Joaquín, additional, and Barrio, Santiago, additional

Published
2023
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8. P822: EPIGENETIC REGULATION OF CD155 ON MULTIPLE MYELOMA CELLS INFLUENCES ANTI-TUMOR NOVEL IMMUNOTHERAPEUTIC APPROACHES

Author

Martinez-Verbo, Laura, primary, Villanueva, Lorea, additional, Llinàs-Arias, Pere, additional, Antonio García-Prieto, Carlos, additional, Piñeyro, David, additional, Oliver-Caldes, Aina, additional, García-Ortiz, Almudena, additional, Valeri, Antonio, additional, De Larrea, Carlos Fernández, additional, Martínez-López, Joaquin, additional, Ferrer, Gerardo, additional, and Esteller, Manel, additional

Published
2023
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9. S256: HLA-E/NKG2A CHECKPOINT DRIVES MULTIPLE MYELOMA RESISTANCE TO CAR-NK THERAPY

Author

Encinas, Jessica, primary, García-Ortiz, Almudena, additional, Maroto-Martín, Elena, additional, Castellano, Eva, additional, Oliva, Raquel, additional, Alonso Fernández, Rafael, additional, Teresa Cedena Romero, Maria, additional, Leivas, Alejandra, additional, Martín-Antonio, Beatriz, additional, Suñe, Guillermo, additional, Lee, Dean A., additional, Powell, Daniel J., additional, Río, Paula, additional, Martinez-Lopez, Joaquín, additional, and Valeri, Antonio, additional

Published
2023
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10. Personalized monitoring of circulating tumor DNA with a specific signature of trackable mutations after chimeric antigen receptor T-cell therapy in follicular lymphoma patients

Author

Jiménez-Ubieto, Ana, Martín-Muñoz, Alejandro, Poza, María, Dorado, Sara, García-Ortiz, Almudena, Revilla, Enrique, Sarandeses, Pilar, Ruiz-Heredia, Yanira, Baumann, Tycho, Rodríguez, Antonia, Calbacho, María, Sánchez, Pilar Martínez, Pina, José María Sánchez, García-Sancho, Alejandro Martín, Figaredo, Gloria, Rufián, Laura, Rodríguez, Margarita, Carneros, Laura, Martínez-Laperche, Carolina, Bastos-Oreiro, Mariana, Wang, Chongwu, Cedena, María-Teresa, Rapado, Inmaculada, de Toledo, Paula, Valeri, Antonio, Ayala, Rosa, Martínez-López, Joaquín, and Barrio, Santiago

Subjects
Immunology, Immunology and Allergy
Published
2023
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11. Personalized monitoring of circulating tumor DNA with a specific signature of trackable mutations after chimeric antigen receptor T-cell therapy in follicular lymphoma patients.

Author

Jiménez-Ubieto, Ana, Martín-Muñoz, Alejandro, Poza, María, Dorado, Sara, García-Ortiz, Almudena, Revilla, Enrique, Sarandeses, Pilar, Ruiz-Heredia, Yanira, Baumann, Tycho, Rodríguez, Antonia, Calbacho, María, Martínez Sánchez, Pilar, Sánchez Pina, José María, García-Sancho, Alejandro Martín, Figaredo, Gloria, Rufián, Laura, Rodríguez, Margarita, Carneros, Laura, Martínez-Laperche, Carolina, and Bastos-Oreiro, Mariana

Subjects
CIRCULATING tumor DNA, CHIMERIC antigen receptors, FOLLICULAR lymphoma, SOMATIC mutation, T cells
Abstract

