Depósito Académico
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Results
- A phase II trial of autologous dendritic cell vaccination and radiochemotherapy following fuorescence-guided surgery in newly diagnosed glioblastoma patients(BMC, 2017) Espinos, J. (Jaime); Garcia-de-Eulate, R. (Reyes); Alonso-Roldán, M.M. (Marta María); Pastor, F. (Fernando); Aristu-Mendioroz, J.J. (José Javier); Domínguez-Echávarri, P.D. (Pablo Daniel); Lopez-Diaz-de-Cerio, A. (Ascensión); Tejada-Solis, S. (Sonia); Diez-Valle, R. (Ricardo); Andreu, E.J. (Enrique José); Inoges, S. (Susana); Idoate, M.A. (Miguel Ángel); Bendandi, M. (Maurizio); Gallego-Perez-Larraya, J. (Jaime); Prosper-Cardoso, F. (Felipe)Background: Prognosis of patients with glioblastoma multiforme (GBM) remains dismal, with median overall survival (OS) of about 15 months. It is therefore crucial to search alternative strategies that improve these results obtained with conventional treatments. In this context, immunotherapy seems to be a promising therapeutic option. We hypoth‐ esized that the addition of tumor lysate-pulsed autologous dendritic cells (DCs) vaccination to maximal safe resection followed by radiotherapy and concomitant and adjuvant temozolomide could improve patients’ survival. Methods: We conducted a phase-II clinical trial of autologous DCs vaccination in patients with newly diagnosed patients GBM who were candidates to complete or near complete resection. Candidates were fnally included if residual tumor volume was lower than 1 cc on postoperative radiological examination. Autologous DCs were generated from peripheral blood monocytes and pulsed with autologous whole tumor lysate. The vaccination calendar started before radiotherapy and was continued during adjuvant chemotherapy. Progression free survival (PFS) and OS were analyzed with the Kaplan–Meier method. Immune response were assessed in blood samples obtained before each vaccines. Results: Thirty-two consecutive patients were screened, one of which was a screening failure due to insufcient resection. Median age was 61 years (range 42–70). Karnofsky performance score (KPS) was 90–100 in 29%, 80 in 35.5% and 60–70 in 35.5% of cases. MGMT (O6 -methylguanine-DNA-methyltransferase) promoter was methylated in 45.2% of patients. No severe adverse efects related to immunotherapy were registered. Median PFS was 12.7 months (CI 95% 7–16) and median OS was 23.4 months (95% CI 16–33.1). Increase in post-vaccination tumor specifc immune response after vaccines (proliferation or cytokine production) was detected in 11/27 evaluated patients. No correla‐ tion between immune response and survival was found. Conclusions: Our results suggest that the addition of tumor lysate-pulsed autologous DCs vaccination to tumor resection and combined radio-chemotherapy is feasible and safe. A multicenter randomized clinical trial is warranted to evaluate the potential survival beneft of this therapeutic approach.
- Differentiation stage of myeloma plasma cells: biological and clinical significance(Nature Publishing Group, 2017) Cedena, M.T. (María Teresa); Martínez-López, J. (Joaquín); Bladé, J. (Joan); Barlogie, B. (Bart); Orfao, A. (Alberto); Vidriales, M.B. (María Belén); Jong, B.G. (Britt G.) de; Gonzalez, Y. (Yolanda); Pascual, M. (Marien); Mateos, M.V. (María Victoria); Epstein, J. (Joshua); Hernandez, M.T. (Miguel Teodoro); Delgado, J.A. (Jose Antonio); Puig, N. (Noemí); Ruiz-Paz, Y; Morgan, G.J. (Gareth J.); Cordón, L. (Lourdes); Alignani, D. (Diego); Lahuerta, J.J. (Juan José); Gutierrez, N.C. (Norma C.); Rapado, I. (Inmaculada); Dongen, J.J.M. (Jacques J. M.) van; Paiva, B. (Bruno); Oriol, A. (Albert); Prosper-Cardoso, F. (Felipe); Aguirre-Ena, X. (Xabier); San-Miguel, J.F. (Jesús F.); Johnson, S.K. (Sarah K.); Echeveste, M.A. (Maria Asuncion); Martin-Subero, J.I. (Jose Ignacio); Van Zelm, M.C. (Menno C.)The notion that plasma cells (PCs) are terminally-differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n=20) that the CD19-CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19-CD81+ and CD19-CD81- BMPCs. Afterwards, we demonstrated in 225 newly-diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully-differentiated (CD19-CD81-) clones, 38% intermediate-differentiated (CD19-CD81+), and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR:1.7;P=.005) and overall survival (HR:2.1;P=.006). Longitudinal comparison of diagnostic vs. minimal-residual-disease samples (n=40) unraveled that in 20% of patients, less-differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less-differentiated clonal PCs retain high expression of genes related to preceding B-cell stages (e.g.:PAX5), and show distinct mutation profile vs. fully-differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harboring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles.
