436 results on '"Leimig, T."'
Search Results
2. Process Development and Manufacturing: NOVEL SOFTWARE FOR ROBUST AND REPRODUCIBLE CLINICAL GRADE ENRICHMENT OF T REGULATORY CELLS EMPLOYING THE CLINIMACS PRODIGY
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Akel, S., primary, Leimig, T., additional, Porter, V., additional, Hu, X., additional, Peppenelli, M., additional, Paszkiet, B., additional, Gottschalk, S., additional, Triplett, B., additional, and Riberdy, J.M., additional
- Published
- 2023
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3. A large-scale method for the selective depletion of αβ T lymphocytes from PBSC for allogeneic transplantation
- Author
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Chaleff, S., Otto, M., Barfield, R.C., Leimig, T., Iyengar, R., Martin, J., Holiday, M., Houston, J., Geiger, T., Huppert, V., and Handgretinger, R.
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- 2007
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4. Large-scale isolation of CD133+ progenitor cells from G-CSF mobilized peripheral blood stem cells
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Gordon, P R, Leimig, T, Babarin-Dorner, A, Houston, J, Holladay, M, Mueller, I, Geiger, T, and Handgretinger, R
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- 2003
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5. A large-scale method for T cell depletion: towards graft engineering of mobilized peripheral blood stem cells
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Gordon, PR, Leimig, T, Mueller, I, Babarin-Dorner, A, Holladay, MA, Houston, J, Kerst, G, Geiger, T, and Handgretinger, R
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- 2002
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6. Predominance and characteristics of Burkitt lymphoma among children with non-Hodgkin lymphoma in northeastern Brazil
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Sandlund, JT, Fonseca, T, Leimig, T, Verissimo, L, Ribeiro, R, Lira, V, Berard, CW, Sixbey, J, Crist, WM, Mao, L, Chen, G, Pui, C-H, Heim, M, and Pedrosa, F
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- 1997
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7. Efficient in vitro generation of adult multipotent cells from mobilized peripheral blood CD133+ cells
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Kuçi, S., Kuçi, Z., Schmid, S., Seitz, G., Müller, I., Dufke, A., Leimig, T., Murti, G., Jurecic, R., Schumm, M., Lang, P., Bruchelt, G., Bader, P., Klingebiel, T., Niethammer, D., and Handgretinger, R.
- Published
- 2008
8. A one-step large-scale method for T- and B-cell depletion of mobilized PBSC for allogeneic transplantation
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Barfield, R.C., Otto, M., Houston, J., Holladay, M., Geiger, T., Martin, J., Leimig, T., Gordon, P., Chen, X., and Handgretinger, R.
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- 2004
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9. Purification of human natural killer cells using a clinical-scale immunomagnetic method
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Iyengar, R., Handgretinger, R., Babarin-Dorner, A., Leimig, T., Otto, M., Geiger, T.L., Holladay, M.S., Houston, J., and Leung, W.
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- 2003
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10. 803 - Process Development and Manufacturing: NOVEL SOFTWARE FOR ROBUST AND REPRODUCIBLE CLINICAL GRADE ENRICHMENT OF T REGULATORY CELLS EMPLOYING THE CLINIMACS PRODIGY.
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Akel, S., Leimig, T., Porter, V., Hu, X., Peppenelli, M., Paszkiet, B., Gottschalk, S., Triplett, B., and Riberdy, J.M.
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REGULATORY T cells , *MANUFACTURING processes - Published
- 2023
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11. Efficient in vitro generation of adult multipotent cells from mobilized peripheral blood CD133+ cells.
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Kuçi, S., Kuçi, Z., Schmid, S., Seitz, G., Müller, I., Dufke, A., Leimig, T., Murti, G., Jurecic, R., Schumm, M., Lang, P., Bruchelt, G., Bader, P., Klingebiel, T., Niethammer, D., and Handgretinger, R.
- Subjects
BLOOD cells ,STEM cells ,CELL proliferation ,ASTROCYTES ,CELL cycle ,LIVER cells - Abstract
Objectives: To generate non-haematopoietic tissues from mobilized haematopoietic CD133
+ stem cells. Materials and methods: Mobilized peripheral blood CD133+ cells from adult healthy donors were used. In vitro ability of highly enriched CD133+ cells from mobilized peripheral blood to generate multipotent cells, and their potential to give rise to cells with characteristics of neuroectoderm, endoderm and mesoderm layers was investigated. Results: We found that a recently identified population of CD45+ adherent cells generated in vitro after culture of highly purified CD133+ cells for 3–5 weeks with Flt3/Flk2 ligand and interleukin-6 can, in presence of the appropriate microenvironmental cues, differentiate into neural progenitor-like cells (NPLCs), hepatocyte-like cells and skeletal muscle-like cells. We have termed them to be adult multipotent haematopoietic cells (AMHCs). AMHC-derived NPLCs expressed morphological, phenotypic and molecular markers associated with primary neural progenitor cells. They can differentiate into astrocyte-like cells, neuronal-like cells and oligodendrocyte-like cells. Moreover, AMHC-derived NPLCs produced 3,4-dihydrophenylalanine and dopamine and expressed voltage-activated ion channels, suggesting their functional maturation. In addition, AMHC-derived hepatocyte-like cells and skeletal muscle-like cells, showed typical morphological features and expressed primary tissue-associated proteins. Conclusion: Our data demonstrate that AMHCs may therefore serve as a novel source of adult multipotent cells for autologous replacement cell therapies. [ABSTRACT FROM AUTHOR]- Published
- 2008
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12. IL-2 adenovector-transduced autologous tumor cells induce antitumor immune responses in patients with neuroblastoma
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Bowman, L., Grossmann, M., Rill, D., Michael Brown, Zhong, W. -Y, Alexander, B., Leimig, T., Coustan-Smith, E., Campana, D., Jenkins, J., Woods, D., Kitchingman, G., Vanin, E., and Brenner, M.
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Adolescent ,Immunology ,Genetic Vectors ,Infant ,Cell Biology ,Hematology ,T-Lymphocytes, Helper-Inducer ,Transfection ,Biochemistry ,Immunotherapy, Adoptive ,Adenoviridae ,Killer Cells, Natural ,Neuroblastoma ,T-Lymphocyte Subsets ,Child, Preschool ,Humans ,Interleukin-2 ,Longitudinal Studies ,Child ,T-Lymphocytes, Cytotoxic - Abstract
In many different murine models, the immunogenicity of tumor cells can be increased by transduction with a range of immunostimulatory genes, inducing an immune response that causes regression of pre-existing unmodified tumor cells. To investigate the relevance of these animal models to pediatric malignancy, we used autologous unirradiated tumor cells transduced with an adenovirus-IL-2 to immunize 10 children with advanced neuroblastoma. In a dose-escalation study, we found that this tumor immunogen induced a moderate local inflammatory response consisting predominantly of CD4+ T lymphocytes, and a systemic response, with a rise in circulating CD25+and DR+ CD3+ T cells. Patients also made a specific antitumor response, manifest by an IgG antitumor antibody and increased cytotoxic T-cell killing of autologous tumor cells. Clinically, five patients had tumor responses after the tumor immunogen alone (one complete tumor response, one partial response, and three with stable disease). Four of these five patients were shown to have coexisting antitumor cytotoxic activity, as opposed to only one of the patients with nonresponsive disease. These results show a promising correlation between preclinical observations and clinical outcome in this disease, and support further exploration of the approach for malignant diseases of children. © 1998 by The American Society of Hematology.
- Published
- 1998
13. Large-scale isolation of CD133+progenitor cells from G-CSF mobilized peripheral blood stem cells.
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Gordon, P.R., Leimig, T., Babarin-Dorner, A., Houston, J., Holladay, M., Mueller, I., Geiger, T., and Handgretinger, R.