Background: CART therapy has produced a paradigm shift in the treatment of relapsing FL patients. Strategies to optimize disease surveillance after these therapies are increasingly necessary. This study explores the potential value of ctDNA monitoring with an innovative signature of personalized trackable mutations. Method: Eleven FL patients treated with anti-CD19 CAR T-cell therapy were included. One did not respond and was excluded. Genomic profiling was performed before starting lymphodepleting chemotherapy to identify somatic mutations suitable for LiqBio-MRD monitoring. The dynamics of the baseline mutations (4.5 per patient) were further analyzed on 59 cfDNA follow-up samples. PET/CT examinations were performed on days +90, +180, +365, and every six months until disease progression or death. Results: After a median follow-up of 36 months, all patients achieved a CR as the best response. Two patients progressed. The most frequently mutated genes were CREBBP, KMT2D and EP300. Simultaneous analysis of ctDNA and PET/CT was available for 18 time-points. When PET/CT was positive, two out of four ctDNA samples were LiqBio-MRD negative. These two negative samples corresponded to women with a unique mesenteric mass in two evaluations and never relapsed. Meanwhile, 14 PET/CT negative images were mutation-free based on our LiqBio-MRD analysis (100%). None of the patients had a negative LiqBio-MRD test by day +7. Interestingly, all durably responding patients had undetectable ctDNA at or around three months after infusion. Two patients presented discordant results by PET/CT and ctDNA levels. No progression was confirmed in these cases. All the progressing patients were LiqBio-MRD positive before progression. Conclusion: This is a proof-of-principle for using ctDNA to monitor response to CAR T-cell therapy in FL. Our results confirm that a non-invasive liquid biopsy MRD analysis may correlate with response and could be used to monitor response. Harmonized definitions of ctDNA molecular response and pinpointing the optimal timing for assessing ctDNA responses are necessary for this setting. If using ctDNA analysis, we suggest restricting follow-up PET/CT in CR patients to a clinical suspicion of relapse, to avoid false-positive results. [ABSTRACT FROM AUTHOR]

Published
2024
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12. Overcoming tumor resistance mechanisms in CAR-NK cell therapy

Author

Valeri, Antonio, primary, García-Ortiz, Almudena, additional, Castellano, Eva, additional, Córdoba, Laura, additional, Maroto-Martín, Elena, additional, Encinas, Jessica, additional, Leivas, Alejandra, additional, Río, Paula, additional, and Martínez-López, Joaquín, additional

Published
2022
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13. P-015: Comprehensive comparison of allogenic CAR NK cells for MM treatment

Author

Martín, Elena Maroto, primary, Encinas, Jessica, additional, García-Ortiz, Almudena, additional, Castellano, Eva, additional, Ugalde, Laura, additional, Alonso, Rafael, additional, Leivas, Alejandra, additional, Paciello, Mari Liz, additional, Garrido, Vanesa, additional, Martín-Antonio, Beatriz, additional, Suñe, Guillermo, additional, Cedena, Maria-Teresa, additional, Jr, Daniel J Powell, additional, Río, Paula, additional, López, Joaquín Martinez, additional, and Valeri, Antonio, additional

Published
2022
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14. P-007: Exploring a safety switch in NKG2D and BCMA CAR NK-92MI immunotherapy

Author

Martín, Elena Maroto, primary, Encinas, Jessica, additional, García-Ortiz, Almudena, additional, Castellano, Eva, additional, Ugalde, Laura, additional, Alonso, Rafael, additional, Leivas, Alejandra, additional, Paciello, Mari Liz, additional, Garrido, Vanesa, additional, Martín-Antonio, Beatriz, additional, Suñe, Guillermo, additional, Cedena, Teresa, additional, Powell, Daniel J., additional, Río, Paula, additional, Martínez-López, Joaquín, additional, and Valeri, Antonio, additional

Published
2021
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15. Personalized Monitoring of Circulating Tumor DNA By a Specific Signature of Trackable Mutations after Chimeric Antigen Receptor t-Cell Therapy in Non-Hodgkin B Cell Lymphoma

Author

Barrio, Santiago, Martinez-Laperche, Carolina, Martín-Muñoz, Alejandro, Rodriguez, Margarita, Rufian, Laura, de la Iglesia, Ismael, Muñiz Sevilla, Paula, Dorado, Sara, Ballesteros, Ana K, Bailen, Rebeca, Poza, María, Chicano, Maria, García-Ortiz, Almudena, Diaz Crespo, Francisco, Sanchez Pina, Jose Maria, Revilla, Enrique, Sarandeses, Pilar, Valeri, Antonio, Kwon, Mi, Martinez-Lopez, Joaquin, Borde, Ismael Buño, Jimenez Ubieto, Ana, and Bastos-Oreiro, Mariana

Published
2023
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17. The Role of Tumor Microenvironment in Multiple Myeloma Development and Progression

