Trasplant de cèl·lules mare i immunoteràpia cel·lular

  • Urbano Group 3
Clínic-UB

Josep Carreras Leukaemia Research Institute
Hospital Clínic Barcelona. Universitat de Barcelona.
Centre Esther Koplowitz
c/ Rosselló, 149-153, 2 pl
08036 Barcelona (Spain

Fax: (+34) 93 312 9407

Summary

Our mission is to convert the best scientific discoveries into the best treatments for patients with malignant hemopathies. Patients with advanced malignant haemopathies have a very short life expectancy. The group devotes their efforts to modifying the patient’s immune system, thus making it possible to generate a more specific and powerful antitumour response. To achieve this we modify the patient’s immune T lymphocytes and also cord blood-derived NK cells with a chimeric antigen receptor (CAR) generating both CART cells and CARNK cells that will recognize specifically tumor cells and once recognized, they will exert a high capacity to proliferate and attack them.

Research

  •       CAR-T and CAR-NK therapy for the treatment of hematological malignancies

Preclinical development of CARs for the treatment of malignant diseases. Specifically, we have developed a CAR against BCMA, which can be used for the treatment of mature B cell malignancies. Moreover, we study tumor cell mechanisms that impact in the CART cell activity, such as loss of the expression of the target antigen and secreted factors that can increase CART cell activity.

  •       Mechanisms of antitumor cytotoxicity of immune cells (NK and T lymphocytes)

We use both NK cells and CAR-NK cells to increase the activity of CART cells avoiding CART cell exhaustion and increasing the antileukemic activity of CARTs. Moreover, we study tumor cell death mechanisms activated by CART and NK cells in order to increase their antitumor activity while avoiding associated problems to this therapy, such as the high inflammatory response which occurs after CART cell administration.

  •       Allogeneic stem cell transplantation: Graft versus host disease (GVHD) and Infectious complications

GVHD and Infectious complications are the main problems occurring after allogeneic stem cell transplantation, being responsible for a mortality rate associated to this procedure. We study clinical and genetic variables associated to these complications and develop clinical procedures in order to avoid them.

Collaborations

  • Spanish group of blood and marrow transplantation (GETH)
  • Manel Juan: IP from Immunology group of Hospital Clinic (Barcelona)
  • Francisco Lozano: Infections Immunology group at IDIBAPS (Barcelona)
  • Oriol Bachs: Cell Biology department at University of Barcelona
  • Josep M Estanyol i Ullate. Proteomic Unit at University of Barcelona
  • Cristina Muñoz Pinedo: Cell Death Regulation group at IDIBELL (Barcelona)

People

NomRol
Álvaro Urbano-IspizuaUrbano squareCampus Coordinator
Beatriz MartínMartin Beatriz 3x3Associate Investigator
Jordi EsteveJordi EsteveResearch Associate

Selected publications

Martín-Antonio B, Suñe G, Najjar A, Perez-Amill L, Antoñana-Vildosola A, Castella M, León S, Velasco-de Andrés M, Lozano F, Lozano E, Bueno C, Estanyol JM, Muñoz-Pinedo C, Robinson SN

Extracellular NK histones promote immune cell anti-tumor activity by inducing cell clusters through binding to CD138 receptor.

J Immunother Cancer 16 Oct 2019, 7 (1) 259. Epub 16 Oct 2019
Natural killer (NK) cells are important anti-tumor cells of our innate immune system. Their anti-cancer activity is mediated through interaction of a wide array of activating and inhibitory receptors with their ligands on tumor cells. After activation, NK cells also secrete a variety of pro-inflammatory molecules that contribute to the final immune response by modulating other innate and adaptive immune cells. In this regard, external proteins from NK cell secretome and the mechanisms by which they mediate these responses are poorly defined.
Més informació
Suárez-Lledó M, Marcos MÁ, Cuatrecasas M, Bombi JA, Fernández-Avilés F, Magnano L, Martínez-Cibrián N, Llobet N, Rosiñol L, Gutiérrez-García G, Jorge S, Martínez C, Rovira M

Quantitative PCR Is Faster, More Objective, and More Reliable Than Immunohistochemistry for the Diagnosis of Cytomegalovirus Gastrointestinal Disease in Allogeneic Stem Cell Transplantation.