- Immune status of high-risk smoldering multiple myeloma patients and its therapeutic modulation under LenDex: a longitudinal analysis(American Society of Hematology, 2016) Perez-Simon, J.A. (José Antonio); Hernández-Martín, J. (J.); Bladé, J. (Joan); Vidriales, M.B. (María Belén); Mateos, M.V. (María Victoria); Arriba, F. (Felipe) de; Sanchez-Abarca, L.I. (Luis Ignacio); Esteves, G. (Graça); Hernandez, M.T. (Miguel Teodoro); Rosiñol, L. (Laura); Puig, N. (Noemí); Lahuerta, J.J. (Juan José); Giraldo, P. (P.); Teruel, A.I. (Ana Isabel); Paiva, B. (Bruno); Oriol, A. (Albert); Rubia, J. (Javier) de la; Corchete, L.A. (Luis A.); Prosper-Cardoso, F. (Felipe); Bargay, J. (Joan); Lopez-Corral, L. (Lucia); San-Miguel, J.F. (Jesús F.)Persistence of chemoresistant minimal residual disease (MRD) plasma cells (PCs) is associated with inferior survival in multiple myeloma (MM). Thus, characterization of the minor MRD subclone may represent a unique model to understand chemoresistance, but to our knowledge, the phenotypic and genetic features of the MRD subclone have never been investigated. Here, we compared the antigenic profile of MRD vs diagnostic clonal PCs in 40 elderly MM patients enrolled in the GEM2010MAS65 study and showed that the MRD subclone is enriched in cells overexpressing integrins (CD11a/CD11c/CD29/CD49d/CD49e), chemokine receptors (CXCR4), and adhesion molecules (CD44/CD54). Genetic profiling of MRD vs diagnostic PCs was performed in 12 patients; 3 of them showed identical copy number alterations (CNAs), in another 3 cases, MRD clonal PCs displayed all genetic alterations detected at diagnosis plus additional CNAs that emerged at the MRD stage, whereas in the remaining 6 patients, there were CNAs present at diagnosis that were undetectable in MRD clonal PCs, but also a selected number of genetic alterations that became apparent only at the MRD stage. The MRD subclone showed significant downregulation of genes related to protein processing in endoplasmic reticulum, as well as novel deregulated genes such as ALCAM that is prognostically relevant in MM and may identify chemoresistant PCs in vitro. Altogether, our results suggest that therapy-induced clonal selection could be already present at the MRD stage, where chemoresistant PCs show a singular phenotypic signature that may result from the persistence of clones with different genetic and gene expression profiles. This trial was registered at www.clinicaltrials.gov as #NCT01237249.
- Target Expression, Generation, Preclinical Activity, and Pharmacokinetics of the BCMA-T Cell Bispecific Antibody EM801 for Multiple Myeloma Treatment(Elsevier, 2017) Lüoend, R. (Remo); Zabaleta, A. (Aintzane); Hundemer, M. (Michael); Murr, R. (Ramona); Fauti, T. (Tanja); Umaña, P. (Pablo); Seckinger, A. (Anja); Hosse, R.J. (Ralf J.); Harnisch, L.J. (Lydia Jasmin); Moser, S. (Samuel); Grab, A. (Anna); Lipp, S. (Susanne); Vu, M.D. (Minh Diem); Ho, A.D. (Anthony D.); Delgado, J.A. (Jose Antonio); Strein, K. (Klaus); Moreno, L. (Laura); Neuber, B. (Brigitte); Klein, C. (Christian); Bacac, M. (Marina); Hose, D. (Dirk); Paiva, B. (Bruno); Hillengass, J. (Jens); Prosper-Cardoso, F. (Felipe); Delon, C. (Camille); Merino, J. (Juana); Cavalcanti-Adam, E.A. (Elisabetta Ada); Emde, M. (Martina); Gianotti, R. (Reto); San-Miguel, J.F. (Jesús F.); Latzko, M. (Melanie)We identified B cell maturation antigen (BCMA) as a potential therapeutic target in 778 newly diagnosed and relapsed myeloma patients. We constructed an IgG-based BCMA-T cell bispecific antibody (EM801) and showed that it increased CD3+ T cell/myeloma cell crosslinking, followed by CD4+/CD8+ T cell activation, and secretion of interferon-γ, granzyme B, and perforin. This effect is CD4 and CD8 T cell mediated. EM801 induced, at nanomolar concentrations, myeloma cell death by autologous T cells in 34 of 43 bone marrow aspirates, including those from high-risk patients and patients after multiple lines of treatment, tumor regression in six of nine mice in a myeloma xenograft model, and depletion of BCMA+ cells in cynomolgus monkeys. Pharmacokinetics and pharmacodynamics indicate weekly intravenous/subcutaneous administration.
