29 results on '"Martin‐Antonio, B."'
Search Results
2. S103: EFFICACY AND SAFETY OF ARI0002H, AN ACADEMIC BCMA-DIRECTED CAR-T CELL THERAPY WITH FRACTIONATED INITIAL THERAPY AND BOOSTER DOSE IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA
- Author
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Fernandez De Larrea, C., primary, González-Calle, V., additional, Oliver-Caldés, A., additional, Cabañas, V., additional, Rodríguez-Otero, P., additional, Español-Rego, M., additional, Reguera, J. L., additional, López-Corral, L., additional, Martin-Antonio, B., additional, Paiva, B., additional, Inogés, S., additional, Rosiñol, L., additional, López-Díaz de Cerio, A., additional, Tovar, N., additional, López-Parra, M., additional, Rodríguez-Lobato, L. G., additional, Sánchez-Salinas, A., additional, Varea, S., additional, Ortiz-Maldonado, V., additional, Pérez Simón, J. A., additional, Prósper, F., additional, Juan, M., additional, Moraleda, J. M., additional, Mateos, M. V., additional, Pascal, M., additional, and Urbano-Ispizua, A., additional
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- 2022
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3. Cellular and molecular immune responses of the sea bass ( Dicentrarchus labrax) experimentally infected with betanodavirus
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Scapigliati, G., Buonocore, F., Randelli, E., Casani, D., Meloni, S., Zarletti, G., Tiberi, M., Pietretti, D., Boschi, I., Manchado, M., Martin-Antonio, B., Jimenez-Cantizano, R., Bovo, G., Borghesan, F., Lorenzen, N., Einer-Jensen, K., Adams, S., Thompson, K., Alonso, C., Bejar, J., Cano, I., Borrego, J.J., and Alvarez, M.C.
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- 2010
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4. In vitro potential of human mesenchymal stem cells for corneal epithelial regeneration
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Nieto-Nicolau, N, Martin-Antonio, B, Muller-Sanchez, C, and Casaroli-Marano, RP
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mesenchymal stem cells ,genetic structures ,corneal epithelial differentiation ,cytokeratins ,wound healing ,sense organs ,limbal stem cell deficiency ,cell therapy ,limbal stem cells ,eye diseases - Abstract
Aim: To determine the potential of mesenchymal stem cells (MSC) for corneal epithelial regeneration in vitro. Materials & methods: Bone marrow MSC (BM-MSC) and adipose tissue MSC were analyzed for corneal epithelial and mesenchymal markers, using limbal stem cells and corneal cells as controls. MSC with better potential were cultured with specific mediums for epithelial induction. Transepithelial electric resistance and wound healing assay with human corneal epithelial cells were performed. Results: BM-MSC showed better potential, increased corneal markers, and higher transepithelial electric resistance values when induced with limbal epithelial culture medium. Induced BM-MSC promoted better wound healing of human corneal epithelial cells by paracrine secretion. Conclusion: BM-MSC has potential for corneal epithelial induction in a protocol compatible with human application. Graphical abstract
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- 2020
5. MicroRNA expression profiling changes along G-CSF treatment and at long term in CD34+ cells from healthy donors: P1128
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Baez, A., Martin-Antonio, B., Gel, B., Prats, C., Carmona, M., Marín, P., Rozman, M., and Urbano-Ispizua, A.
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- 2011
6. Association of CXCL12, VCAM1 and CD34 gene polymorphisms with peripheral blood progenitor cell mobilisation in healthy donors: O419
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Martin-Antonio, B., Carmona, M., Trujillo, P., Espigado, I., Alcántara, J., Freire, A., and Urbano-Ispizua, A.
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- 2009
7. Genomic polymorphisms of the innate immune system and allogeneic stem cell transplantation
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Martin-Antonio, B, Granell, M, and Urbano-Ispizua, A
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antimicrobial peptides ,allogeneic stem cell transplantation ,pattern-recognition receptor ,graft-versus-host disease ,innate immune system ,natural killer cell ,infection ,polymorphism - Abstract
Allogeneic stem cell transplantation (allo-HSCT) is largely employed for treating patients affected by many hematological disorders, but despite the considerable improvement in the treatment of its complications, graft-versus-host disease and infections remain important causes of morbidity and mortality. Innate immunity is crucial in the immune defense against infections after allo-HSCT, and in the biological reactions leading to graft-versus-host disease. Thus, the innate immune system plays an important role in allo-HSCT clinical outcome. It is known now that cytokine gene polymorphisms greatly influence the outcome of allo-HSCT. In addition, genetic variability of some pattern-recognition receptors and antimicrobial peptides represent a promising field to be researched for allo-HSCT impact. Furthermore, more recent work suggests the importance of genetic variability between donor and recipient in the killer cell immunoglobulin-like receptors of the natural killer cells on the allo-HSCT outcome. This article discusses the main cytokines and innate immune gene polymorphisms influencing allo-HSCT outcome, presents new innate immune genes with promising expectations and points at the importance of genetic variability in natural killer cells in allo-HSCT outcome.
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- 2010
8. Transmissible cytotoxicity of multiple myeloma cells by cord blood-derived NK cells is mediated by vesicle trafficking
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Martin-Antonio, B, primary, Najjar, A, additional, Robinson, S N, additional, Chew, C, additional, Li, S, additional, Yvon, E, additional, Thomas, M W, additional, Mc Niece, I, additional, Orlowski, R, additional, Muñoz-Pinedo, C, additional, Bueno, C, additional, Menendez, P, additional, Fernández de Larrea, C, additional, Urbano-Ispizua, A, additional, Shpall, E J, additional, and Shah, N, additional
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- 2014
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9. Bone marrow mesenchymal stem cells from patients with aplastic anemia maintain functional and immune properties and do not contribute to the pathogenesis of the disease
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Bueno, C., primary, Roldan, M., additional, Anguita, E., additional, Romero-Moya, D., additional, Martin-Antonio, B., additional, Rosu-Myles, M., additional, Canizo, C. d., additional, Campos, F., additional, Garcia, R., additional, Gomez-Casares, M., additional, Fuster, J. L., additional, Jurado, M., additional, Delgado, M., additional, and Menendez, P., additional
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- 2014
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10. Granulocyte colony-stimulating factor produces long-term changes in gene and microRNA expression profiles in CD34+ cells from healthy donors
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Baez, A., primary, Martin-Antonio, B., additional, Piruat, J. I., additional, Prats, C., additional, Alvarez-Laderas, I., additional, Barbado, M. V., additional, Carmona, M., additional, Urbano-Ispizua, A., additional, and Perez-Simon, J. A., additional
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- 2013
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11. Impact of constitutional polymorphisms in VCAM1 and CD44 on CD34+ cell collection yield after administration of granulocyte colony-stimulating factor to healthy donors
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Martin-Antonio, B., primary, Carmona, M., additional, Falantes, J., additional, Gil, E., additional, Baez, A., additional, Suarez, M., additional, Marin, P., additional, Espigado, I., additional, and Urbano-Ispizua, A., additional
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- 2010
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12. Transmissible cytotoxicity of multiple myeloma cells by cord blood-derived NK cells is mediated by vesicle trafficking.