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STEM cells ,CELL transplantation ,LEUKAPHERESIS - Abstract
We have evaluated the feasibility of large-scale isolation of CD133+ progenitors from healthy mobilized adult donors for potential clinical use in autologous and allogeneic transplantation. A total of 11 healthy volunteer adult donors were mobilized with G-CSF. CD133 + stem cells were isolated from a single leukapheresis using the Clinimacs method. The median percentage of CD133 before positive selection was 0.75% (range 0.39-2.03%). After selection, the median purity and recovery was 94% (range 85.2-98.0%) and 69% (range 44-100%), respectively. The median log10 T-cell depletion obtained by CD133+ positive selection was 4.2 (range 3.8-4.7). The CD133+ progenitors were highly enriched in colony-forming units (CFU) and transplantation into NOD/SCID mice resulted in a high engraftment rate. Transplantation of sorted CD133 +/CD34 + cells into NOD/SCID mice showed a higher engraftment compared to CD133-/CD34+ cells. Mobilized peripheral CD133+ stem cells can be purified in large scale for potential clinical use. The biological function of the cells is not impaired. The majority of the NOD/SCID repopulating cells are within the CD133 +/CD34 + subpopulation. Therefore, clinical studies using purified CD133 + stem cells can be envisoued to further clarify the role of CD133+ stem cells in hematopoietic reconstitution after transplantation. [ABSTRACT FROM AUTHOR]
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- 2003
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14. Mobilization of Endogenous CD34+/CD133+ Endothelial Progenitor Cells by Enhanced External Counter Pulsation for Treatment of Refractory Angina.
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Tartaglia, Joseph T., Eisenberg, Carol A., DeMarco, Joseph C., Puccio, Gregory, Tartaglia, Christina E., and Hamby, Carl V.
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TREADMILL exercise tests ,STEM cell treatment ,PROGENITOR cells ,STEM cells ,AEROBIC capacity ,COLLATERAL circulation - Abstract
Adult stem cell therapy via intramyocardial injection of autologous CD34+ stem cells has been shown to improve exercise capacity and reduce angina frequency and mortality in patients with refractory angina (RA). However, the cost of such therapy is a limitation to its adoption in clinical practice. Our goal was to determine whether the less costly, less invasive, and widely accessible, FDA-approved alternative treatment for RA patients, known as enhanced external counterpulsation (EECP), mobilizes endogenous CD34+ stem cells and whether such mobilization is associated with the clinical benefits seen with intramyocardial injection. We monitored changes in circulating levels of CD34+/CD133+ and CD34+/KDR+ cells in RA patients undergoing EECP therapy and in a comparator cohort of RA patients undergoing an exercise regimen known as cardiac rehabilitation. Changes in exercise capacity in both cohorts were monitored by measuring treadmill times (TT), double product (DP) scores, and Canadian Cardiovascular Society (CCS) angina scores between pre- and post-treatment treadmill stress tests. Circulating levels of CD34+/CD133+ cells increased in patients undergoing EECP and were significant (β = −2.38, p = 0.012) predictors of improved exercise capacity in these patients. CD34+/CD133+ cells isolated from RA patients could differentiate into endothelial cells, and their numbers increased during EECP therapy. Our results support the hypothesis that mobilized CD34+/CD133+ cells repair vascular damage and increase collateral circulation in RA patients. They further support clinical interventions that can mobilize adult CD34+ stem cells as therapy for patients with RA and other vascular diseases. [ABSTRACT FROM AUTHOR]
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- 2024
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15. Combination immunotherapy with clinical-scale enriched human gammadelta T cells, hu14.18 antibody, and the immunocytokine Fc-IL7 in disseminated neuroblastoma.
- Author
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Otto M, Barfield RC, Martin WJ, Iyengar R, Leung W, Leimig T, Chaleff S, Gillies SD, and Handgretinger R
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- Animals, Antibodies, Monoclonal immunology, Blood Donors, Cell Survival drug effects, Cell Survival immunology, Cytotoxicity Tests, Immunologic, Female, Flow Cytometry, Gangliosides immunology, Granulocyte Colony-Stimulating Factor pharmacology, Humans, Interleukin-7 immunology, Leukapheresis, Mice, Mice, Inbred NOD, Mice, SCID, Neuroblastoma immunology, Neuroblastoma secondary, T-Lymphocytes, Cytotoxic metabolism, Transplantation, Heterologous, Antibodies, Monoclonal pharmacology, Cytotoxicity, Immunologic immunology, Immunotherapy, Neuroblastoma prevention & control, Receptors, Antigen, T-Cell, gamma-delta immunology, T-Lymphocyte Subsets immunology, T-Lymphocytes, Cytotoxic immunology
- Abstract
Purpose: To evaluate a combined cellular and humoral immunotherapy regimen in a mouse model of disseminated human neuroblastoma. We tested combinations of clinical-grade, isolated human gammadelta T cells with the humanized anti-GD2 antibody hu14.18 and a novel fusion cytokine, Fc-IL7., Experimental Design: gammadelta T cells were large-scale enriched from leukapheresis product obtained from granulocyte colony-stimulating factor-mobilized donors. gammadelta T cell cytotoxicity was tested in a europium-TDA release assay. The effect of Fc-IL7 on gammadelta T-cell survival in vitro was assessed by flow cytometry. NOD.CB17-Prkdc(scid)/J mice received 1 x 10(6) NB-1691 neuroblastoma cells via the tail vein 5 to 6 days before therapy began. Treatment, for five consecutive weeks, consisted of injections of 1 x 10(6) gammadelta T cells weekly, 1 x 10(6) gammadelta T cells weekly, and 20 microg hu14.18 antibody four times per week, or 1 x 10(6) gammadelta T cells weekly with 20 microg hu14.18 antibody four times per week, and 20 mug Fc-IL7 once weekly., Results: The natural cytotoxicity of gammadelta T cells to NB-1691 cells in vitro was dramatically enhanced by hu14.18 antibody. Fc-IL7 effectively kept cultured gammadelta T cells viable. Combination therapy with gammadelta T cells and hu14.18 antibody significantly enhanced survival (P = 0.001), as did treatment with gammadelta T cells, hu14.18 antibody, and Fc-IL7 (P = 0.005). Inclusion of Fc-IL7 offered an additional survival benefit (P=0.04)., Conclusions: We have shown a new and promising immunotherapy regimen for neuroblastoma that requires clinical evaluation. Our approach might also serve as a therapeutic model for other malignancies.
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- 2005
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16. Phenotype and function of human natural killer cells purified by using a clinical-scale immunomagnetic method.
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Leung W, Iyengar R, Leimig T, Holladay MS, Houston J, and Handgretinger R
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- Animals, Antilymphocyte Serum pharmacology, Cell Adhesion Molecules metabolism, Cell Proliferation, Cytokines metabolism, Graft vs Host Disease immunology, Granulocyte Colony-Stimulating Factor pharmacology, Granzymes, Humans, Immunomagnetic Separation, Membrane Glycoproteins metabolism, Mice, Mice, Inbred NOD, Mice, SCID, Perforin, Pore Forming Cytotoxic Proteins, Receptors, Immunologic immunology, Serine Endopeptidases metabolism, Immunophenotyping, Killer Cells, Natural immunology
- Abstract
Infection, disease relapse, graft failure, and graft-versus-host disease (GVHD) are significant adverse events associated with allogeneic bone marrow transplantation. Donor natural killer (NK) cells may be an ideal cell type for prevention or treatment of all these adverse events. Therefore, we investigated the phenotype and function of human NK cells purified by using a clinical-scale immunomagnetic method. We found that the NK cell purification procedures did not adversely affect the expression of killer cell immunoglobulin-like receptors, adhesion molecules, intracellular cytokines, perforin, and granzyme B. Purified NK cells had extensive proliferative capacity and potent antitumor activity when assessed using an immunodeficient mouse model. While all mice transplanted with unpurified mononuclear cells developed GVHD, none of the mice transplanted with purified NK cells did. NK cells were highly susceptible to lysis by antithymocyte globulin (ATG), whereas G-CSF had a minimal effect on their natural cytotoxicity. These results support future clinical investigation of the use of purified NK cells for adoptive immunotherapy in the absence of ATG.
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- 2005
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17. Biology and plasticity of CD133+ hematopoietic stem cells.