Biol. Blood Marrow Transplant. 17 Jul 2019, . Epub 17 Jul 2019
Diagnosis of gastrointestinal (GI) cytomegalovirus (CMV) disease relies on the presence of GI symptoms and detection of CMV, mainly by immunohistochemistry (IHC), in GI biopsy specimens. Thus, in a symptomatic patient, a positive CMV-IHC result is accepted as a diagnosis of CMV disease. However, a positive CMV-PCR in GI tissue is considered "possible" CMV disease. Therefore, it would be very useful if, in practice, both techniques showed equal sensitivity and reliability. This is because PCR has many practical advantages over IHC for detecting CMV. The aim of this study was to compare quantitative PCR with IHC for the diagnosis of GI CMV disease. A total of 186 endoscopic GI biopsy specimens from 123 patients with GI symptoms after an allogeneic stem cell transplantation (allo-SCT; 2004-2017) were analyzed by IHC and PCR on 113 paraffin-embedded and 73 fresh samples. The results were then compared. Of the patients with macroscopic lesions in the mucosa and CMV-IHC-positive biopsy specimens (eg, "proven" CMV disease, n = 28), all but 1 were CMV-PCR positive. Of the patients without macroscopic lesions in the mucosa and CMV-IHC-positive biopsy specimens (eg, probable CMV disease, n = 4), only 1 was CMV-PCR positive. Eight patients had CMV-IHC-negative/CMV-PCR-positive gut biopsy specimens. These cases fall within the current definition of possible CMV disease. In 6 of these 8 cases (75%), the viral load in GI tissue was very high (>10,000 copies/µg). Taken together, the results from the proven and probable cases revealed that CMV-PCR shows the same sensitivity (100%), specificity (98%), and positive (93%) and negative predictive value (100%) as CMV-IHC. Detection of CMV in fresh GI mucosa by quantitative PCR is as useful as IHC for the diagnosis of GI CMV disease. The results show that quantitative PCR has the same sensitivity, specificity, and positive/negative predictive value as IHC.
Més informació
Castella M, Boronat A, Martín-Ibáñez R, Rodríguez V, Suñé G, Caballero M, Marzal B, Pérez-Amill L, Martín-Antonio B, Castaño J, Bueno C, Balagué O, González-Navarro EA, Serra-Pages C, Engel P, Vilella R, Benitez-Ribas D, Ortiz-Maldonado V, Cid J, Tabera J, Canals JM, Lozano M, Baumann T, Vilarrodona A, Trias E, Campo E, Menendez P, Urbano-Ispizua Á, Yagüe J, Pérez-Galán P, Rives S, Delgado J, Juan M

Development of a Novel Anti-CD19 Chimeric Antigen Receptor: A Paradigm for an Affordable CAR T Cell Production at Academic Institutions.

Mol Ther Methods Clin Dev 15 Mar 2019, 12 134-144. Epub 6 Des 2018
Genetically modifying autologous T cells to express an anti-CD19 chimeric antigen receptor (CAR) has shown impressive response rates for the treatment of CD19+ B cell malignancies in several clinical trials (CTs). Making this treatment available to our patients prompted us to develop a novel CART19 based on our own anti-CD19 antibody (A3B1), followed by CD8 hinge and transmembrane region, 4-1BB- and CD3z-signaling domains. We show that A3B1 CAR T cells are highly cytotoxic and specific against CD19+ cells
Més informació
Lopez-Millan B, Diaz de la Guardia R, Roca-Ho H, Anguita E, Islam ABMMK, Romero-Moya D, Prieto C, Gutierrez-Agüera F, Bejarano-Garcia JA, Perez-Simon JA, Costales P, Rovira M, Marín P, Menendez S, Iglesias M, Fuster JL, Urbano-Ispizua A, Anjos-Afonso F, Bueno C, Menendez P

IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q- AML.

Oncoimmunology 2018, 7 (9) e1477460. Epub 26 Jul 2018
Treatment for acute myeloid leukemia (AML) remains suboptimal and many patients remain refractory or relapse upon standard chemotherapy based on nucleoside analogs plus anthracyclines. The crosstalk between AML cells and the BM stroma is a major mechanism underlying therapy resistance in AML. Lenalidomide and pomalidomide, a new generation immunomodulatory drugs (IMiDs), possess pleiotropic anti-leukemic properties including potent immune-modulating effects and are commonly used in hematological malignances associated with intrinsic dysfunctional BM such as myelodysplastic syndromes and multiple myeloma. Whether IMiDs may improve the efficacy of current standard treatment in AML remains understudied. Here, we have exploited
Més informació
Perez-Amill L, Marzal B, Urbano-Ispizua A, Juan M, Martín-Antonio B

CAR-T Cell Therapy: A Door Is Open to Find Innumerable Possibilities of Treatments for Cancer Patients