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Martin-Antonio, B, Najjar, A, Robinson, S N, Chew, C, Li, S, Yvon, E, Thomas, M W, Mc Niece, I, Orlowski, R, Muñoz-Pinedo, C, Bueno, C, Menendez, P, Fernández de Larrea, C, Urbano-Ispizua, A, Shpall, E J, and Shah, N
- Subjects
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CELL-mediated cytotoxicity , *MYELOMA proteins , *TUMOR proteins , *KILLER cells , *VESICLES (Cytology) - Abstract
Natural killer cells (NK) are important effectors of anti-tumor immunity, activated either by the downregulation of HLA-I molecules on tumor cells and/or the interaction of NK-activating receptors with ligands that are overexpressed on target cells upon tumor transformation (including NKG2D and NKP30). NK kill target cells by the vesicular delivery of cytolytic molecules such as Granzyme-B and Granulysin activating different cell death pathways, which can be Caspase-3 dependent or Caspase-3 independent. Multiple myeloma (MM) remains an incurable neoplastic plasma-cell disorder. However, we previously reported the encouraging observation that cord blood-derived NK (CB-NK), a new source of NK, showed anti-tumor activity in an in vivo murine model of MM and confirmed a correlation between high levels of NKG2D expression by MM cells and increased efficacy of CB-NK in reducing tumor burden. We aimed to characterize the mechanism of CB-NK-mediated cytotoxicity against MM cells. We show a Caspase-3- and Granzyme-B-independent cell death, and we reveal a mechanism of transmissible cell death between cells, which involves lipid-protein vesicle transfer from CB-NK to MM cells. These vesicles are secondarily transferred from recipient MM cells to neighboring MM cells amplifying the initial CB-NK cytotoxicity achieved. This indirect cytotoxicity involves the transfer of NKG2D and NKP30 and leads to lysosomal cell death and decreased levels of reactive oxygen species in MM cells. These findings suggest a novel and unique mechanism of CB-NK cytotoxicity against MM cells and highlight the importance of lipids and lipid transfer in this process. Further, these data provide a rationale for the development of CB-NK-based cellular therapies in the treatment of MM. [ABSTRACT FROM AUTHOR]
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- 2015
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13. A novel genetic and clinical predictive model for severe acute and chronic graft versus host disease after identical HLA-allogeneic stem-cell transplantation
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Buces, E., Martinez-Laperche, C., Aguilera Morillo, C., Picornell, A., Lillo, R., Gonzalez-Rivera, M., Bosch-Vizcaya, A., Martin-Antonio, B., Guillem, V., Nieto, J., Gonzalez, M., Rafael de la Camara, Brunet, S., Jimenez-Velasco, A., Espigado, I., Vallejo, C., Sampol, A., Bellon, J. M., Serrano, D., Kwon, M., Gayoso, J., Balsalobre, P., Urbano-Izpizua, A., Solano, C., Gallardo, D., Diez-Martin, J. L., Buno, I., and Gvhd, Immunotheraphy Spanish Grp
14. LOSS OF THE INHIBITORY RECEPTOR CD85J/LILRB1 ON MALIGNANT PLASMA CELLS: FROM MGUS TO SYMPTOMATIC MULTIPLE MYELOMA
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Ester Lozano, Diaz, T., Mena, M. P., Calvo, X., Calderon, M., Martin-Antonio, B., Cibeira, M. T., Rosinol, L., Blade, J., and Fernandez Larrea, C.
15. SNPS IN THE PROMOTER REGION OF THE IL17A GENE ALLOW ANTICIPATION OF COMPLICATIONS AFTER SIBLING HLA-IDENTICAL ALLOGENEIC STEM CELL TRANSPLANTATION (ALLO-SCT)
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Buces, E., Martinez-Laperche, C., Gonzalez-Rivera, M., Bosch-Vizcaya, A., Martin-Antonio, B., Guillem, V., Nieto, J., Gonzalez, M., La Camara, R., Brunet, S., ILDEFONSO ESPIGADO, Vallejo, C., Sampol, A., Serrano, D., Kwon, M., Gayoso, J., Balsalobre, P., Solano, C., Urbano-Izpizua, A., Jimenez-Velasco, A., Gallardo, D., Diez-Martin, J., and Buno, I.
16. GENERATION OF TWO NEW IMMUNOTHERAPEUTIC PRODUCTS WITH GENETICALLY MODIFIED NK CELLS. COMPARISON OF CLINICALLY RELEVANT CARS IN MULTIPLE MYELOMA
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Maroto-Martin, E., Encinas, J., Garcia-Ortiz, A., Ugalde, L., Alonso, R., Leivas, A., Paciello Mari, L., Garrido, V., Martin-Antonio, B., Sune, G., Cedena, T., Powell, D., Rio, P., Joaquin Martinez-Lopez, and Valeri, A.
17. A NEW PREDICTIVE MODEL BASED ON THE GENOMIC PROFILE OF POLYMORPHISMS IN GENES OF CYTOKINES ALLOWS TO PREDICT THE INCIDENCE OF POST-TRANSPLANT EICR ALLOGENEIC HEMATOPOIETIC
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Buces Gonzalez, E., Martinez Laperche, C., Aguilera Morillo, M. C., Picornell, A., Lillo, R., Gonzalez Rivera, M., Bosch Vizcaya, A., Martin-Antonio, B., Guillem, V., Nieto, J. B., Gonzalez, M., La Camara, R., Brunet, S., Jimenez Velasco, A., ILDEFONSO ESPIGADO, Vallejo, C., Sampol, A., Serrano, D., Kwon, M., Gayoso, J., Balsalobre, P., Bellon, J. M., Urbano Izpizua, A., Solano, C., Gallardo, D., Diez-Martin, J. L., Romo, J., and Buno, I.