- The Mutational Landscape of Circulating Tumor Cells in Multiple Myeloma(Elsevier, 2017) Freeman, S.S. (Samuel S.); Shi, J. (Jiantao); Sacco, A. (Antonio); Massoud, M. (Mira); Van-Allen, E.M. (Eliezer M.); Detappe, A. (Alexandre); Manier, S. (Salomon); Adalsteinsson, V.A. (Viktor A.); Ha, G. (Gavin); Capelletti, M. (Marzia); Mishima, Y. (Yuji); Alignani, D. (Diego); Anderson, K.C. (K.C.); Takagi, S. (Satoshi); Munshi, N.C. (Nikhil C.); Paiva, B. (Bruno); Park, J. (Jihye); Michor, F. (Franziska); Huynh, D. (Daisy); Prosper-Cardoso, F. (Felipe); Roccaro, A.M. (Aldo M.); Lohr, J.G. (Jens G.); Ghobrial, I.M. (Irene M.); San-Miguel, J.F. (Jesús F.); Aljawai, Y. (Yosra); Perilla-Glen, A. (Adriana)The development of sensitive and non-invasive ‘‘liquid biopsies’’ presents new opportunities for longitudinal monitoring of tumor dissemination and clonal evolution. The number of circulating tumor cells (CTCs) is prognostic in multiple myeloma (MM), but there is little information on their genetic features. Here, we have analyzed the genomic landscape of CTCs from 29 MM patients, including eight cases with matched/paired bone marrow (BM) tumor cells. Our results show that 100% of clonal mutations in patient BM were detected in CTCs and that 99% of clonal mutations in CTCs were present in BM MM. These include typical driver mutations in MM such as in KRAS, NRAS, or BRAF. These data suggest that BM and CTC samples have similar clonal structures, as discordances between the two were restricted to subclonal mutations. Accordingly, our results pave the way for potentially less invasive mutation screening of MM patients through characterization of CTCs.
- Polymeric electrospun scaffolds: neuregulin encapsulation and biocompatibility studies in a model of myocardial ischemia(Mary Ann Liebert, 2015) Heffels K.H. (Karl‐Heinz); Groll, J. (Jürgen); Blanco-Prieto, M.J. (María José); Rossi, A. (Ángela); Prosper-Cardoso, F. (Felipe); Simon-Yarza, T. (Teresa)Cardiovascular disease represents one of the major health challenges in modern times and is the number one cause of death globally. Thus, numerous studies are under way to identify effective cell‐ and/or growth factor‐based therapies for repairing damaged cardiac tissue. In this regard, improving the engraftment or survival of regenerative cells and prolonging growth factor exposure have become fundamental goals in advancing these therapeutic approaches. Biomaterials have emerged as innovative scaffolds for the delivery of both cells and proteins in tissue engineering applications. In the present study, electrospinning was used to generate smooth homogenous polymeric fibers, which consisted of a PLGA/NCO‐sP(EO‐stat‐PO) polymer blend encapsulating the cardioactive growth factor, Neuregulin‐1 (Nrg). We evaluated the biocompatibility and degradation of this Nrg‐containing biomaterial in a rat model of myocardial ischemia. Histological analysis revealed the presence of an initial acute inflammatory response after implantation, which was followed by a chronic inflammatory phase, characterized by the presence of giant cells. Notably, the scaffold remained in the heart after 3 months. Furthermore, an increase in the M2:M1 macrophage ratio following implantation suggested the induction of constructive tissue remodeling. Taken together, the combination of Nrg‐encapsulating scaffolds with cells capable of inducing cardiac regeneration could represent an ambitious and promising therapeutic strategy for repairing diseased or damaged myocardial tissue.
- Generation and characterization of human iPSC line generated from mesenchymal stem cells derived from adipose tissue(Elsevier, 2016) Rodriguez-Madoz, J.R. (Juan Roberto); Rodriguez, S. (Saray); Andreu, E.J. (Enrique José); Barajas, M. (Miguel); Mazo, M. (Manuel); Prosper-Cardoso, F. (Felipe); Abizanda-Sarasa, G. (Gloria); Zapata-Linares, N.M. (Natalia María)Abstract In this work, mesenchymal stem cells derived from adipose tissue (ADSCs) were used for the generation of the human-induced pluripotent stem cell line G15.AO. Cell reprogramming was performed using retroviral vectors containing the Yamanaka factors, and the generated G15.AO hiPSC line showed normal karyotype, silencing of the exogenous reprogramming factors, induction of the typical pluripotency-associated markers, alkaline phosphatase enzymatic activity, and in vivo and in vitro differentiation ability to the three germ layers.