Author

García Ortiz, Almudena, Rodríguez García, Yaiza, Encinas, Jessica, Maroto Martín, Elena, Castellano, Eva, Teixidó, Joaquín, Martínez López, Joaquín, García Ortiz, Almudena, Rodríguez García, Yaiza, Encinas, Jessica, Maroto Martín, Elena, Castellano, Eva, Teixidó, Joaquín, and Martínez López, Joaquín

Abstract

Multiple myeloma (MM) is a hematologic cancer characterized by clonal proliferation of plasma cells in the bone marrow (BM). The progression, from the early stages of the disease as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to MM and occasionally extramedullary disease, is drastically affected by the tumor microenvironment (TME). Soluble factors and direct cell–cell interactions regulate MM plasma cell trafficking and homing to the BM niche. Mesenchymal stromal cells, osteoclasts, osteoblasts, myeloid and lymphoid cells present in the BM create a unique milieu that favors MM plasma cell immune evasion and promotes disease progression. Moreover, TME is implicated in malignant cell protection against anti-tumor therapy. This review describes the main cellular and non-cellular components located in the BM, which condition the immunosuppressive environment and lead the MM establishment and progression., Ministerio de Ciencia e Innovación (MICINN), Instituto de Salud Carlos III/ CRIS Foundation, Instituto de Salud Carlos III (ISCIII), Research Institute Hospital 12 de Octubre, Depto. de Medicina, Fac. de Medicina, TRUE, pub

Published
2021

18. Myc-Related Mitochondrial Activity as a Novel Target for Multiple Myeloma

Author

Ortiz Ruiz, Alejandra, Ruiz Heredia, Yanira, Morales, María Luz, Aguilar Garrido, Pedro, García Ortiz, Almudena, Valeri Lozano, Antonio, Bárcena Asensio, Carmen, García Martín, Rosa María, Garrido, Vanesa, Moreno Gutiérrez, Laura, Gimenez, Alicia, Navarro Aguadero, Miguel Ángel, Velasco Estévez, María, Lospitao, Eva, Cedena Romero, M. Teresa, Barrio, Santiago, Martínez López, Joaquín, Linares Gómez, María, Gallardo, Miguel, Ortiz Ruiz, Alejandra, Ruiz Heredia, Yanira, Morales, María Luz, Aguilar Garrido, Pedro, García Ortiz, Almudena, Valeri Lozano, Antonio, Bárcena Asensio, Carmen, García Martín, Rosa María, Garrido, Vanesa, Moreno Gutiérrez, Laura, Gimenez, Alicia, Navarro Aguadero, Miguel Ángel, Velasco Estévez, María, Lospitao, Eva, Cedena Romero, M. Teresa, Barrio, Santiago, Martínez López, Joaquín, Linares Gómez, María, and Gallardo, Miguel

Abstract

Mitochondria are involved in the development and acquisition of a malignant phenotype in hematological cancers. Recently, their role in the pathogenesis of multiple myeloma (MM) has been suggested to be therapeutically explored. MYC is a master regulator of b-cell malignancies such as multiple myeloma, and its activation is known to deregulate mitochondrial function. We investigated the impact of mitochondrial activity on the distinct entities of the disease and tested the efficacy of the mitochondrial inhibitor, tigecycline, to overcome MM proliferation. COXII expression, COX activity, mitochondrial mass, and mitochondrial membrane potential demonstrated a progressive increase of mitochondrial features as the disease progresses. In vitro and in vivo therapeutic targeting using the mitochondrial inhibitor tigecycline showed promising efficacy and cytotoxicity in monotherapy and combination with the MM frontline treatment bortezomib. Overall, our findings demonstrate how mitochondrial activity emerges in MM transformation and disease progression and the efficacy of therapies targeting these novel vulnerabilities., Instituto de Salud Carlos III/Ministerio de Economía, Comercio y Empresa (España)/Fondo Europeo de Desarrollo Regional, Asociación Española Contra el Cáncer: Fundación CRIS contra el cáncer, Comunidad de Madrid, Sección Deptal. de Bioquímica y Biología Molecular (Farmacia), Depto. de Medicina, Fac. de Farmacia, Fac. de Medicina, TRUE, pub