18. Serum mass spectrometry for treatment monitoring in patients with multiple myeloma receiving ARI0002h CAR T-cells.
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Ortiz de Landazuri I, Oliver-Caldés A, Español-Rego M, Agulló C, Contreras MT, Zabaleta A, Puig N, Cabañas V, González-Calle V, Zugasti I, Inogés S, Rodríguez Otero P, Martin-Antonio B, Reguera JL, López-Diaz de Cerio A, Aróstegui JI, Uribe-Herranz M, Benítez-Ribas D, Rodríguez-Lobato LG, González EA, Tovar N, Charry P, Navarro S, Rosiñol L, Tréboles K, Mora G, Yagüe J, Moraleda JM, Urbano-Ispizua Á, Mateos MV, Pascal M, Paiva B, Juan M, and Fernández de Larrea C
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- Humans, Male, Female, Middle Aged, Aged, Receptors, Chimeric Antigen, Myeloma Proteins analysis, Adult, Antibodies, Monoclonal, Humanized therapeutic use, B-Cell Maturation Antigen, Multiple Myeloma therapy, Multiple Myeloma blood, Immunotherapy, Adoptive methods, Mass Spectrometry methods
- Abstract
Chimeric antigen receptor (CAR) T-cell therapies have increased the patients with relapsed/refractory multiple myeloma (RRMM) in whom standard electrophoretic techniques fail to detect the M-protein. Quantitative immunoprecipitation mass spectrometry (QIP-MS) can accurately measure serum M-protein with high sensitivity, and identify interferences caused by therapeutic monoclonal antibodies. Here, we investigate the outcome of QIP-MS in 33 patients treated with the academic BCMA-directed CAR T-cell ARI0002h (Cesnicabtagene Autoleucel). QIP-MS offered more detailed insights than serum immunofixation (sIFE), identifying glycosylated M-proteins and minor additional peaks. Moreover, the potential interferences owing to daratumumab or tocilizumab treatments were successfully detected. When analysing different assay platforms during patient's monitoring after ARI0002h administration, we observed that QIP-MS showed a high global concordance (78.8%) with sIFE, whereas it was only moderate (55.6%) with bone marrow (BM)-based next-generation flow cytometry (NGF). Furthermore, QIP-MS consistently demonstrated the lowest negativity rate across the different timepoints (27.3% vs. 60.0% in months 1 and 12, respectively). Patients with QIP-MS(+)/BM-based NGF(-) showed a non-significant shorter median progression free survival than those with QIP-MS(-)/BM-based NGF(-). In summary, we show the first experience to our knowledge demonstrating that QIP-MS could be particularly useful as a non-invasive technique when evaluating response after CAR T-cell treatment in MM., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
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- 2024
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19. Biomarkers of Efficacy and Safety of the Academic BCMA-CART ARI0002h for the Treatment of Refractory Multiple Myeloma.
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Oliver-Caldes A, Español-Rego M, Zabaleta A, González-Calle V, Navarro-Velázquez S, Inogés S, de Cerio AL, Cabañas V, López-Muñoz N, Rodríguez-Otero P, Reguera JL, Moreno DF, Martínez-Cibrian N, López-Corral L, Pérez-Amill L, Martin-Antonio B, Rosiñol L, Cid J, Tovar N, Sáez-Peñataro J, López-Parra M, Olesti E, Guillén E, Varea S, Rodríguez-Lobato LG, Battram AM, González MS, Sánchez-Salinas A, González-Navarro A, Ortiz-Maldonado V, Delgado J, Prósper F, Juan M, Martínez-López J, Moraleda JM, Mateos MV, Urbano-Ispizua Á, Paiva B, Pascal M, and Fernández de Larrea C
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- Humans, Male, Female, Middle Aged, Aged, Adult, Biomarkers, Tumor, Receptors, Chimeric Antigen immunology, Treatment Outcome, Multiple Myeloma therapy, Multiple Myeloma immunology, Multiple Myeloma drug therapy, B-Cell Maturation Antigen immunology, B-Cell Maturation Antigen antagonists & inhibitors, Immunotherapy, Adoptive adverse effects, Immunotherapy, Adoptive methods
- Abstract
Purpose: B-cell maturation antigen (BCMA)-chimeric antigen receptor T-cells (CART) improve results obtained with conventional therapy in the treatment of relapsed/refractory multiple myeloma. However, the high demand and expensive costs associated with CART therapy might prove unsustainable for health systems. Academic CARTs could potentially overcome these issues. Moreover, response biomarkers and resistance mechanisms need to be identified and addressed to improve efficacy and patient selection. Here, we present clinical and ancillary results of the 60 patients treated with the academic BCMA-CART, ARI0002h, in the CARTBCMA-HCB-01 trial., Patients and Methods: We collected apheresis, final product, peripheral blood and bone marrow samples before and after infusion. We assessed BCMA, T-cell subsets, CART kinetics and antibodies, B-cell aplasia, cytokines, and measurable residual disease by next-generation flow cytometry, and correlated these to clinical outcomes., Results: At cut-off date March 17, 2023, with a median follow-up of 23.1 months (95% CI, 9.2-37.1), overall response rate in the first 3 months was 95% [95% confidence interval (CI), 89.5-100]; cytokine release syndrome (CRS) was observed in 90% of patients (5% grades ≥3) and grade 1 immune effector cell-associated neurotoxicity syndrome was reported in 2 patients (3%). Median progression-free survival was 15.8 months (95% CI, 11.5-22.4). Surface BCMA was not predictive of response or survival, but soluble BCMA correlated with worse clinical outcomes and CRS severity. Activation marker HLA-DR in the apheresis was associated with longer progression-free survival and increased exhaustion markers correlated with poorer outcomes. ARI0002h kinetics and loss of B-cell aplasia were not predictive of relapse., Conclusions: Despite deep and sustained responses achieved with ARI0002h, we identified several biomarkers that correlate with poor outcomes., (©2024 American Association for Cancer Research.)