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Handgretinger R, Gordon PR, Leimig T, Chen X, Buhring HJ, Niethammer D, and Kuci S
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- AC133 Antigen, Adult, Animals, Antigens, CD, Antigens, CD34 metabolism, Cell Division, Cell Size, Flow Cytometry, Humans, Mice, Mice, SCID, Transplantation, Heterologous, Cell Differentiation, Glycoproteins metabolism, Hematopoietic Stem Cells cytology, Peptides metabolism
- Abstract
AC133 (CD133) is a highly conserved antigen expressed on hematopoietic stem cells with unknown function. In order to further characterize CD133(+) progenitor cells, we purified CD133(+) stem cells using the method of magnetic activated cell sorting (MACS) from healthy adult volunteers mobilized with granulocyte colony-stimulating growth factor (G-CSF) to a mean purity of 94%. The purified CD133(+) cells highly engrafted NOD/SCID mice. In addition, unseparated mononuclear cells or CD133(+) stem cells isolated from the bone marrow of transplanted NOD/SCID mice gave rise to engraftment of secondary recipients. Upon ex vivo culture of purified CD133(+) cells with FLT3/Flk2 ligand (FL) and interleukin-6 (IL-6), a plastic-adherent cell population could be observed after 6 weeks in culture. These adherent cells did not express CD34 or CD133 antigens on their surface, nor did they express markers for endothelial, mesenchymal, or dendritic cells. After incubation of these adherent cells with stem cell factor (SCF), non-adherent cells were observed which partially co-expressed CD133, but were negative for CD34. These nonadherent CD34(-) cells showed a high engraftment capacity in NOD/SCID mice. From our results, we conclude that CD133 might be a marker of early progenitors with a high NOD/SCID engraftment potential. The fact that CD133(+) hematopoietic progenitors can give rise to an adherent population which is CD133(-) and CD34(-) and that these cells can again give rise to a CD133(+)CD34(-) stem cell population with high NOD/SCID engraftment potential indicates the plasticity of hematopoietic precursors. CD133(+) stem cells might be useful for research and for clinical application.
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- 2003
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18. Functional amelioration of murine galactosialidosis by genetically modified bone marrow hematopoietic progenitor cells.
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Leimig T, Mann L, Martin Mdel P, Bonten E, Persons D, Knowles J, Allay JA, Cunningham J, Nienhuis AW, Smeyne R, and d'Azzo A
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- Animals, Ataxia etiology, Ataxia therapy, Bone Marrow Cells cytology, Carboxypeptidases administration & dosage, Carboxypeptidases genetics, Carboxypeptidases pharmacokinetics, Cathepsin A, Central Nervous System Diseases etiology, Central Nervous System Diseases therapy, Genetic Therapy methods, Green Fluorescent Proteins, Hematopoietic Stem Cell Transplantation, Kidney Diseases etiology, Kidney Diseases therapy, Luminescent Proteins genetics, Mice, Mice, Knockout, Mucolipidoses complications, Mucolipidoses pathology, Neuraminidase deficiency, Organ Specificity, Tissue Distribution, Treatment Outcome, beta-Galactosidase deficiency, Hematopoietic Stem Cells metabolism, Lysosomal Storage Diseases therapy, Mucolipidoses therapy
- Abstract
Protective protein/cathepsin A (PPCA), a lysosomal carboxypeptidase, is deficient in the neurodegenerative lysosomal disorder galactosialidosis (GS). PPCA(-/-) mice display a disease course similar to that of severe human GS, resulting in nephropathy, ataxia, and premature death. Bone marrow transplantation (BMT) in mutant animals using transgenic BM overexpressing the corrective enzyme in either erythroid cells or monocytes/macrophages has proven effective for the improvement of the phenotype, and encouraged the use of genetically modified BM cells for ex vivo gene therapy of GS. Here, we established stable donor hematopoiesis in PPCA(-/-) mice that received hematopoietic progenitors transduced with a murine stem cell virus (MSCV)-based, bicistronic retroviral vector overexpressing PPCA and the green fluorescent protein (GFP) marker. We observed complete correction of the disease phenotype in the systemic organs up to 10 months after transplantation. PPCA(+) BM-derived cells were detected in all tissues, with the highest expression in liver, spleen, BM, thymus, and lung. In addition, a lysosomal immunostaining was seen in nonhematopoietic cells, indicating efficient uptake of the corrective protein by these cells and cross-correction. Expression in the brain occurred throughout the parenchyma but was mainly localized on perivascular areas. However, PPCA expression in the central nervous system was apparently sufficient to delay the onset of Purkinje cell degeneration and to correct the ataxia. The long-term expression and internalization of the PPCA by cells of systemic organs and the clear improvement of the neurologic phenotype support the use of this approach for the treatment of GS in humans. (Blood. 2002;99:3169-3178)
- Published
- 2002
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19. Retrovirus-mediated gene transfer of the cytokine genes interleukin-1beta and tumor necrosis factor-alpha into human neuroblastoma cells: consequences for cell line behavior and immunomodulatory properties.
- Author
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Coze C, Leimig T, Jimeno MT, and Mannoni P
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- Cell Division, Coculture Techniques, Genetic Vectors, Humans, Lymphocyte Culture Test, Mixed, Lymphocyte Subsets, Neuroblastoma pathology, Phenotype, Tumor Cells, Cultured, Gene Transfer Techniques, Interleukin-1 genetics, Neuroblastoma genetics, Retroviridae genetics, Tumor Necrosis Factor-alpha genetics
- Abstract
We have investigated the value of a gene therapy approach for neuroblastoma (NB), based on retroviral transduction of the IL-1beta or TNF-alpha cytokine genes into human NB lines. Secretion of the corresponding cytokine, was demonstrated in all lines, although with considerable quantitative variations. Cytokine gene expression significantly reduced the proliferation index (p = 0.0001); this effect was associated with either terminal neuronal (one TNF-alpha line) or fibroblast-like differentiation (two IL-1beta lines), leading to growth arrest after a few weeks. Cell surface levels of CD54 and HLA class II remained unaffected, but HLA class I (p < 0.001) and CD58 expression (p = 0.01) increased on SKNSH after TNF-alpha gene transfer. Mononuclear cells from normal allogeneic donors cocultured with both IL-1beta (p < 0.001) and TNF-alpha lines (p < 0.01), showed a significant increase in the proportion of activated T cells (CD3+DR+); however, their cytotoxicity and proliferation rate remained unchanged. Immunotherapy of neuroblastoma will require identification of transduced lines in which cytokine secretion induces phenotypic changes in such a way as to augment their likely immunomodulatory properties without impeding cell growth. Because of the limited efficacy of IL-1beta or TNF-alpha gene transfer alone, further studies should focus on combination with other immunomodulatory agents, to improve their potential efficacy in neuroblastoma.
- Published
- 2001
20. Interleukin-2 gene-modified allogeneic tumor cells for treatment of relapsed neuroblastoma.
- Author
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Bowman LC, Grossmann M, Rill D, Brown M, Zhong WY, Alexander B, Leimig T, Coustan-Smith E, Campana D, Jenkins J, Woods D, and Brenner M
- Subjects
- Cell Transplantation, Child, Child, Preschool, Humans, Injections, Subcutaneous, Neuroblastoma pathology, Phenotype, Recurrence, Transplantation, Homologous, Treatment Outcome, Tumor Cells, Cultured, Cancer Vaccines, Cytotoxicity, Immunologic, Genetic Therapy, Interleukin-2 biosynthesis, Interleukin-2 genetics, Neuroblastoma immunology, Neuroblastoma therapy
- Abstract
Tumor cells that have been genetically modified to express immunostimulatory genes will induce effective antitumor responses in a range of syngeneic animal models. For human applications, transduced autologous tumor cell lines are often difficult or impossible to prepare, so that there are strong incentives for substituting a standardized allogeneic tumor cell line. However, such lines may be inferior immunogens if they differ from host tumors in the antigens they express. We have evaluated the safety, immunostimulatory, and antitumor activity of an interleukin-2-secreting allogeneic neuroblastoma cell line in 12 children with relapsed stage IV neuroblastoma. They received two to four subcutaneous injections of cells in a dose-escalating schedule, up to a maximum of 10(8) cells per injection. There was induration and pruritus at the injection site, and skin biopsies revealed mild panniculitis with CD3+ cells surrounding scanty residual tumor cells. There was a limited but significant peripheral monocytosis. No patient showed any increase in direct cytotoxic effector function against the immunizing cell line, but 3 patients had a rise in the frequency of neuroblastoma-reactive cytotoxic T lymphocyte precursor cells. One child had > 90% tumor response (PR), 7 had stable disease, and 4 had progressive disease in response to vaccine alone. Although these results offer some encouragement for the continued pursuit of allogeneic vaccine strategies in human cancer, the antitumor immune responses we observed are inferior to those obtained in an earlier immunization study using autologous neuroblastoma cells. Hence, we suggest that this earlier approach remains preferable, its difficulties notwithstanding.