- RUNX/AML and C/EBP factors regulate CD11a integrin expression in myeloid cells through overlapping regulatory elements(American Society of Hematology, 2003) Drabkin, H. (H.); Erickson, P. (P.); Jensen, U.B. (U. B.); Puig-Kröger, A. (Amaya); Sanchez-Elsner, T. (Tilman); Groner, Y. (Y.); Andreu, E.J. (Enrique José); Ruiz, N. (Natividad); Gil, J. (Juana); Prosper-Cardoso, F. (Felipe); Corbi, A.L. (Angel L.)The CD11a/CD18 (leukocyte functionassociated antigen 1 [LFA-1]) integrin mediates critical leukocyte adhesive interactions during immune and inflammatory responses. The CD11a promoter directs CD11a/CD18 integrin expression, and its activity in lymphoid cells depends on a functional RUNX1/AML-1–binding site (AML-110) within the MS7 sequence. We now report that MS7 contains a C/EBPbinding site (C/EBP-100), which overlaps with AML-110 and is bound by C/EBP factors in myeloid cells. C/EBP and RUNX/ AML factors compete for binding to their respective cognate elements and bind to the CD11a promoter MS7 sequence in a cell lineage- and differentiation-dependent manner. In myeloid cells MS7 is primarily recognized by C/EBP factors in proliferating cells whereas RUNX/AMLfactors (especially RUNX3/AML-2) bind to MS7 in differentiated cells. RUNX3/AML-2 binding to the CD11a promoter correlates with increased RUNX3/AML-2 protein levels and enhanced CD11a/CD18 cell surface expression. The relevance of the AML-110 element is underscored by the ability of AML-1/ETO to inhibit CD11a promoter activity, thus explaining the low CD11a/CD18 expression in t(8;21)–containing myeloid leukemia cells. Therefore, the expression of the CD11a/CD18 integrin in myeloid cells is determined through the differential occupancy of the CD11a proximal promoter by transcription factors implicated in the pathogenesis of myeloid leukemia.
- Cellular Cardiomyoplasty: Clinical Application(Elsevier, 2004) Herreros, J. (Jesús); Chachques, J. (J.); Trainini, J. (Jorge); Fabiani, J.N. (J.N.); Carpentier, A. (A.); Acar, C. (Christophe); D’Attellis, N. (N.); Prosper-Cardoso, F. (Felipe)Myocardial regeneration can be induced with the implantation of a variety of myogenic and angiogenic cell types. More than 150 patients have been treated with cellular cardiomyoplasty worldwide, 18 patients have been treated by our group. Cellular cardiomyoplasty seems to reduce the size and fibrosis of infarct scars, limit postischemic remodelling, and restore regional myocardial contractility. Techniques for skeletal myoblasts culture and ex vivo expansion using autologous patient serum (obtained from plasmapheresis) have been developed by our group. In this article we propose (1) a total autologous cell culture technique and procedures for cell delivery and (2) a clinical trial with appropriate endpoints structured to determine the efficacy of cellular cardiomyoplasty.
- Promoter hypermethylation of cancer-related genes: a strong independent prognostic factor in acute lymphoblastic leukemia(American Society of Hematology, 2004) Jimenez-Velasco, A. (A.); Molina, F.J. (Francisco J.); Roman-Gomez, J. (José); Heiniger, A. (A.); Navarro, G. (Germán); Barrios, M. (M.); Castillejo, J.A. (J.A.); Prosper-Cardoso, F. (Felipe); Torres, A. (Antonio); Calasanz-Abinzano, M.J. (Maria Jose); Aguirre-Ena, X. (Xabier)Promoter hypermethylation plays an important role in the inactivation of cancerrelated genes. This abnormality occurs early in leukemogenesis and seems to be associated with poor prognosis in acute lymphoblastic leukemia (ALL). To determine the extent of hypermethylation in ALL, we analyzed the methylation status of the CDH1, p73, p16, p15, p57, NES-1, DKK-3, CDH13, p14, TMS-1, APAF-1, DAPK, PARKIN, LATS-1, and PTEN genes in 251 consecutive ALL patients.Atotal of 77.3% of samples had at least 1 gene methylated, whereas 35.9% of cases had 4 or more genes methylated. Clinical features and complete remission rate did not differ among patients without methylated genes, patients with 1 to 3 methylated genes (methylated group A), or patients with more than 3 methylated genes (methylated group B). Estimated disease-free survival (DFS) and overall survival (OS) at 11 years were 75.5% and 66.1%, respectively, for the nonmethylated group; 37.2% and 45.5% for methylated group A; and 9.4% and 7.8% for methylated group B (P < .0001 and P .0004, respectively). Multivariate analysis demonstrated that the methylation profile was an independent prognostic factor in predicting DFS (P < .0001) and OS (P .003). Our results suggest that the methylation profile may be a potential new biomarker of risk prediction in ALL