- Published
- 2024
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20. Fractionated initial infusion and booster dose of ARI0002h, a humanised, BCMA-directed CAR T-cell therapy, for patients with relapsed or refractory multiple myeloma (CARTBCMA-HCB-01): a single-arm, multicentre, academic pilot study.
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Oliver-Caldés A, González-Calle V, Cabañas V, Español-Rego M, Rodríguez-Otero P, Reguera JL, López-Corral L, Martin-Antonio B, Zabaleta A, Inogés S, Varea S, Rosiñol L, López-Díaz de Cerio A, Tovar N, Jiménez R, López-Parra M, Rodríguez-Lobato LG, Sánchez-Salinas A, Olesti E, Calvo-Orteu M, Delgado J, Pérez-Simón JA, Paiva B, Prósper F, Sáez-Peñataro J, Juan M, Moraleda JM, Mateos MV, Pascal M, Urbano-Ispizua A, and Fernández de Larrea C
- Subjects
- Humans, Male, Female, Middle Aged, Immunotherapy, Adoptive adverse effects, B-Cell Maturation Antigen, Pilot Projects, Cytokines, Multiple Myeloma drug therapy, COVID-19
- Abstract
Background: Chimeric antigen receptor (CAR) T-cell therapy is a promising option for patients with heavily treated multiple myeloma. Point-of-care manufacturing can increase the availability of these treatments worldwide. We aimed to assess the safety and activity of ARI0002h, a BCMA-targeted CAR T-cell therapy developed by academia, in patients with relapsed or refractory multiple myeloma., Methods: CARTBCMA-HCB-01 is a single-arm, multicentre study done in five academic centres in Spain. Eligible patients had relapsed or refractory multiple myeloma and were aged 18-75 years; with an Eastern Cooperative Oncology Group performance status of 0-2; two or more previous lines of therapy including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody; refractoriness to the last line of therapy; and measurable disease according to the International Myeloma Working Group criteria. Patients received an initial fractionated infusion of 3 × 10
6 CAR T cells per kg bodyweight in three aliquots (0·3, 0·9, and 1·8 × 106 CAR-positive cells per kg intravenously on days 0, 3, and 7) and a non-fractionated booster dose of up to 3 × 106 CAR T cells per kg bodyweight, at least 100 days after the first infusion. The primary endpoints were overall response rate 100 days after first infusion and the proportion of patients developing cytokine-release syndrome or neurotoxic events in the first 30 days after receiving treatment. Here, we present an interim analysis of the ongoing trial; enrolment has ended. This study is registered with ClinicalTrials.gov, NCT04309981, and EudraCT, 2019-001472-11., Findings: Between June 2, 2020, and Feb 24, 2021, 44 patients were assessed for eligibility, of whom 35 (80%) were enrolled. 30 (86%) of 35 patients received ARI0002h (median age 61 years [IQR 53-65], 12 [40%] were female, and 18 [60%] were male). At the planned interim analysis (cutoff date Oct 20, 2021), with a median follow-up of 12·1 months (IQR 9·1-13·5), overall response during the first 100 days from infusion was 100%, including 24 (80%) of 30 patients with a very good partial response or better (15 [50%] with complete response, nine [30%] with very good partial response, and six [20%] with partial response). Cytokine-release syndrome was observed in 24 (80%) of 30 patients (all grade 1-2). No cases of neurotoxic events were observed. Persistent grade 3-4 cytopenias were observed in 20 (67%) patients. Infections were reported in 20 (67%) patients. Three patients died: one because of progression, one because of a head injury, and one due to COVID-19., Interpretation: ARI0002h administered in a fractioned manner with a booster dose after 3 months can provide deep and sustained responses in patients with relapsed or refractory multiple myeloma, with a low toxicity, especially in terms of neurological events, and with the possibility of a point-of-care approach., Funding: Instituto de Salud Carlos III (co-funded by the EU), Fundación La Caixa, and Fundació Bosch i Aymerich., Competing Interests: Declaration of interests AO-C declares support for attending meetings from Janssen. VG-C declares receiving honoraria from Janssen, Pfizer, Bristol Myers Squibb (BMS)/Celgene, and GSK; support for attending meetings or travel from Janssen and GSK; and participation on data safety monitoring or advisory board from Janssen. VC declares receiving honoraria from Janssen, BMS, Sanofi, GSK, and Amgen; support for attending meetings or travel from Janssen; and participation on data safety monitoring or advisory board from Janssen, Sanofi, and Amgen. PR-O declares receiving honoraria from consulting activities from BMS, Janssen, Sanofi, Abbvie, Pfizer, Roche, and GSK; honoraria from lectures from BMS, Janssen, Sanofi and GSK; support for attending meetings or travel from Abbvie; and participation on data safety monitoring or advisory board from Janssen. JLR declares receiving consulting fees from Janssen; honoraria from Janssen, Amgen, Sanofi, Kite/Gilead, Novartis, and BMS; support for attending meetings or travel from Kite/Gilead; and participation on data safety monitoring or advisory board from Janssen, BMS, and Novartis. LL-C declares receiving honoraria from Kite/Gilead, Celgene, Janssen, and Novartis; support for attending meetings or travel from Kite/Gilead, Celgene, Janssen, and Novartis; and participation on data safety monitoring or advisory board from Janssen. BM-A declares to be co-inventor in the patent of ARI0002. LR declares honoraria from Janssen, BMS/Celgene, Amgen, Takeda, Sanofi, and GSK; participation on data safety monitoring or advisory board of Janssen, BMS-Celgene, Amgen, Takeda, Sanofi, and GSK. ML-P declares receiving consulting fees from Celgene/BMS; honoraria from Janssen and Kite/Gilead; and participation on data safety monitoring or advisory board from Celgene/BMS and Novartis. LGR-L declares honoraria from Janssen, GSK, Sanofi, and BMS; travel grants from Janssen, Amgen, GSK, Pfizer and Sanofi; and participation on data safety monitoring or advisory board from GSK and Sanofi. AS-S declares receiving travel grants from Jazz Pharmaceuticals, Pfizer, and MSD. JAP-S declares research and travel support Takeda, Abbvie, Gilead, AMGEN, Jazz, Alexion, Pierre Fabre and Beigene; educational activities, speaker, and advisory fees with Gilead, Jazz, Alexion, AMGEN, Novartis, Janssen, BMS, and MSD; and participation on data safety monitoring or advisory board from Gilead, Jazz, Alexion, AMGEN, Novartis, Janssen, BMS and MSD. BP reports research funding from BMS, GSK, Roche, Beigene, and Sanofi; consultancy