Published
2021

19. The role of tumor microenvironment in multiple myeloma development and progression

Author

Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Sociedad Española de Hematología y Hemoterapia, García-Ortiz, Almudena, Rodríguez-García, Yaiza, Encinas, Jessica, Maroto-Martín, Elena, Castellano, Eva, Teixidó, Joaquín, Martínez-López, Joaquín, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Sociedad Española de Hematología y Hemoterapia, García-Ortiz, Almudena, Rodríguez-García, Yaiza, Encinas, Jessica, Maroto-Martín, Elena, Castellano, Eva, Teixidó, Joaquín, and Martínez-López, Joaquín

Abstract

Multiple myeloma (MM) is a hematologic cancer characterized by clonal proliferation of plasma cells in the bone marrow (BM). The progression, from the early stages of the disease as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to MM and occasionally extramedullary disease, is drastically affected by the tumor microenvironment (TME). Soluble factors and direct cell–cell interactions regulate MM plasma cell trafficking and homing to the BM niche. Mesenchymal stromal cells, osteoclasts, osteoblasts, myeloid and lymphoid cells present in the BM create a unique milieu that favors MM plasma cell immune evasion and promotes disease progression. Moreover, TME is implicated in malignant cell protection against anti-tumor therapy. This review describes the main cellular and non-cellular components located in the BM, which condition the immunosuppressive environment and lead the MM establishment and progression.

Published
2021

20. Myc-Related Mitochondrial Activity as a Novel Target for Multiple Myeloma

Author

Ortiz-Ruiz, Alejandra, primary, Ruiz-Heredia, Yanira, additional, Morales, María Luz, additional, Aguilar-Garrido, Pedro, additional, García-Ortiz, Almudena, additional, Valeri, Antonio, additional, Bárcena, Carmen, additional, García-Martin, Rosa María, additional, Garrido, Vanesa, additional, Moreno, Laura, additional, Gimenez, Alicia, additional, Navarro-Aguadero, Miguel Ángel, additional, Velasco-Estevez, María, additional, Lospitao, Eva, additional, Cedena, María Teresa, additional, Barrio, Santiago, additional, Martínez-López, Joaquín, additional, Linares, María, additional, and Gallardo, Miguel, additional

Published
2021
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22. Erm proteins at the crossroad of leukocyte polarization, migration and intercellular adhesion

Author

García-Ortiz, Almudena, Serrador, Juan M., Ministerio de Ciencia, Innovación y Universidades (España), and Consejo Superior de Investigaciones Científicas (España)

Subjects
Polarization, Moesin, Leukocytes, macromolecular substances, Ezrin, actin, Iimmune synapse
Abstract

Ezrin, radixin and moesin proteins (ERMs) are plasma membrane (PM) organizers that link the actin cytoskeleton to the cytoplasmic tail of transmembrane proteins, many of which are adhesion receptors, in order to regulate the formation of F-actin-based structures (e.g., microspikes and microvilli). ERMs also effect transmission of signals from the PM into the cell, an action mainly exerted through the compartmentalized activation of the small Rho GTPases Rho, Rac and Cdc42. Ezrin and moesin are the ERMs more highly expressed in leukocytes, and although they do not always share functions, both are mainly regulated through phosphatidylinositol 4,5-bisphosphate (PIP) binding to the N-terminal band 4.1 protein-ERM (FERM) domain and phosphorylation of a conserved Thr in the C-terminal ERM association domain (C-ERMAD), exerting their functions through a wide assortment of mechanisms. In this review we will discuss some of these mechanisms, focusing on how they regulate polarization and migration in leukocytes, and formation of actin-based cellular structures like the phagocytic cup-endosome and the immune synapse in macrophages/neutrophils and lymphocytes, respectively, which represent essential aspects of the effector immune response. Ministerio de Ciencia Innovación y Universidades (MICIU)/FEDER, grant number RTI2018-100815-B-100 (J.M.S.). We acknowledge support of the publication fee by the Spanish Research Council (CSIC) Open Access Publication Support Initiative

Published
2020

23. Erm proteins at the crossroad of leukocyte polarization, migration and intercellular adhesion

Author

Ministerio de Ciencia, Innovación y Universidades (España), Consejo Superior de Investigaciones Científicas (España), García-Ortiz, Almudena, Serrador, Juan M., Ministerio de Ciencia, Innovación y Universidades (España), Consejo Superior de Investigaciones Científicas (España), García-Ortiz, Almudena, and Serrador, Juan M.