Turk J Haematol 13 Nov 2018, 35 (4) 217-228. Epub 6 Set 2018
Seven years ago a chronic lymphocytic leukemia patient was for the first time successfully treated with chimeric antigen receptor (CAR)-modified T cells (CAR-T cells) to target CD19 overexpression in tumor cells. This was the beginning of the development of a new type of immunotherapy treatment in cancer patients. Since then, identification of novel antigens expressed in tumor cells and optimization of both CAR constructs and protocols of administration have opened up new avenues for the successful treatment of other hematological malignancies. However, research still continues to avoid some problems such as toxicities associated with the treatment and to find strategies to avoid tumor cell immune evasion mechanisms. On the other hand, for solid tumors, CAR-T therapy results are still in an early phase. In contrast to hematological malignancies, the complex tumor heterogeneity of solid tumors has led to the research of novel and challenging strategies to improve CAR-T cell activity. Here, we will review the main clinical results obtained with CAR-T cells in hematological malignancies, specifically focusing on CAR-T-19 and CAR-T against B-cell maturation antigen (CAR-T-BCMA). Moreover, we will mention the main problems that decrease CAR-T cell activity in solid tumors and the strategies to overcome them. Finally, we will present some of the first clinical results obtained for solid tumors.
Més informació
Martínez-Laperche C, Buces E, Aguilera-Morillo MC, Picornell A, González-Rivera M, Lillo R, Santos N, Martín-Antonio B, Guillem V, Nieto JB, González M, de la Cámara R, Brunet S, Jiménez-Velasco A, Espigado I, Vallejo C, Sampol A, Bellón JM, Serrano D, Kwon M, Gayoso J, Balsalobre P, Urbano-Izpizua Á, Solano C, Gallardo D, Díez-Martín JL, Romo J, Buño I

A novel predictive approach for GVHD after allogeneic SCT based on clinical variables and cytokine gene polymorphisms.

Blood Adv 24 Jul 2018, 2 (14) 1719-1737.
Despite considerable advances in our understanding of the pathophysiology of graft-versus-host disease (GVHD), its prediction remains unresolved and depends mainly on clinical data. The aim of this study is to build a predictive model based on clinical variables and cytokine gene polymorphism for predicting acute GVHD (aGVHD) and chronic GVHD (cGVHD) from the analysis of a large cohort of HLA-identical sibling donor allogeneic stem cell transplant (allo-SCT) patients. A total of 25 SNPs in 12 cytokine genes were evaluated in 509 patients. Data were analyzed using a linear regression model and the least absolute shrinkage and selection operator (LASSO). The statistical model was constructed by randomly selecting 85% of cases (training set), and the predictive ability was confirmed based on the remaining 15% of cases (test set). Models including clinical and genetic variables (CG-M) predicted severe aGVHD significantly better than models including only clinical variables (C-M) or only genetic variables (G-M). For grades 3-4 aGVHD, the correct classification rates (CCR1) were: 100% for CG-M, 88% for G-M, and 50% for C-M. On the other hand, CG-M and G-M predicted extensive cGVHD better than C-M (CCR1: 80% vs. 66.7%, respectively). A risk score was calculated based on LASSO multivariate analyses. It was able to correctly stratify patients who developed grades 3-4 aGVHD (
Més informació
Martín-Antonio B, Suñe G, Perez-Amill L, Castella M, Urbano-Ispizua A

Natural Killer Cells: Angels and Devils for Immunotherapy.

Int J Mol Sci 29 Ago 2017, 18 (9) . Epub 29 Ago 2017
In recent years, the relevance of the immune system to fight cancer has led to the development of immunotherapy, including the adoptive cell transfer of immune cells, such as natural killer (NK) cells and chimeric antigen receptors (CAR)-modified T cells. The discovery of donor NK cells' anti-tumor activity in acute myeloid leukemia patients receiving allogeneic stem cell transplantation (allo-SCT) was the trigger to conduct many clinical trials infusing NK cells. Surprisingly, many of these studies did not obtain optimal results, suggesting that many different NK cell parameters combined with the best clinical protocol need to be optimized. Various parameters including the high array of activating receptors that NK cells have, the source of NK cells selected to treat patients, different cytotoxic mechanisms that NK cells activate depending on the target cell and tumor cell survival mechanisms need to be considered before choosing the best immunotherapeutic strategy using NK cells. In this review, we will discuss these parameters to help improve current strategies using NK cells in cancer therapy. Moreover, the chimeric antigen receptor (CAR) modification, which has revolutionized the concept of immunotherapy, will be discussed in the context of NK cells. Lastly, the dark side of NK cells and their involvement in inflammation will also be discussed.
Més informació
Urbano-Ispizua Á, Muus P, Schrezenmeier H, Almeida AM, Wilson A, Ware RE

Different clinical characteristics of paroxysmal nocturnal hemoglobinuria in pediatric and adult patients.