fees from BMS, GSK, Janssen, Sanofi and Takeda; honoraria from Adaptive, Amgen, Becton Dickinson, BMS/Celgene, GSK, Janssen, Sanofi, and Roche; and support for attending meetings from GSK. FP declares receiving grants from the Spanish Ministry of Health (ISCIII) and the Government of Navarra; honoraria from Janssen, Oryzon, Dialectica, Novartis, Instituto Roche, Servier, ViviaBiotech, and Techspert; support for attending meetings or travel from Gilead, Celgene, and Janssen; and a leadership or fiduciary role in RICORS Terav and IDISNA. MJ declares receiving research or travel support by Fundació Bancaria la Caixa, ISCIII, and CellNex Teleom; honoraria from educational activities, speaker, and advisory roles with Miltenyi and indirectly with sponsors of congresses; and participation on data safety monitoring or advisory boards with MAB Gyala. JMM declares receiving honoriaria from Gilead/Kite, Novartis, BMS/Celgene, and Roche; travel grants, accommodation, and expenses from Jazz Pharma, Gilead-Kite, Janssen, and Sandoz; and consulting or advisory board fees in Jazz Pharma, Novartis, and Sandoz. M-VM declares honoraria derived from lectures and participation in advisory boards from Janssen, BMS/Celgene, Takeda, Amgen, GSK, Pfizer, Regeneron, Roche, and Sanofi. MP declares receiving honoraria from Thermofisher Scientific and LetiPharma. AU-I declares receiving grants from the Spanish Ministry of Health (ISCIII); honoraria for lectures from BMS and Gilead; support for attending meetings from Amgen; 23% of participation in ARI-002 patent ARI-001 patent in preparation; advisory board fees and participation in Miltenyi biomedicine; being coordinator of the Spanish group of CAR T-cell therapy. CFL declares receiving grants through his institution from BMS, Janssen, and Amgen; honoraria from Amgen, Janssen, BMS, GSK, and Sanofi; support for attending meetings or travel from Janssen, BMS, GSK, and Amgen; and participation in data safety monitoring or advisory boards with Janssen, BMS, Amgen, Pfizer, and Sanofi. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)- Published
- 2023
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21. CAR density influences antitumoral efficacy of BCMA CAR T cells and correlates with clinical outcome.
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Rodriguez-Marquez P, Calleja-Cervantes ME, Serrano G, Oliver-Caldes A, Palacios-Berraquero ML, Martin-Mallo A, Calviño C, Español-Rego M, Ceballos C, Lozano T, San Martin-Uriz P, Vilas-Zornoza A, Rodriguez-Diaz S, Martinez-Turrillas R, Jauregui P, Alignani D, Viguria MC, Redondo M, Pascal M, Martin-Antonio B, Juan M, Urbano-Ispizua A, Rodriguez-Otero P, Alfonso-Pierola A, Paiva B, Lasarte JJ, Inoges S, Lopez-Diaz de Cerio A, San-Miguel J, Fernandez de Larrea C, Hernaez M, Rodriguez-Madoz JR, and Prosper F
- Abstract
Identification of new markers associated with long-term efficacy in patients treated with CAR T cells is a current medical need, particularly in diseases such as multiple myeloma. In this study, we address the impact of CAR density on the functionality of BCMA CAR T cells. Functional and transcriptional studies demonstrate that CAR T cells with high expression of the CAR construct show an increased tonic signaling with up-regulation of exhaustion markers and increased in vitro cytotoxicity but a decrease in in vivo BM infiltration. Characterization of gene regulatory networks using scRNA-seq identified regulons associated to activation and exhaustion up-regulated in CAR
High T cells, providing mechanistic insights behind differential functionality of these cells. Last, we demonstrate that patients treated with CAR T cell products enriched in CARHigh T cells show a significantly worse clinical response in several hematological malignancies. In summary, our work demonstrates that CAR density plays an important role in CAR T activity with notable impact on clinical response.- Published
- 2022
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22. First report of CART treatment in AL amyloidosis and relapsed/refractory multiple myeloma.
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Oliver-Caldes A, Jiménez R, Español-Rego M, Cibeira MT, Ortiz-Maldonado V, Quintana LF, Castillo P, Guijarro F, Tovar N, Montoro M, Benitez-Ribas D, Bataller A, González-Navarro EA, Cid J, Lozano M, Perez-Amill L, Martin-Antonio B, Mena MP, Moreno DF, Rodríguez-Lobato LG, Campistol JM, Calvo G, Bladé J, Rosiñol L, Juan M, Pascal M, Urbano-Ispizua A, and Fernández de Larrea C
- Subjects
- Female, Humans, Immunoglobulin Light-chain Amyloidosis complications, Immunoglobulin Light-chain Amyloidosis immunology, Middle Aged, Multiple Myeloma complications, Multiple Myeloma immunology, Neoplasm Recurrence, Local immunology, Neoplasm Recurrence, Local pathology, Drug Resistance, Neoplasm, Immunoglobulin Light-chain Amyloidosis therapy, Immunotherapy, Adoptive methods, Multiple Myeloma therapy, Neoplasm Recurrence, Local therapy
- Abstract
Multiple myeloma (MM) remains incurable despite the number of novel therapies that have become available in recent years. Occasionally, a patient with MM will develop an amyloid light-chain (AL) amyloidosis with organ dysfunction. Chimeric antigen receptor T-cell (CART) therapy has become a promising approach in treating hematological malignancies. Our institution has developed a second-generation B-cell maturation antigen (BCMA)-CART which is currently being tested in a clinical trial for relapsed/refractory MM.We present the first reported case, to our knowledge, of a patient with AL amyloidosis and renal involvement in the course of an MM, successfully treated with CART therapy targeting BCMA. The patient received a fractioned dose of 3×10
6 /kg BCMA-CARTs after lymphodepletion. At 3 months from infusion, the patient had already obtained a deep hematological response with negative measurable residual disease by flow cytometry in the bone marrow. After 12 months, the patient remains in hematological stringent complete remission and has achieved an organ renal response with a decrease of 70% of proteinuria.This case suggests that concomitant AL amyloidosis in the setting of MM can benefit from CART therapy, even in patients in which predominant symptoms at the time of treating are caused by AL amyloidosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2021
- Full Text
- View/download PDF
23. Gene Expression Analysis of the Bone Marrow Microenvironment Reveals Distinct Immunotypes in Smoldering Multiple Myeloma Associated to Progression to Symptomatic Disease.