- Published
- 1998
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21. Gene marking and gene therapy for transplantation medicine.
- Author
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Dilloo D, Rill DR, Grossmann ME, Leimig T, and Brenner MK
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- Biomarkers, Gene Transfer Techniques, Humans, Genetic Therapy, Hematopoietic Stem Cell Transplantation methods
- Abstract
The classic application for gene therapy is in the correction of single gene defects, although this has been complicated by the low efficiency of gene transfer into hematopoietic cells. Gene therapy, however, has potential for the modulation of tumor cell growth, drug sensitivity, and antitumor immune responses. In addition, gene marking can be used, in spite of this limited transfer efficiency, to provide information on hematopoiesis, sources of cancer relapse after stem cell transplant, and the relative efficacy of graft manipulation techniques. This article reviews the applications of gene therapy and gene marking in transplantation medicine.
- Published
- 1996
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22. High-efficiency transduction of freshly isolated human tumor cells using adenoviral interleukin-2 vectors.
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Leimig T, Brenner M, Ramsey J, Vanin E, Blaese M, and Dilloo D
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- Coculture Techniques, Gene Deletion, HLA-DR Antigens analysis, Humans, Interleukin-2 biosynthesis, Lac Operon genetics, Lymphocytes immunology, Retroviridae, T-Lymphocyte Subsets, T-Lymphocytes immunology, T-Lymphocytes, Cytotoxic immunology, Tumor Cells, Cultured, Adenoviruses, Human genetics, Gene Transfer Techniques, Genetic Vectors genetics, Interleukin-2 genetics, Neuroblastoma immunology, Neuroblastoma metabolism
- Abstract
Tumor cells genetically modified to express immunostimulatory molecules can produce high levels of antitumor immunity in rodent models. Although a number of clinical trials are currently in progress to assess the value of the approach in human disease, almost all require ex vivo transduction of cultured tumor cells with retroviral vectors. This process is not feasible for many human malignancies, hampering clinical evaluation of the approach. We have used an E1a,1b/E3 deletion mutant of adenovirus containing either the lacZ or the human interleukin-2 (IL-2) gene to transduce human neuroblastoma cells. This vector transduces fresh neuroblastoma cells and neuroblastoma cell lines with an efficiency of 80-90%, compared to an efficiency of 0-14% obtained with retroviral vectors. Cells transduced with the IL-2 adenovector produce up to 12,000 pg of IL-2/10(6) cells/24 hr. IL-2 adenovector-transduced neuroblasts are immunostimulatory; when they are cultured with patient lymphocytes, they increase the proportion of DR+ T cells and generate major histocompatibility complex (MHC) unrestricted cytotoxic effector cells active against parental (nontransduced) tumor cells. We conclude that IL-2 adenovector can be used to transduce freshly isolated human tumor cells efficiently, which will then produce immunomodulatory quantities of the cytokine. The use of adenoviral rather than retroviral vectors facilitates preparation of human tumor "vaccines" and these vectors are now being used in our clinical study of neuroblastoma patients.
- Published
- 1996
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23. Immunomodulatory effects of human neuroblastoma cells transduced with a retroviral vector encoding interleukin-2.
- Author
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Leimig T, Foreman N, Rill D, Coze C, Holladay M, and Brenner M
- Subjects
- Antibodies, Monoclonal immunology, Antibodies, Monoclonal pharmacology, Antigens, CD analysis, DNA, Complementary genetics, Genes, Reporter, Humans, Immunotherapy, Interleukin-2 immunology, Interleukin-2 metabolism, Kanamycin Kinase, Lymphocyte Subsets immunology, Neuroblastoma immunology, Phosphotransferases (Alcohol Group Acceptor) biosynthesis, Phosphotransferases (Alcohol Group Acceptor) genetics, Recombinant Fusion Proteins biosynthesis, Transfection, Tumor Cells, Cultured, Vaccination, Genetic Vectors genetics, Interleukin-2 genetics, Neuroblastoma pathology, Retroviridae genetics
- Abstract
We have investigated whether retroviral mediated transfer of the IL-2 gene renders human neuroblastoma cells immunogenic, justifying their use in a clinical tumor immunization study. Fourteen neuroblastoma cell lines were established from patients with disseminated neuroblastoma and transduced with the vector G1Ncvl2, which contains the neomycin phosphotransferase gene and the cDNA of the human interleukin-2 gene. Clones secreting > 150 pg/10(6) cells/24 h of IL-2 were selected for further study. Secretion of IL-2 was maintained for at least 3 weeks in nonselective media, implying that production of the cytokine would continue under in vivo conditions. Co-culture of IL-2 transduced cell lines with patient lymphocytes induced potent cytotoxic activity against both transduced and parental neuroblastoma cell lines. This activity was HLA unrestricted, and predominantly mediated by CD16+ or CD56+ and CD8- lymphocytes. These data form the preclinical justification for our current immunization protocol for patients with relapsed or resistant neuroblastoma.
- Published
- 1994
24. Cellular Strategies for Separating GvHD from GvL in Haploidentical Transplantation.
- Author
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Di Ianni, Mauro, Liberatore, Carmine, Santoro, Nicole, Ranalli, Paola, Guardalupi, Francesco, Corradi, Giulia, Villanova, Ida, Di Francesco, Barbara, Lattanzio, Stefano, Passeri, Cecilia, Lanuti, Paola, and Accorsi, Patrizia
- Subjects
REGULATORY T cells ,SUICIDE ,CELLULAR therapy ,GENE therapy ,BRAIN death - Abstract
GvHD still remains, despite the continuous improvement of transplantation platforms, a fearful complication of transplantation from allogeneic donors. Being able to separate GvHD from GvL represents the greatest challenge in the allogeneic transplant setting. This may be possible through continuous improvement of cell therapy techniques. In this review, current cell therapies are taken into consideration, which are based on the use of TCR alpha/beta depletion, CD45RA depletion, T regulatory cell enrichment, NK-cell-based immunotherapies, and suicide gene therapies in order to prevent GvHD and maximally amplify the GvL effect in the setting of haploidentical transplantation. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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25. Comorbidities and Angiogenic Regulators Affect Endothelial Progenitor Cell Subtype Numbers in a Healthy Volunteer Control Group.
- Author
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Rakkar K, Kadir RRA, Othman OA, Sprigg N, Bath PM, and Bayraktutan U
- Abstract
Endothelial progenitor cells (EPCs) are stem cells that can repair injured blood vessels through neovascularisation. This is achieved through secretion of growth factors and endothelial maturation. EPC numbers and function have been studied to determine their diagnostic, prognostic and therapeutic potential in many ischaemic diseases such as stroke. However their activation homing and migration is not definitively understood in stroke patients. In this study, we profiled the non-stroke control group recruited into the Dunhill Medical Trust Endothelial Progenitor Cell Study. Demographic, clinical and plasma levels of angiogenic regulators of participants were analysed to determine if there was any correlation with EPC numbers, subtypes and function. Participants with diabetes had significantly supressed EPC numbers (CD45-CD34 + CD133 + KDR+) and CD34 + KDR + and KDR + EPC subtypes. Male participants had significantly lower EPC numbers compared to female participants and the proliferative capacity of endothelial colony forming cells significantly decreased with increasing participant age. Pro-angiogenic proteins such as granulocyte colony-stimulating factor and stromal cell-derived factor were positively correlated with both undifferentiated and endothelial-committed EPC subtype numbers (CD133+, KDR+, CD34 + CD133+, CD34 + KDR+), whereas anti-angiogenic proteins such as thrombospondin-1 showed a negative correlation with undifferentiated EPC subtypes (CD133+, CD34 + CD133+) but a positive correlation with endothelial-committed EPC subtype numbers (KDR+, CD34 + KDR+). These results show that EPC numbers and subtypes are affected by many factors and larger studies which can analyse and deconvolute the interactions between comorbidities, plasma biomarker levels and EPC are needed., (© 2024. The Author(s).)
