Stem Cell Transplantation

  • Urbano Group 3
Campus Clinic-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

Stem cell transplantation, either allogeneic (allo-SCT) or autologous (auto-SCT), is one of the treatment options for patients diagnosed with different types of hematological malignancies. However, this procedure is still associated with complications which decrease the survival of patients. Our main field of research is trying to find options to overcome the problems associated to this procedure including, how to improve the engraftment, how to decrease the morbidity and mortality and how to increase the possible anti-leukemia effect mediated either by donor lymphocytes in cases of allo-SCT or by the healthy T cells of the patient in cases of auto-SCT.

Research

In the stem cell transplantation (SCT) group our research is focused in five different areas to try to improve the outcome of hematological patients submitted to SCT, either allogeneic or autologous. These areas are:

  • In vitro expansion of hemopoietic progenitor cells by using mesenchymal stem cells to improve the engraftment after SCT.
  • Immune cell therapy with cord blood derived natural killer (CB-NK) cells to improve the anti-leukemic effect mediated by T lymphocytes after SCT.
  • Immune cell therapy with CB-NK cells to decrease refractoriness in patients submitted to previous treatments.
  • Identify the most specific marker in tumor cells for each type of hematological malignancy to target it by using chimeric antigen receptors (CARs) in NK cells and in T cells.
  • Study the mechanisms of glucocorticoid (GC) resistance in patients submitted to SCT and treated with GC for graft versus host disease in order to identify targets to eliminate resistance.

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

Selected publications

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. Sep 2013, 48 (9) 1205-11. Epub 1 Apr 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.
More information
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. May 2014, 20 (5) 630-9. Epub 23 Jan 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.
More information
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, Shpall EJ

Antigen presenting cell-mediated expansion of human umbilical cord blood yields log-scale expansion of natural killer cells with anti-myeloma activity.

PLoS ONE 2013, 8 (10) e76781. Epub 18 Oct 2013
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.
More information
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. Jan 2015, 22 (1) 96-107. Epub 29 Aug 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.
More information
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 Sep 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.
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Current projects

Project

Project leader:Álvaro Urbano
Code:PI11/01090
Funding:
Start date:01/01/2011
End date:31/12/2014

Myeloma and Bone Marrow Transplantation

Project leader:Álvaro Urbano
Code:RD12/0036/004
Funding:
Start date:01/01/2013
End date:31/12/2016