- Author
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Isola I, Brasó-Maristany F, Moreno DF, Mena MP, Oliver-Calders A, Paré L, Rodríguez-Lobato LG, Martin-Antonio B, Cibeira MT, Bladé J, Rosiñol L, Prat A, Lozano E, and Fernández de Larrea C
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Tumor genetics, Carcinogenesis, Cellular Microenvironment, Cohort Studies, Cytotoxicity, Immunologic genetics, Disease Progression, Female, Gene Expression Regulation, Neoplastic, Humans, Immune Checkpoint Proteins genetics, Male, Middle Aged, Monoclonal Gammopathy of Undetermined Significance genetics, Monoclonal Gammopathy of Undetermined Significance mortality, Multiple Myeloma genetics, Multiple Myeloma mortality, Phenotype, Smoldering Multiple Myeloma genetics, Smoldering Multiple Myeloma mortality, Survival Analysis, Tumor Necrosis Factor-alpha genetics, Bone Marrow physiology, Monoclonal Gammopathy of Undetermined Significance immunology, Multiple Myeloma immunology, Smoldering Multiple Myeloma immunology
- Abstract
Background: We previously reported algorithms based on clinical parameters and plasma cell characteristics to identify patients with smoldering multiple myeloma (SMM) with higher risk of progressing who could benefit from early treatment. In this work, we analyzed differences in the immune bone marrow (BM) microenvironment in SMM to better understand the role of immune surveillance in disease progression and to identify immune biomarkers associated to higher risk of progression., Methods: Gene expression analysis of BM cells from 28 patients with SMM, 22 patients with monoclonal gammopathy of undetermined significance (MGUS) and 22 patients with symptomatic MM was performed by using Nanostring Technology., Results: BM cells in SMM compared to both MGUS and symptomatic MM showed upregulation of genes encoding for key molecules in cytotoxicity. However, some of these cytotoxic molecules positively correlated with inhibitory immune checkpoints, which may impair the effector function of BM cytotoxic cells. Analysis of 28 patients with SMM revealed 4 distinct clusters based on immune composition and activation markers. Patients in cluster 2 showed a significant increase in expression of cytotoxic molecules but also inhibitory immune checkpoints compared to cluster 3, suggesting the presence of cytotoxic cells with an exhausted phenotype. Accordingly, patients in cluster 3 had a significantly longer progression free survival. Finally, individual gene expression analysis showed that higher expression of TNF superfamily members (TNF, TNFAIP3, TNFRSF14) was associated with shorter progression free survival., Conclusions: Our results suggest that exhausted cytotoxic cells are associated to high-risk patients with SMM. Biomarkers overexpressed in patients with this immune gene profile in combination with clinical parameters and PC characterization may be useful to identify SMM patients with higher risk of progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Isola, Brasó-Maristany, Moreno, Mena, Oliver-Calders, Paré, Rodríguez-Lobato, Martin-Antonio, Cibeira, Bladé, Rosiñol, Prat, Lozano and Fernández de Larrea.)
- Published
- 2021
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24. NK cells enhance CAR-T cell antitumor efficacy by enhancing immune/tumor cells cluster formation and improving CAR-T cell fitness.
- Author
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Bachiller M, Perez-Amill L, Battram AM, Carné SC, Najjar A, Verhoeyen E, Juan M, Urbano-Ispizua A, and Martin-Antonio B
- Subjects
- Animals, Cell Line, Tumor, Hematologic Neoplasms immunology, Heterografts, Humans, K562 Cells, Killer Cells, Natural transplantation, Mice, T-Lymphocytes transplantation, Hematologic Neoplasms therapy, Immunotherapy, Adoptive methods, Killer Cells, Natural immunology, Receptors, Chimeric Antigen immunology, T-Lymphocytes immunology
- Abstract
Background: Chimeric antigen receptor (CAR)-T cell immunotherapy has modified the concept of treatment in hematological malignancies. In comparison with pediatric patients, where responses are maintained over many years, older patients, such as those with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM), present lower persistence of CAR-T cells that might be due to decreased fitness of T cells acquired with aging. Moreover, cord blood derived-NK cells (CB-NKs) and CAR-NK cells derived from CB-NK can be used 'off-the-shelf' as immune cells with antitumor properties for the treatment of cancer patients. However, to date, clinical studies have only demonstrated the safety of these therapies but not optimal efficacy. To confront the shortcomings of each therapy, we devised a novel approach consisting of simultaneous (CAR-)NK cell and CAR-T cell administration. In this setting, NK cells demonstrate an important immunoregulation of T cells that could be exploited to enhance the efficacy of CAR-T cells., Methods: A combinatorial treatment based on either CAR-T and CAR-NK cells or CB-NK and CAR-T cells in two models of NHL and MM was performed. Antitumor efficacy was analyzed in vitro and in vivo, and parameters related to early activation, exhaustion and senescence of T cells were analyzed., Results: We show that CAR-NK cells derived from CB-NK are only effective at high doses (high E:T ratio) and that their activity rapidly decreases over time in comparison with CAR-T cells. In comparison and to exploit the potential of 'off-the-shelf' CB-NK, we demonstrate that a low number of CB-NK in the CAR-T cell product promotes an early activation of CAR-T cells and their migration to MM cells leading to enhanced anti-MM efficacy. Moreover, cytokines related to CRS development were not increased, and importantly, CB-NK enhanced the fitness of both CAR
pos and CARneg T cells, promoting lower levels of exhaustion and senescence., Conclusion: This study demonstrates a relevant immunoregulatory role of CB-NK collaborating with CAR-T cells to enhance their antitumor activity. A novel and different approach to consider in CAR-T cell immunotherapy studies is presented here with the goal to enhance the efficacy of the treatment., Competing Interests: Competing interests: None., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2021
- Full Text
- View/download PDF
25. Nectin-2 Expression on Malignant Plasma Cells Is Associated with Better Response to TIGIT Blockade in Multiple Myeloma.