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- 2024
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26. Defining the Role of Metastasis-Initiating Cells in Promoting Carcinogenesis in Ovarian Cancer.
- Author
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Wang, Ji, Ford, James C., and Mitra, Anirban K.
- Subjects
OVARIAN cancer ,CARCINOGENESIS ,METASTASIS ,CANCER cells ,CANCER prognosis - Abstract
Simple Summary: Metastasis is the main cause of poor outcomes in ovarian cancer and metastasis-initiating cells are a subpopulation of cancer cells that can effectively establish metastases. We provide an overview of their characteristics, function, and the potential of targeting them in ovarian cancer. Ovarian cancer is the deadliest gynecological malignancy with a high prevalence of transcoelomic metastasis. Metastasis is a multi-step process and only a small percentage of cancer cells, metastasis-initiating cells (MICs), have the capacity to finally establish metastatic lesions. These MICs maintain a certain level of stemness that allows them to differentiate into other cell types with distinct transcriptomic profiles and swiftly adapt to external stresses. Furthermore, they can coordinate with the microenvironment, through reciprocal interactions, to invade and establish metastases. Therefore, identifying, characterizing, and targeting MICs is a promising strategy to counter the spread of ovarian cancer. In this review, we provided an overview of OC MICs in the context of characterization, identification through cell surface markers, and their interactions with the metastatic niche to promote metastatic colonization. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
27. Costimulatory signals can be effectively delivered by gene modified cells in a leukemia vaccine
- Author
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Dilloo, D., Leimig, T., Zhong, W., Mei, Z., and Brenner, M.
- Subjects
Vaccines -- Research ,Leukemia research -- Models ,Cancer cells -- Adaptation ,Business ,Health care industry - Abstract
According to an abstract submitted by the authors to the 37th Annual Meeting of the American Society of Hematology, held December 1-5, 1995, in Seattle, Washington, 'Tumor cells engineered to [...]
- Published
- 1996
28. Immunomodulatory effects of human neuroblastoma cells transduced with a retroviral vector encoding interleukin-2
- Author
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Leimig, T., Foreman, N., Rill, D., Coze, C., Holladay, M., and Brenner, M.
- Subjects
Gene therapy -- Research ,Neuroblastoma -- Physiological aspects ,Biological response modifiers -- Research ,Immune response -- Regulation ,Business ,Health care industry - Abstract
According to the authors' abstract of an article published in Cancer Gene Therapy, 'We have investigated whether retroviral mediated transfer of the IL-2 gene renders human neuroblastoma cells immunogenic, justifying [...]
- Published
- 1995
29. Circulating endothelial and angiogenic cells predict hippocampal volume as a function of HIV status.
- Author
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McIntosh, Roger, Hidalgo, Melissa, Lobo, Judith, Dillon, Kaitlyn, Szeto, Angela, and Hurwitz, Barry E.
- Subjects
ENDOTHELIAL cells ,HIV ,HIV status ,GRAY matter (Nerve tissue) ,HIPPOCAMPUS (Brain) ,VOXEL-based morphometry ,HIV infections - Abstract
Circulating endothelial cells (CECs) and myeloid angiogenic cells (MACs) have the capacity to stabilize human blood vessels in vivo. Evidence suggests that these cells are depleted in dementia and in persons living with HIV (PWH), who have a higher prevalence of dementia and other cognitive deficits associated with aging. However, the associations of CECs and MACs with MRI-based measures of aging brain health, such as hippocampal gray matter volume, have not been previously demonstrated. The present study examined differences in these associations in 51 postmenopausal women with and without HIV infection. Gray matter volume was quantified using MRI. CECs and MACs were enumerated using fluorescence-activated cell sorting. Analyses examined the association of these cell counts with left and right hippocampal gray matter volume while controlling for age and hypertension status. The main finding was an interaction suggesting that compared to controls, postmenopausal PWH with greater levels of CECs and MACs had significantly greater hippocampus GMV. Further research is necessary to examine potential underlying pathophysiological mechanisms in HIV infection linking morpho-functional circulatory reparative processes with more diminished hippocampal volume in postmenopausal women. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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30. New Forms of Transplantation.
- Author
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Handgretinger, R., Leimig, T., Babarin-Domer, A., Holladay, M.A., Gordon, J. Houston P., Corbacioglu, S., Greil, J., laws, H., Dilloo, D., Strahm, B., Peters, C., Sykora, K., Luethy, A. Ridolfi, Friedrich, W., Gungor, T., Schulz, A., Wachowiak, J., Chybicka, A., and Boruczkowski, D.
- Subjects
- *
TRANSPLANTATION of organs, tissues, etc. , *STEM cell transplantation - Abstract
Bone Marrow Transplantation (2002) 30, S11–S15. doi:10.1038/sj.bmt.1703744 [ABSTRACT FROM AUTHOR]
- Published
- 2002
- Full Text
- View/download PDF
31. Natural killer cells in clinical development as non-engineered, engineered, and combination therapies.
- Author
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Lamers-Kok, Nina, Panella, Denise, Georgoudaki, Anna-Maria, Liu, Haiping, Özkazanc, Didem, Kučerová, Lucia, Duru, Adil Doganay, Spanholtz, Jan, and Raimo, Monica
- Subjects
KILLER cells ,CELLULAR recognition ,MANUFACTURING cells ,CHIMERIC antigen receptors ,GRAFT versus host disease - Abstract
Natural killer (NK) cells are unique immune effectors able to kill cancer cells by direct recognition of surface ligands, without prior sensitization. Allogeneic NK transfer is a highly valuable treatment option for cancer and has recently emerged with hundreds of clinical trials paving the way to finally achieve market authorization. Advantages of NK cell therapies include the use of allogenic cell sources, off-the-shelf availability, and no risk of graft-versus-host disease (GvHD). Allogeneic NK cell therapies have reached the clinical stage as ex vivo expanded and differentiated non-engineered cells, as chimeric antigen receptor (CAR)-engineered or CD16-engineered products, or as combination therapies with antibodies, priming agents, and other drugs. This review summarizes the recent clinical status of allogeneic NK cell-based therapies for the treatment of hematological and solid tumors, discussing the main characteristics of the different cell sources used for NK product development, their use in cell manufacturing processes, the engineering methods and strategies adopted for genetically modified products, and the chosen approaches for combination therapies. A comparative analysis between NK-based non-engineered, engineered, and combination therapies is presented, examining the choices made by product developers regarding the NK cell source and the targeted tumor indications, for both solid and hematological cancers. Clinical trial outcomes are discussed and, when available, assessed in comparison with preclinical data. Regulatory challenges for product approval are reviewed, highlighting the lack of specificity of requirements and standardization between products. Additionally, the competitive landscape and business field is presented. This review offers a comprehensive overview of the effort driven by biotech and pharmaceutical companies and by academic centers to bring NK cell therapies to pivotal clinical trial stages and to market authorization. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
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32. Strategies for Potentiating NK-Mediated Neuroblastoma Surveillance in Autologous or HLA-Haploidentical Hematopoietic Stem Cell Transplants.