Abstract

Ezrin, radixin and moesin proteins (ERMs) are plasma membrane (PM) organizers that link the actin cytoskeleton to the cytoplasmic tail of transmembrane proteins, many of which are adhesion receptors, in order to regulate the formation of F-actin-based structures (e.g., microspikes and microvilli). ERMs also effect transmission of signals from the PM into the cell, an action mainly exerted through the compartmentalized activation of the small Rho GTPases Rho, Rac and Cdc42. Ezrin and moesin are the ERMs more highly expressed in leukocytes, and although they do not always share functions, both are mainly regulated through phosphatidylinositol 4,5-bisphosphate (PIP) binding to the N-terminal band 4.1 protein-ERM (FERM) domain and phosphorylation of a conserved Thr in the C-terminal ERM association domain (C-ERMAD), exerting their functions through a wide assortment of mechanisms. In this review we will discuss some of these mechanisms, focusing on how they regulate polarization and migration in leukocytes, and formation of actin-based cellular structures like the phagocytic cup-endosome and the immune synapse in macrophages/neutrophils and lymphocytes, respectively, which represent essential aspects of the effector immune response.

Published
2020

25. Exploring NKG2D and BCMA-CAR NK-92 for Adoptive Cellular Therapy to Multiple Myeloma

Author

Martín, Elena Maroto, primary, Encinas, Jessica, additional, García-Ortiz, Almudena, additional, Ugalde, Laura, additional, Fernández, Rafael Alonso, additional, Leivas, Alejandra, additional, Paciello, María Liz, additional, Garrido, Vanesa, additional, Martín-Antonio, Beatriz, additional, Suñe, Guillermo, additional, Cedena, Maria-Teresa, additional, Powell, Daniel J., additional, Río, Paula, additional, Martinez-Lopez, Joaquin, additional, and Valeri, Antonio, additional

Published
2019
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26. eNOS S-nitrosylates β-actin on Cys374 and regulates PKC-θ at the immune synapse by impairing actin binding to profilin-1

Author

García-Ortiz, Almudena, primary, Martín-Cofreces, Noa B., additional, Ibiza, Sales, additional, Ortega, Ángel, additional, Izquierdo-Álvarez, Alicia, additional, Trullo, Antonio, additional, Victor, Víctor M., additional, Calvo, Enrique, additional, Sot, Begoña, additional, Martínez-Ruiz, Antonio, additional, Vázquez, Jesús, additional, Sánchez-Madrid, Francisco, additional, and Serrador, Juan M., additional

Published
2017
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Author

Laura Machesky, García-Ortiz, Almudena, Martín-Cofreces, Noa B., Ibiza, Sales, Ortega, Ángel, Izquierdo-Álvarez, Alicia, Trullo, Antonio, Victor, Víctor M., Calvo, Enrique, Sot, Begoña, Martínez Ruiz, Antonio, Jesús Vázquez, Francisco Sánchez-Madrid, Juan M. Serrador, Laura Machesky, García-Ortiz, Almudena, Martín-Cofreces, Noa B., Ibiza, Sales, Ortega, Ángel, Izquierdo-Álvarez, Alicia, Trullo, Antonio, Victor, Víctor M., Calvo, Enrique, Sot, Begoña, Martínez Ruiz, Antonio, Jesús Vázquez, Francisco Sánchez-Madrid, and Juan M. Serrador

Abstract

Instituto de Salud Carlos III, Depto. de Bioquímica y Biología Molecular, Fac. de Farmacia, TRUE, pub

Published
2017

28. eNOS S-nitrosylates ß-actin on Cys374 and regulates PKC-¿ at the immune synapse by impairing actin binding to profilin-1

Author

Instituto de Salud Carlos III, García-Ortiz, Almudena, Serrador, Juan M., Instituto de Salud Carlos III, García-Ortiz, Almudena, and Serrador, Juan M.