- Author
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Lozano E, Mena MP, Díaz T, Martin-Antonio B, León S, Rodríguez-Lobato LG, Oliver-Caldés A, Cibeira MT, Bladé J, Prat A, Rosiñol L, and Fernández de Larrea C
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Tumor analysis, Bone Marrow pathology, Clinical Decision-Making, Female, Humans, Male, Middle Aged, Multiple Myeloma pathology, Nectins analysis, Patient Selection, Plasma Cells pathology, Receptors, Immunologic metabolism, Receptors, Virus analysis, Receptors, Virus metabolism, Treatment Outcome, Biomarkers, Tumor metabolism, Multiple Myeloma drug therapy, Nectins metabolism, Plasma Cells metabolism, Receptors, Immunologic antagonists & inhibitors
- Abstract
Purpose: T-cell immunoreceptor with Ig and ITIM domain (TIGIT) blockade could represent an alternative therapeutic option to release the immune response in patients with multiple myeloma. Here we analyzed the expression of TIGIT and its ligands poliovirus receptor (PVR) and nectin-2 in the bone marrow (BM) of patients with monoclonal gammopathies and the efficacy of TIGIT blockade activating antimyeloma immunity., Experimental Design: Expression levels of TIGIT and its ligands were characterized by flow cytometry and ELISA. TIGIT blockade was analyzed in in vitro functional assays with peripheral T cells. BM cells were studied with NanoString technology, real-time PCR, and ex vivo patient BM cell models., Results: TIGIT and its ligands are highly expressed in the BM of patients with multiple myeloma, suggesting that may play a role in restraining immune activation. TIGIT blockade depleted FoxP3
+ Tregs while increasing proliferation of IFNγ-producing CD4+ T cells from patients with multiple myeloma. PVR ligation inhibited CD8+ T-cell signaling and cell proliferation which could be overcome with anti-TIGIT mAb. However, BM cells showed a remarkable heterogeneity in immune signature. Accordingly, functional ex vivo BM assays revealed that only some patients respond to checkpoint blockade. Thus, response to TIGIT blockade correlated with low frequency of TIGIT+ cells and high nectin-2 expression on malignant plasma cells., Conclusions: TIGIT blockade efficiently reinvigorated peripheral T cells from patients with multiple myeloma. However, in the BM, the efficacy of blocking anti-TIGIT mAb to achieve tumor cell death may depend on the expression of TIGIT and nectin-2, becoming potential predictive biomarkers for identifying patients who may benefit from TIGIT blockade., (©2020 American Association for Cancer Research.)- Published
- 2020
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26. Loss of the Immune Checkpoint CD85j/LILRB1 on Malignant Plasma Cells Contributes to Immune Escape in Multiple Myeloma.
- Author
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Lozano E, Díaz T, Mena MP, Suñe G, Calvo X, Calderón M, Pérez-Amill L, Rodríguez V, Pérez-Galán P, Roué G, Cibeira MT, Rosiñol L, Isola I, Rodríguez-Lobato LG, Martin-Antonio B, Bladé J, and Fernández de Larrea C
- Subjects
- Adult, Aged, Aged, 80 and over, B-Lymphocytes, Cell Line, Tumor, Down-Regulation immunology, Female, Humans, Killer Cells, Natural immunology, Male, Middle Aged, T-Lymphocytes immunology, Transcriptome immunology, Antigens, CD immunology, Leukocyte Immunoglobulin-like Receptor B1 immunology, Multiple Myeloma immunology, Plasma Cells immunology
- Abstract
Mechanisms of immune regulation may control proliferation of aberrant plasma cells (PCs) in patients with monoclonal gammopathy of undetermined significance (MGUS) preventing progression to active multiple myeloma (MM). We hypothesized that CD85j ( LILRB1 ), an inhibitory immune checkpoint for B cell function, may play a role in MM pathogenesis. In this study, we report that patients with active MM had significantly lower levels of CD85j and its ligand S100A9. Decreased CD85j expression could also be detected in the premalignant condition MGUS, suggesting that loss of CD85j may be an early event promoting tumor immune escape. To gain insight into the molecular mechanisms underlying CD85j functions, we next enforced expression of CD85j in human myeloma cell lines by lentiviral transduction. Interestingly, gene expression profiling of CD85j-overexpressing cells revealed a set of downregulated genes with crucial functions in MM pathogenesis. Furthermore, in vitro functional assays demonstrated that CD85j overexpression increased susceptibility to T cell- and NK-mediated killing. Consistently, ligation of CD85j decreased the number of PCs from individuals with MGUS but not from patients with MM. In conclusion, downregulation of inhibitory immune checkpoints on malignant PCs may provide a novel mechanism of immune escape associated with myeloma pathogenesis., (Copyright © 2018 by The American Association of Immunologists, Inc.)
- Published
- 2018
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27. Antigen presenting cell-mediated expansion of human umbilical cord blood yields log-scale expansion of natural killer cells with anti-myeloma activity.