- Author
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Bottino, Cristina, Della Chiesa, Mariella, Sorrentino, Stefania, Morini, Martina, Vitale, Chiara, Dondero, Alessandra, Tondo, Annalisa, Conte, Massimo, Garaventa, Alberto, and Castriconi, Roberta
- Subjects
THERAPEUTIC use of monoclonal antibodies ,PUBLIC health surveillance ,CYTOKINES ,PROGRAMMED cell death 1 receptors ,NEUROBLASTOMA ,HLA-B27 antigen ,EXOSOMES ,CELLULAR therapy ,KILLER cells ,HEMATOPOIETIC stem cell transplantation ,TUMOR antigens ,T cells ,IMMUNOTHERAPY - Abstract
Simple Summary: High-risk neuroblastomas (HR-NB) are malignant tumors of childhood that are treated with a very aggressive and life-threatening approach; this includes autologous hemopoietic stem cell transplantation (HSCT) and the infusion of a mAb targeting the GD2 tumor-associated antigen. Although the current treatment provided benefits, the 5-year overall survival remains below 50% due to relapses and refractoriness to therapy. Thus, there is an urgent need to ameliorate the standard therapeutic protocol, particularly improving the immune-mediated anti-tumor responses. Our review aims at summarizing and critically discussing novel immunotherapeutic strategies in HR-NB, including NK cell-based therapies and HLA-haploidentical HSCT from patients' family. High-risk neuroblastomas (HR-NB) still have an unacceptable 5-year overall survival despite the aggressive therapy. This includes standardized immunotherapy combining autologous hemopoietic stem cell transplantation (HSCT) and the anti-GD2 mAb. The treatment did not significantly change for more than one decade, apart from the abandonment of IL-2, which demonstrated unacceptable toxicity. Of note, immunotherapy is a promising therapeutic option in cancer and could be optimized by several strategies. These include the HLA-haploidentical αβT/B-depleted HSCT, and the antibody targeting of novel NB-associated antigens such as B7-H3, and PD1. Other approaches could limit the immunoregulatory role of tumor-derived exosomes and potentiate the low antibody-dependent cell cytotoxicity of CD16 dim/neg NK cells, abundant in the early phase post-transplant. The latter effect could be obtained using multi-specific tools engaging activating NK receptors and tumor antigens, and possibly holding immunostimulatory cytokines in their construct. Finally, treatments also consider the infusion of novel engineered cytokines with scarce side effects, and cell effectors engineered with chimeric antigen receptors (CARs). Our review aims to discuss several promising strategies that could be successfully exploited to potentiate the NK-mediated surveillance of neuroblastoma, particularly in the HSCT setting. Many of these approaches are safe, feasible, and effective at pre-clinical and clinical levels. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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- View/download PDF
33. Lysosomal sialidase NEU1, its intracellular properties, deficiency, and use as a therapeutic agent.
- Author
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Itoh K and Tsukimoto J
- Subjects
- Animals, Humans, Mice, Lysosomes metabolism, Mammals metabolism, Neuraminidase chemistry, Mucolipidoses genetics, Mucolipidoses metabolism, Lysosomal Storage Diseases
- Abstract
Neuraminidase 1 (NEU1) is a lysosomal sialidase that cleaves terminal α-linked sialic acid residues from sialylglycans. NEU1 is biosynthesized in the rough endoplasmic reticulum (RER) lumen as an N-glycosylated protein to associate with its protective protein/cathepsin A (CTSA) and then form a lysosomal multienzyme complex (LMC) also containing β-galactosidase 1 (GLB1). Unlike other mammalian sialidases, including NEU2 to NEU4, NEU1 transport to lysosomes requires association of NEU1 with CTSA, binding of the CTSA carrying terminal mannose 6-phosphate (M6P)-type N-glycan with M6P receptor (M6PR), and intralysosomal NEU1 activation at acidic pH. In contrast, overexpression of the single NEU1 gene in mammalian cells causes intracellular NEU1 protein crystallization in the RER due to self-aggregation when intracellular CTSA is reduced to a relatively low level. Sialidosis (SiD) and galactosialidosis (GS) are autosomal recessive lysosomal storage diseases caused by the gene mutations of NEU1 and CTSA, respectively. These incurable diseases associate with the NEU1 deficiency, excessive accumulation of sialylglycans in neurovisceral organs, and systemic manifestations. We established a novel GS model mouse carrying homozygotic Ctsa IVS6 + 1 g/a mutation causing partial exon 6 skipping with simultaneous deficiency of Ctsa and Neu1. Symptoms developed in the GS mice like those in juvenile/adult GS patients, such as myoclonic seizures, suppressed behavior, gargoyle-like face, edema, proctoptosis due to Neu1 deficiency, and sialylglycan accumulation associated with neurovisceral inflammation. We developed a modified NEU1 (modNEU1), which does not form protein crystals but is transported to lysosomes by co-expressed CTSA. In vivo gene therapy for GS and SiD utilizing a single adeno-associated virus (AAV) carrying modNEU1 and CTSA genes under dual promoter control will be created., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2023
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34. A NK Cell Odyssey: From Bench to Therapeutics Against Hematological Malignancies.
- Author
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Ramos-Mejia, Veronica, Arellano-Galindo, Jose, Mejía-Arangure, Juan Manuel, and Cruz-Munoz, Mario Ernesto
- Subjects
KILLER cells ,HEMATOLOGIC malignancies ,CYTOLOGY ,THERAPEUTICS ,IMMUNE response - Abstract
In 1975 two independent groups noticed the presence of immune cells with a unique ability to recognize and eliminate transformed hematopoietic cells without any prior sensitization or expansion of specific clones. Since then, NK cells have been the axis of thousands of studies that have resulted until June 2021, in more than 70 000 publications indexed in PubMed. As result of this work, which include approaches in vitro , in vivo , and in natura , it has been possible to appreciate the role played by the NK cells, not only as effectors against specific pathogens, but also as regulators of the immune response. Recent advances have revealed previous unidentified attributes of NK cells including the ability to adapt to new conditions under the context of chronic infections, or their ability to develop some memory-like characteristics. In this review, we will discuss significant findings that have rule our understanding of the NK cell biology, the developing of these findings into new concepts in immunology, and how these conceptual platforms are being used in the design of strategies for cancer immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
35. Isolation, Maintenance and Expansion of Adult Hematopoietic Stem/Progenitor Cells and Leukemic Stem Cells.
- Author
-
Mayer, Isabella Maria, Hoelbl-Kovacic, Andrea, Sexl, Veronika, and Doma, Eszter
- Subjects
STEM cell transplantation ,LEUKEMIA treatment ,CELL differentiation ,CELL culture ,STEM cells ,HEMATOPOIETIC stem cell transplantation ,HEMATOPOIETIC stem cells - Abstract
Simple Summary: Transplantation of adult hematopoietic stem cells is an important therapeutic tool to help patients suffering from diverse hematological disorders. All types of blood cells can develop from a single hematopoietic stem cell underlining their enormous potential. Intense efforts are ongoing to generate "engraftable" human hematopoietic stem cells to treat hematopoietic diseases and to understand the molecular machinery driving them. Leukemic stem cells represent a low frequency subpopulation of leukemia cells that possess stem cell properties. They can instigate, maintain, and serially propagate leukemia in vivo, while they retain the capacity to differentiate into committed progenitors. Leukemic stem cells are unaffected by many therapeutic strategies and represent the major cause of relapse. We here describe all methods to maintain and expand murine and human hematopoietic cells in culture and describe their specific advantages. These methods are also employed to understand the biology of leukemic stem cells and to identify novel therapeutic strategies. Hematopoietic stem cells (HSCs) are rare, self-renewing cells that perch on top of the hematopoietic tree. The HSCs ensure the constant supply of mature blood cells in a tightly regulated process producing peripheral blood cells. Intense efforts are ongoing to optimize HSC engraftment as therapeutic strategy to treat patients suffering from hematopoietic diseases. Preclinical research paves the way by developing methods to maintain, manipulate and expand HSCs ex vivo to understand their regulation and molecular make-up. The generation of a sufficient number of transplantable HSCs is the Holy Grail for clinical therapy. Leukemia stem cells (LSCs) are characterized by their acquired stem cell characteristics and are responsible for disease initiation, progression, and relapse. We summarize efforts, that have been undertaken to increase the number of long-term (LT)-HSCs and to prevent differentiation towards committed progenitors in ex vivo culture. We provide an overview and compare methods currently available to isolate, maintain and enrich HSC subsets, progenitors and LSCs and discuss their individual advantages and drawbacks. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
36. Cadaveric Stem Cells: Their Research Potential and Limitations.
- Author
-
Cieśla, Julia and Tomsia, Marcin
- Subjects
STEM cell research ,PLURIPOTENT stem cells ,NEURAL stem cells ,HEMATOPOIETIC stem cells ,STEM cells - Abstract
In the era of growing interest in stem cells, the availability of donors for transplantation has become a problem. The isolation of embryonic and fetal cells raises ethical controversies, and the number of adult donors is deficient. Stem cells isolated from deceased donors, known as cadaveric stem cells (CaSCs), may alleviate this problem. So far, it was possible to isolate from deceased donors mesenchymal stem cells (MSCs), adipose delivered stem cells (ADSCs), neural stem cells (NSCs), retinal progenitor cells (RPCs), induced pluripotent stem cells (iPSCs), and hematopoietic stem cells (HSCs). Recent studies have shown that it is possible to collect and use CaSCs from cadavers, even these with an extended postmortem interval (PMI) provided proper storage conditions (like cadaver heparinization or liquid nitrogen storage) are maintained. The presented review summarizes the latest research on CaSCs and their current therapeutic applications. It describes the developments in thanatotranscriptome and scaffolding for cadaver cells, summarizes their potential applications in regenerative medicine, and lists their limitations, such as donor's unknown medical condition in criminal cases, limited differentiation potential, higher risk of carcinogenesis, or changing DNA quality. Finally, the review underlines the need to develop procedures determining the safe CaSCs harvesting and use. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
37. Combining Immunocytokine and Ex Vivo Activated NK Cells as a Platform for Enhancing Graft-Versus-Tumor Effects Against GD2+ Murine Neuroblastoma.