Haematologica Mar 2017, 102 (3) e76-e79. Epub 24 Nov 2016Més informació
Martin-Antonio B, Najjar A, Robinson SN, Chew C, Li S, Yvon E, Thomas MW, Mc Niece I, Orlowski R, Muñoz-Pinedo C, Bueno C, Menendez P, Fernández de Larrea C, Urbano-Ispizua A, Shpall EJ, Shah N

Transmissible cytotoxicity of multiple myeloma cells by cord blood-derived NK cells is mediated by vesicle trafficking.

Cell Death Differ. Gen 2015, 22 (1) 96-107. Epub 29 Ago 2014
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.
Més informació
Báez A, Martín-Antonio B, Piruat JI, Barbado MV, Prats C, Álvarez-Laderas I, Carmona M, Pérez-Simón JA, Urbano-Ispizua Á

Gene and miRNA expression profiles of hematopoietic progenitor cells vary depending on their origin.

Biol. Blood Marrow Transplant. Mai 2014, 20 (5) 630-9. Epub 23 Gen 2014
Hematopoietic progenitor cells (HPCs) from granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood (G-PB), bone marrow (BM), or umbilical cord blood (CB) have differing biological properties and differing kinetics of engraftment post-transplantation, which might be explained, at least in part, by differing gene and miRNA expression patterns. To assess the differences in gene and miRNA expression, we analyzed whole genome expression profiles as well as the expression of 384 miRNAs in CD34(+) cells isolated from 18 healthy individuals (6 individuals per subtype of HPC source). We identified 43 genes and 36 miRNAs differentially expressed in the various CD34(+) cell sources. We observed that CD34(+) cells from CB and BM showed similar gene and miRNA expression profiles, whereas CD34(+) cells from G-PB had a very different expression pattern. Remarkably, 20 of the differentially expressed genes are targets of the differentially expressed miRNAs. Of note, the majority of genes differentially expressed in CD34(+) cells from G-PB are involved in cell cycle regulation, promoting the process of proliferation, survival, hematopoiesis, and cell signaling, and are targets of overexpressed and underexpressed miRNAs in CD34(+) cells from the same source. These data suggest significant differences in gene and miRNA expression among the various HPC sources used in transplantation. We hypothesize that the differentially expressed genes and miRNAs involved in cell cycle and proliferation might explain the differing kinetics of engraftment observed after transplantation of hematopoietic stem cells obtained from these different sources.
Més informació
Báez A, Martín-Antonio B, Piruat JI, Prats C, Álvarez-Laderas I, Barbado MV, Carmona M, Urbano-Ispizua Á, Pérez-Simón JA

Granulocyte colony-stimulating factor produces long-term changes in gene and microRNA expression profiles in CD34+ cells from healthy donors.

Haematologica Feb 2014, 99 (2) 243-51. Epub 20 Set 2013
Granulocyte colony-stimulating factor is the most commonly used cytokine for the mobilization of hematopoietic progenitor cells from healthy donors for allogeneic stem cell transplantation. Although the administration of this cytokine is considered safe, knowledge about its long-term effects, especially in hematopoietic progenitor cells, is limited. On this background, the aim of our study was to analyze whether or not granulocyte colony-stimulating factor induces changes in gene and microRNA expression profiles in hematopoietic progenitor cells from healthy donors, and to determine whether or not these changes persist in the long-term. For this purpose, we analyzed the whole genome expression profile and the expression of 384 microRNA in CD34(+) cells isolated from peripheral blood of six healthy donors, before mobilization and at 5, 30 and 365 days after mobilization with granulocyte colony-stimulating factor. Six microRNA were differentially expressed at all time points analyzed after mobilization treatment as compared to the expression in samples obtained before exposure to the drug. In addition, 2424 genes were also differentially expressed for at least 1 year after mobilization. Of interest, 109 of these genes are targets of the differentially expressed microRNA also identified in this study. These data strongly suggest that granulocyte colony-stimulating factor modifies gene and microRNA expression profiles in hematopoietic progenitor cells from healthy donors. Remarkably, some changes are present from early time-points and persist for at least 1 year after exposure to the drug. This effect on hematopoietic progenitor cells has not been previously reported.
Més informació
Martín-Antonio B, Suarez-Lledo M, Arroyes M, Fernández-Avilés F, Martínez C, Rovira M, Espigado I, Gallardo D, Bosch A, Buño I, Martínez-Laperche C, Jiménez-Velasco A, de la Cámara R, Brunet S, Nieto JB, Urbano-Ispizua A

A variant in IRF3 impacts on the clinical outcome of AML patients submitted to Allo-SCT.