- Author
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Shah N, Martin-Antonio B, Yang H, Ku S, Lee DA, Cooper LJ, Decker WK, Li S, Robinson SN, Sekine T, Parmar S, Gribben J, Wang M, Rezvani K, Yvon E, Najjar A, Burks J, Kaur I, Champlin RE, Bollard CM, and Shpall EJ
- Subjects
- Animals, CD3 Complex immunology, CD3 Complex metabolism, CD56 Antigen immunology, CD56 Antigen metabolism, Cell Culture Techniques, Cell Line, Tumor, Cells, Cultured, Coculture Techniques, Cytotoxicity, Immunologic drug effects, Cytotoxicity, Immunologic immunology, Fetal Blood cytology, Fetal Blood metabolism, Humans, Interleukin Receptor Common gamma Subunit deficiency, Interleukin Receptor Common gamma Subunit genetics, Interleukin Receptor Common gamma Subunit immunology, Interleukin-2 immunology, Interleukin-2 pharmacology, K562 Cells, Killer Cells, Natural metabolism, Mice, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Microscopy, Confocal, Multiple Myeloma pathology, Multiple Myeloma therapy, NK Cell Lectin-Like Receptor Subfamily C immunology, NK Cell Lectin-Like Receptor Subfamily C metabolism, NK Cell Lectin-Like Receptor Subfamily D immunology, NK Cell Lectin-Like Receptor Subfamily D metabolism, Xenograft Model Antitumor Assays methods, Antigen-Presenting Cells immunology, Cell Proliferation, Fetal Blood immunology, Killer Cells, Natural immunology, Multiple Myeloma immunology
- Abstract
Natural killer (NK) cells are important mediators of anti-tumor immunity and are active against several hematologic malignancies, including multiple myeloma (MM). Umbilical cord blood (CB) is a promising source of allogeneic NK cells but large scale ex vivo expansion is required for generation of clinically relevant CB-derived NK (CB-NK) cell doses. Here we describe a novel strategy for expanding NK cells from cryopreserved CB units using artificial antigen presenting feeder cells (aAPC) in a gas permeable culture system. After 14 days, mean fold expansion of CB-NK cells was 1848-fold from fresh and 2389-fold from cryopreserved CB with >95% purity for NK cells (CD56(+)/CD3(-)) and less than 1% CD3(+) cells. Though surface expression of some cytotoxicity receptors was decreased, aAPC-expanded CB-NK cells exhibited a phenotype similar to CB-NK cells expanded with IL-2 alone with respect to various inhibitory receptors, NKG2C and CD94 and maintained strong expression of transcription factors Eomesodermin and T-bet. Furthermore, CB-NK cells formed functional immune synapses with and demonstrated cytotoxicity against various MM targets. Finally, aAPC-expanded CB-NK cells showed significant in vivo activity against MM in a xenogenic mouse model. Our findings introduce a clinically applicable strategy for the generation of highly functional CB-NK cells which can be used to eradicate MM.
- Published
- 2013
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28. Genomic characterization and gene expression analysis of four hepcidin genes in the redbanded seabream (Pagrus auriga).
- Author
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Martin-Antonio B, Jiménez-Cantizano RM, Salas-Leiton E, Infante C, and Manchado M
- Subjects
- Amino Acid Sequence, Animals, Antimicrobial Cationic Peptides chemistry, Cloning, Molecular, Gene Expression Profiling, Gene Expression Regulation, Developmental, Hepcidins, Kidney immunology, Larva growth & development, Larva metabolism, Lipopolysaccharides pharmacology, Molecular Sequence Data, Phylogeny, Sequence Alignment, Antimicrobial Cationic Peptides genetics, Gene Expression Regulation drug effects, Genome genetics, Sea Bream genetics, Sea Bream metabolism
- Abstract
Hepcidin antimicrobial peptides (HAMPs) are key molecules of the innate immune system against bacterial infections and in iron metabolism. In this study we report the molecular cloning and genomic characterization of four HAMP genes (referred to as HAMP1, HAMP2, HAMP3 and HAMP4) in the redbanded seabream (Pagrus auriga). All these genes possessed the eight characteristic cysteine residues involved in protein folding. No canonical sequence for convertase-mediated processing of the HAMP3 propeptide was identified. At the genomic level, all four HAMP genes consisted of two introns and three exons. Phylogenetic analysis revealed that HAMPs could group in two main clusters with HAMP2, HAMP3 and HAMP4 belonging to the more complex and diversified HAMP2-like group of acanthopterygians. Quantitation of mRNA levels in adult tissues showed that HAMP1 was ubiquitously expressed, HAMP2 mainly in kidney, spleen and intestine, whereas HAMP3 and HAMP4 in liver. During development, HAMP2 and HAMP3 were expressed at a high level in embryos. Moreover, the expression levels of the four HAMP genes increased between 5 and 15 days after hatching when larvae started external feeding. Induction experiments with lipopolysaccharide revealed significant changes in gene expression of the four HAMP genes in kidney, liver and spleen. However, expression profiles differed in magnitude and time course response. HAMP1 mRNAs increased rapidly in kidney at 1 h p.i. whereas HAMP2 did later at 24 h. Moreover, HAMP4 transcripts increased more than 5000-fold in liver whereas HAMP2 mRNAs dropped significantly in spleen at 3 h p.i. All these data suggest that HAMPs are involved in the response against bacterial infections although additional functions in iron regulation and embryogenesis in fish should be considered.
- Published
- 2009
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29. Molecular characterization, phylogeny, and expression of c-type and g-type lysozymes in brill (Scophthalmus rhombus).
- Author
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Jiménez-Cantizano RM, Infante C, Martin-Antonio B, Ponce M, Hachero I, Navas JI, and Manchado M
- Subjects
- Amino Acid Sequence, Animals, Fish Diseases enzymology, Fish Diseases microbiology, Gram-Negative Bacterial Infections enzymology, Gram-Negative Bacterial Infections veterinary, Lipopolysaccharides pharmacology, Molecular Sequence Data, Photobacterium immunology, Sequence Alignment, Flatfishes genetics, Flatfishes metabolism, Gene Expression Regulation, Enzymologic drug effects, Muramidase classification, Muramidase genetics, Phylogeny
- Abstract
Lysozymes are key proteins of the innate immune system against bacterial infections. In this study we report the molecular cloning and characterization of the c-type and g-type lysozymes in brill (Scophthalmus rhombus). Catalytic and other conserved residues required for functionality were identified. Phylogenetic analysis revealed distinct evolutionary histories for each lysozyme type. Expression profiles of both lysozyme genes were studied in juvenile tissues using a real-time PCR approach. c-Type lysozyme was expressed mainly in stomach and liver, whereas the g-type was detected in all tissues with highest mRNA levels observed in the spleen. Induction experiments revealed that g-type transcripts increased significantly in head kidney after lipopolysaccharide (25- and 23-fold at 12 and 24h, respectively) and Photobacterium damselae subsp. piscicida (17-fold at 24h) treatments. In contrast, no induction was observed for c-type lysozyme. All these data suggest that g-type lysozyme is involved in the response against bacterial infections, whereas c-type lysozyme may also play a role in digestion.
- Published
- 2008
- Full Text
- View/download PDF
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