- Author
-
Bates, Paul D., Rakhmilevich, Alexander L., Cho, Monica M., Bouchlaka, Myriam N., Rao, Seema L., Hales, Joanna M., Orentas, Rimas J., Fry, Terry J., Gilles, Stephen D., Sondel, Paul M., and Capitini, Christian M.
- Subjects
KILLER cells ,TUMOR-infiltrating immune cells ,CYTOKINE release syndrome ,STEM cell transplantation ,HEMATOPOIETIC stem cells - Abstract
Management for high-risk neuroblastoma (NBL) has included autologous hematopoietic stem cell transplant (HSCT) and anti-GD2 immunotherapy, but survival remains around 50%. The aim of this study was to determine if allogeneic HSCT could serve as a platform for inducing a graft-versus-tumor (GVT) effect against NBL with combination immunocytokine and NK cells in a murine model. Lethally irradiated C57BL/6 (B6) x A/J recipients were transplanted with B6 bone marrow on Day +0. On day +10, allogeneic HSCT recipients were challenged with NXS2, a GD2
+ NBL. On days +14-16, mice were treated with the anti-GD2 immunocytokine hu14.18-IL2. In select groups, hu14.18-IL2 was combined with infusions of B6 NK cells activated with IL-15/IL-15Rα and CD137L ex vivo. Allogeneic HSCT alone was insufficient to control NXS2 tumor growth, but the addition of hu14.18-IL2 controlled tumor growth and improved survival. Adoptive transfer of ex vivo CD137L/IL-15/IL-15Rα activated NK cells with or without hu14.18-IL2 exacerbated lethality. CD137L/IL-15/IL-15Rα activated NK cells showed enhanced cytotoxicity and produced high levels of TNF-α in vitro , but induced cytokine release syndrome (CRS) in vivo. Infusing Perforin-/- CD137L/IL-15/IL-15Rα activated NK cells had no impact on GVT, whereas TNF-α-/- CD137L/IL-15/IL-15Rα activated NK cells improved GVT by decreasing peripheral effector cell subsets while preserving tumor-infiltrating lymphocytes. Depletion of Ly49H+ NK cells also improved GVT. Using allogeneic HSCT for NBL is a viable platform for immunocytokines and ex vivo activated NK cell infusions, but must be balanced with induction of CRS. Regulation of TNFα or activating NK subsets may be needed to improve GVT effects. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
38. Intermittent hypoxia: Friend or foe on endothelial repair in mouse model.
- Author
-
Song, Tao, Chen, Mo, Wang, Xin, Zhu, Endong, Xue, Yanchao, Wang, Juan, Sun, Bei, and Feng, Jing
- Subjects
VASCULAR endothelial growth factor receptors ,MONONUCLEAR leukocytes ,WESTERN immunoblotting ,HYPOXEMIA ,SLEEP apnea syndromes - Abstract
Aim of the study: Obstructive sleep apnea, which is characterized by intermittent hypoxia (IH), is a common respiratory disease. The aim of the present study was to explore the relationship between hypoxia and endothelial progenitor cell (EPC) function, and explain the role of IH in endothelial repair. Materials and methods: Peripheral blood mononuclear cells (PBMCs) were isolated from a mouse model of IH. The number of CD133
+ kinase insert domain receptor (KDR)+ , CD133+ CD34+ , CD34+ KDR+ and ALDHlow CD34+ KDR+ EPCs was determined by flow cytometry. HIF-1α, stromal-derived factor-1 (SDF-1) α and VEGF were measured by ELISA. The proliferative ability of PBMCs was determined. EPC migration was assessed by Transwell assay and surface proteins by western blot analysis. EPCs were co-cultured with mouse brain endothelial cells and their angiogenic ability was analyzed. Results: The number of CD133+ KDR+ , CD133+ CD34+ and CD34+ KDR+ EPCs increased with IH ingravescence. The number of ALDHlow CD34+ KDR+ EPCs with mild IH stimulation was higher and gradually decreased in the moderate and severe IH groups. The release of HIF-1α, SDF-1α and VEGF in the serum increased with the increase in the degree of IH. In the mild IH treatment, the migration and angiogenesis of EPCs, as well as the expression of vascular endothelial growth factor receptor 2 and cysteine-X-cysteine receptor 4, were higher than those in the control group, but progressively decreased in the groups with moderate and severe IH. Conclusion: Increased levels of IH accelerated the increase in vasoactive factors in peripheral blood, thereby mobilizing a large number of EPCs. Increasing of IH diminished the mobilization, chemotactic and angiogenetic ability of EPCs. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
39. Natural killer cell therapy for hematologic malignancies: successes, challenges, and the future.
- Author
-
Lamb, Margaret G., Rangarajan, Hemalatha G., Tullius, Brian P., and Lee, Dean A.
- Subjects
CELLULAR therapy ,LEUKAPHERESIS ,HEMATOPOIETIC stem cell transplantation ,HEMATOPOIETIC stem cells ,STEM cell treatment - Abstract
The adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. In the last 3 decades, NK cells have been utilized to harness the anti-tumor immune response in a wide range of malignancies, most notably with early evidence of efficacy in hematologic malignancies. NK cells are dysfunctional in patients with hematologic malignancies, and their number and function are further impaired by chemotherapy, radiation, and immunosuppressants used in initial therapy and hematopoietic stem cell transplantation. Restoring this innate immune deficit may lead to improved therapeutic outcomes. NK cell adoptive transfer has proven to be a safe in these settings, even in the setting of HLA mismatch, and a deeper understanding of NK cell biology and optimized expansion techniques have improved scalability and therapeutic efficacy. Here, we review the use of NK cell therapy in hematologic malignancies and discuss strategies to further improve the efficacy of NK cells against these diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
40. Decreased iKIR-HLA C Pair Confers Worse Clinical Outcomes for Patients With Myeloid Disease Receiving Antithymocyte Globulin-Based Haploidentical Hematopoietic Stem Cell Transplantation.
- Author
-
Zhao, Yanmin, Gao, Fei, Wu, Yibo, Shi, Jimin, Luo, Yi, Tan, Yamin, Yu, Jian, Lai, Xiaoyu, Zhang, Mingming, Zhang, Wei, and Huang, He
- Subjects
HEMATOPOIETIC stem cell transplantation ,TREATMENT effectiveness ,BLOOD diseases ,KILLER cells - Abstract
Hematopoietic stem cell transplantation (HSCT) is a curative therapy for patients with malignant hematologic diseases. Killer immunoglobin-like receptor (KIR) expressed by NK cells is closely associated with the transplant outcomes, and it has been widely explored and debated for a few decades. Recently published studies have revealed that inhibitory KIRs (iKIRs) are educated by their cognate human lymphocyte antigen (HLA) ligands, and that decreased iKIR-HLA pairs post-transplantation may indicate a reduced NK cell function and impaired control of the primary disease. However, this theory still needs to be validated by additional clinical studies. Here we conducted a retrospective analysis of 246 patients who received haploidentical (haplo)-HSCT at our treatment center between January 2015 and June 2018. Our data suggests that decreased iKIR-HLA C pair post-HSCT correlated with a significantly higher risk of relapse [hazard risk (HR) = 2.95, p = 0.019] and reduced overall survival (OS) (HR = 3.74, p = 0.001) and disease-free survival (DFS) (HR = 4.05, p = 0.0004) in patients with myeloid disease. In conclusion, decreased iKIR-HLA C pair should be avoided during anti-thymocyte globulin (ATG)-based haplo-HSCT, especially for patients with myeloid disease. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