Abstract

The actin cytoskeleton coordinates the organization of signaling microclusters at the immune synapse (IS); however, the mechanisms involved remain poorly understood. We show here that nitric oxide (NO) generated by endothelial nitric oxide synthase (eNOS) controls the coalescence of protein kinase C-¿ (PKC-¿) at the central supramolecular activation cluster (c-SMAC) of the IS. eNOS translocated with the Golgi to the IS and partially colocalized with F-actin around the c-SMAC. This resulted in reduced actin polymerization and centripetal retrograde flow of ß-actin and PKC-¿ from the lamellipodium-like distal (d)-SMAC, promoting PKC-¿ activation. Furthermore, eNOS-derived NO S-nitrosylated ß-actin on Cys374 and impaired actin binding to profilin-1 (PFN1), as confirmed with the transnitrosylating agent S-nitroso-L-cysteine (Cys-NO). The importance of NO and the formation of PFN1-actin complexes on the regulation of PKC-¿ was corroborated by overexpression of PFN1- and actin-binding defective mutants of ß-actin (C374S) and PFN1 (H119E), respectively, which reduced the coalescence of PKC-¿ at the c-SMAC. These findings unveil a novel NO-dependent mechanism by which the actin cytoskeleton controls the organization and activation of signaling microclusters at the IS.

Published
2017

29. Increase of Mitochondrial Activity Contributes to the Bortezomib-Relapsed in Multiple Myeloma, a Novel Therapeutic Opportunity

Author

Ortiz-Ruiz, Alejandra, Ruiz-Heredia, Yanira, Samur, Mehmet, Aguilar-Garrido, Pedro, Morales, Maria Luz, Valeri, Antonio, Garcia-Ortiz, Almudena, Barrio, Santiago, Bárcena, Carmen, Garcia-Martin, Rosa Maria, Garrido, Vanesa, Fulciniti, Mariateresa, Munshi, Nikhil C., Cedena, María Teresa, Martinez-Lopez, Joaquin, Linares, Maria, and Gallardo, Miguel

Published
2019
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31. Engineered T cells secreting anti-BCMA T cell engagers control multiple myeloma and promote immune memory in vivo

Author

Díez-Alonso, Laura, Falgas, Aïda, Arroyo-Ródenas, Javier, Romencín, Paola A., Martínez, Alba, Gómez-Rosel, Marina, Blanco, Belén, Jiménez-Reinoso, Anaïs, Mayado, Andrea, Pérez-Pons, Alba, Aguilar-Sopeña, Óscar, Ramírez-Fernández, Ángel, Segura-Tudela, Alejandro, Perez-Amill, Lorena, Tapia-Galisteo, Antonio, Domínguez-Alonso, Carmen, Rubio-Pérez, Laura, Jara, Maria, Solé, Francesc, Hangiu, Oana, Almagro, Laura, Albitre, Ángela, Penela, Petronila, Sanz, Laura, Anguita, Eduardo, Valeri, Antonio, García-Ortiz, Almudena, Río, Paula, Juan, Manel, Martínez-López, Joaquín, Roda-Navarro, Pedro, Martín-Antonio, Beatriz, Orfao, Alberto, Menéndez, Pablo, Bueno, Clara, and Álvarez-Vallina, Luis

Abstract

Multiple myeloma is the second most common hematological malignancy in adults and remains an incurable disease. B cell maturation antigen (BCMA)–directed immunotherapy, including T cells bearing chimeric antigen receptors (CARs) and systemically injected bispecific T cell engagers (TCEs), has shown remarkable clinical activity, and several products have received market approval. However, despite promising results, most patients eventually become refractory and relapse, highlighting the need for alternative strategies. Engineered T cells secreting TCE antibodies (STAb) represent a promising strategy that combines the advantages of adoptive cell therapies and bispecific antibodies. Here, we undertook a comprehensive preclinical study comparing the therapeutic potential of T cells either expressing second-generation anti-BCMA CARs (CAR-T) or secreting BCMAxCD3 TCEs (STAb-T) in a T cell–limiting experimental setting mimicking the conditions found in patients with relapsed/refractory multiple myeloma. STAb-T cells recruited T cell activity at extremely low effector-to-target ratios and were resistant to inhibition mediated by soluble BCMA released from the cell surface, resulting in enhanced cytotoxic responses and prevention of immune escape of multiple myeloma cells in vitro. These advantages led to robust expansion and persistence of STAb-T cells in vivo, generating long-lived memory BCMA-specific responses that could control multiple myeloma progression in xenograft models, outperforming traditional CAR-T cells. These promising preclinical results encourage clinical testing of the BCMA-STAb-T cell approach in relapsed/refractory multiple myeloma.

Published
2024
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