Bone Marrow Transplant. Set 2013, 48 (9) 1205-11. Epub 1 Abr 2013
Allo-SCT has a strong curative potential for AML patients mainly due to a GVL effect. Unfortunately, GvL and GVHD are intimately linked. IFN regulatory factor-3 (IRF3), by modulating innate immune reactions, could impact on the incidence and intensity of GVL and GVHD. We analyzed two gene variants in IRF3 (rs7251 and rs2304205) on the clinical outcome of 249 AML patients submitted to HLA-identical sibling allo-SCT. Patients with a donor carrying the dominant GG gene variant in rs7251 had, as compared with GC and CC variants, a lower acute GVHD (aGVHD) III-IV incidence (4% vs 11% vs 27%; P=0.0078), a higher relapse incidence (49% vs 35% vs 26%; P=0.018), and lower TRM (7% vs 24% vs 18%; P=0.0065). In functional studies, the GG variant was associated with lower production of IFN-γ, decreased lymphocyte proliferation after antigen presentation by DCs, and lower cytotoxic response of mature natural killer cells. Patients carrying the AA dominant variant in rs2304205 had higher relapse incidence (50% vs 39% vs 18%, P=0.0068). The presence of both variants (GG in rs7251 and AA in rs2304205) in donors and patients resulted in a stronger clinical impact.
Més informació
Isern J, Martín-Antonio B, Ghazanfari R, Martín AM, López JA, del Toro R, Sánchez-Aguilera A, Arranz L, Martín-Pérez D, Suárez-Lledó M, Marín P, Van Pel M, Fibbe WE, Vázquez J, Scheding S, Urbano-Ispizúa Á, Méndez-Ferrer S

Self-renewing human bone marrow mesenspheres promote hematopoietic stem cell expansion.

Cell Rep 30 Mai 2013, 3 (5) 1714-24. Epub 25 Abr 2013
Strategies for expanding hematopoietic stem cells (HSCs) include coculture with cells that recapitulate their natural microenvironment, such as bone marrow stromal stem/progenitor cells (BMSCs). Plastic-adherent BMSCs may be insufficient to preserve primitive HSCs. Here, we describe a method of isolating and culturing human BMSCs as nonadherent mesenchymal spheres. Human mesenspheres were derived from CD45- CD31- CD71- CD146+ CD105+ nestin+ cells but could also be simply grown from fetal and adult BM CD45--enriched cells. Human mesenspheres robustly differentiated into mesenchymal lineages. In culture conditions where they displayed a relatively undifferentiated phenotype, with decreased adherence to plastic and increased self-renewal, they promoted enhanced expansion of cord blood CD34+ cells through secreted soluble factors. Expanded HSCs were serially transplantable in immunodeficient mice and significantly increased long-term human hematopoietic engraftment. These results pave the way for culture techniques that preserve the self-renewal of human BMSCs and their ability to support functional HSCs.
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Current projects

Modifications of inter-cellular communication between immune and multiple myeloma cells to improve sensibility to immunotherapy and conventional treatments

Responsable:Álvaro Urbano-Ispizua
Financiadors:
Import:93.170 €
Data d'inici:01/01/2018
Data de finalització:31/10/2019

Antitumor activity of NK cells mediated by lipid exchange. Potential therapeutic use after stem cell transplantation in multiple myeloma patients.

Responsable:Álvaro Urbano-Ispizua
Codi:M
Financiadors:
Import:83,000 €
Data d'inici:01/01/2015
Data de finalització:31/12/2017

Study of the impact of gene variants of the innate immune system in donor in the outcome of patients after allogeneic stem cell transplantation.

Responsable:Álvaro Urbano-Ispizua
Codi:M2
Financiadors:
Import:83,830 €
Data d'inici:01/01/2012
Data de finalització:31/12/2014

FIS ISCIII Project

Responsable:Álvaro Urbano-Ispizua
Codi:PI11/01090
Financiadors:
Data d'inici:01/01/2011
Data de finalització:31/12/2014

Myeloma and Bone Marrow Transplantation

Responsable:Álvaro Urbano-Ispizua
Codi:RD12/0036/004
Financiadors:
Data d'inici:01/01/2013
Data de finalització:31/12/2016