41. The transformative potential of HSC gene therapy as a genetic medicine.
- Author
-
Sagoo P and Gaspar HB
- Subjects
- Humans, Hematopoietic Stem Cells, Genetic Therapy, Hematopoiesis, Hematopoietic Stem Cell Transplantation, Hematologic Diseases
- Abstract
Hematopoietic stem cells (HSCs) are precursor cells that give rise to blood, immune and tissue-resident progeny in humans. Their position at the starting point of hematopoiesis offers a unique therapeutic opportunity to treat certain hematologic diseases by implementing corrective changes that are subsequently directed through to multiple cell lineages. Attempts to exploit HSCs clinically have evolved over recent decades, from initial approaches that focused on transplantation of healthy donor allogeneic HSCs to treat rare inherited monogenic hematologic disorders, to more contemporary genetic modification of autologous HSCs offering the promise of benefits to a wider range of diseases. We are on the cusp of an exciting new era as the transformative potential of HSC gene therapy to offer durable delivery of gene-corrected cells to a range of tissues and organs, including the central nervous system, is beginning to be realized. This article reviews the rationale for targeting HSCs, the approaches that have been used to date for delivering therapeutic genes to these cells, and the latest technological breakthroughs in manufacturing and vector design. The challenges faced by the biotechnology cell and gene therapy sector in the commercialization of HSC gene therapy are also discussed., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2023
- Full Text
- View/download PDF
42. First-line steroid-free systemic treatment of acute and chronic graft-versus-host disease after novel prophylaxis regimens.
- Author
-
Moiseev I, Barabanshikova M, Dotsenko A, Smirnova A, Vlasova Y, Morozova E, Bondarenko S, and Kulagin A
- Subjects
- Humans, Cyclophosphamide therapeutic use, Bone Marrow Transplantation adverse effects, Calcineurin Inhibitors therapeutic use, Adrenal Cortex Hormones therapeutic use, Acute Disease, Bronchiolitis Obliterans Syndrome, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation methods
- Abstract
In the early randomized trials the efficacy of calcineurin inhibitors (CNI) in the treatment of graft-versus-host disease (GVHD) was comparable to corticosteroids (CS), but these results became obsolete with the introduction of CNIs in prophylaxis. Recently several effective CNI-free GVHD prophylaxis regimens were introduced based on posttransplantation cyclophosphamide (PTCY) and αβ ex vivo T-cell depletion (αβ-TCD). Among patients treated under these protocols 34 patients with grade II-IV acute (aGVHD) and 40 with moderate and severe chronic (cGVHD) disease were treated with CNIs or other CS-free regimens as the first line. Overall response rate (ORR) was significantly higher in cGVHD than in aGVHD: 80% (95% CI 68-92) vs 47% (95% CI 30-64%), p = 0.0031. In aGVHD it was almost completely restricted to isolated stage III skin GVHD. In cGVHD patients with moderate disease ORR was higher than in severe: 96% (95% CI 88-100%) vs 56% (95%CI 32-81%), p = 0.0022. Two-year overall survival was 76% (95% CI 58-87%) in aGVHD and 95% (95% CI 81-99%) in cGVHD. Failure-free survival was 21% (95% CI 9-37%) in aGVHD and 81% (95% CI 64-91%) in cGVHD. Patients responding to steroid-free regimens had lower use of systemic antibiotics (p = 0.0095), antifungals (p = 0.0319) and antivirals (p < 0.0001)., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2023
- Full Text
- View/download PDF
43. How to Combine the Two Landmark Treatment Methods—Allogeneic Hematopoietic Stem Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy Together to Cure High-Risk B Cell Acute Lymphoblastic Leukemia?
- Author
-
Zhang, Mingming and Huang, He
- Subjects
HEMATOPOIETIC stem cell transplantation ,CHIMERIC antigen receptors ,HISTOCOMPATIBILITY antigens ,CELLULAR therapy ,LYMPHOBLASTIC leukemia ,SEVERE combined immunodeficiency - Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has made tremendous progress in the last few decades and is increasingly being used worldwide. The success of haploidentical HSCT has made it possible to have "a donor for everyone". Patients who received transplantation in remission may have a favorable outcome, while those who were transplanted in advanced stages of disease have a poor prognosis. Although chimeric antigen receptor T (CAR-T) cell therapy is currently a milestone in the immunotherapy of relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (B-ALL) and has demonstrated high remission rates in patients previously treated in multiple lines, the relatively high relapse rate remains a barrier to CAR-T cell therapy becoming an excellent cure option. Therefore, combining these two approaches (allo-HSCT and CAR-T cell therapy) is an attractive area of research to further improve the prognosis of R/R B-ALL. In this review, we will discuss the current clinical practices of combining allo-HSCT with CAR-T cell therapy based on available data, including CAR-T cells as a bridge to allo-HSCT for R/R B-ALL and CAR-T cell infusion for post-transplant relapse. We will further explore not only other possible ways to combine the two approaches, including CAR-T cell therapy to clear minimal residual disease peri-transplantation and incorporation of CAR technology to treat graft- versus -host disease, but also the potential of CAR-T cells as a part of allo-HSCT. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
44. Endothelial progenitor cells in the peripheral blood of patients with moyamoya disease labeled with superparamagnetic iron oxide in vitro for MRI detection.
- Author
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Xirui Wang, Wengao Zhang, and Gangfeng Yin
- Published
- 2020
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45. Helper Innate Lymphoid Cells in Allogenic Hematopoietic Stem Cell Transplantation and Graft Versus Host Disease.
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Quatrini, Linda, Tumino, Nicola, Moretta, Francesca, Besi, Francesca, Vacca, Paola, and Moretta, Lorenzo
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HEMATOPOIETIC stem cell transplantation ,INNATE lymphoid cells ,GRAFT versus host disease ,HEMATOPOIETIC stem cells ,MUCOUS membranes ,IMMUNE reconstitution inflammatory syndrome - Abstract
Helper Innate Lymphoid Cells (hILCs), including ILC1s, ILC2s, and ILC3s, are mainly localized at the mucosal barriers where they play an important role in tissue regeneration and homeostasis through the secretion of specific sets of cytokines. The recent identification of a circulating ILC precursor able to generate all ILC mature subsets in physiological conditions, suggests that "ILC-poiesis" may be important in the context of hematopoietic stem cell transplantation (HSCT). Indeed, in HSCT the conditioning regimen (chemotherapy and radiotherapy) and Graft vs Host Disease (GvHD) may cause severe damages to mucosal tissues. Therefore, it is conceivable that rapid reconstitution of the hILC compartment may be beneficial in HSCT, by promoting mucosal tissue repair/regeneration and providing protection from opportunistic infections. In this review, we will summarize the evidence for a role of hILCs in allogenic HSCT for the treatment of hematological malignancies in all its steps, from the preparative regimen to the immune reconstitution in the recipient. The protective properties of hILCs at the mucosal barrier interfaces make them an attractive target to exploit in future cellular therapies aimed at improving allogenic HSCT outcome. [ABSTRACT FROM AUTHOR]
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- 2020
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46. Premobilization of CD133+ progenitors is associated with attenuated inflammation-induced pulmonary dysfunction following extracorporeal circulation in mice.
- Author
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Luo, Dan, Liu, Xinhao, Zhang, Jie, Du, Lei, Bai, Lin, and Luo, Shuhua
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- 2020
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47. Immune Modulation Properties of Zoledronic Acid on TcRγδ T-Lymphocytes After TcRαβ/CD19-Depleted Haploidentical Stem Cell Transplantation: An analysis on 46 Pediatric Patients Affected by Acute Leukemia.
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Merli, Pietro, Algeri, Mattia, Galaverna, Federica, Milano, Giuseppe Maria, Bertaina, Valentina, Biagini, Simone, Girolami, Elia, Palumbo, Giuseppe, Sinibaldi, Matilde, Becilli, Marco, Leone, Giovanna, Boccieri, Emilia, Grapulin, Lavinia, Gaspari, Stefania, Airoldi, Irma, Strocchio, Luisa, Pagliara, Daria, and Locatelli, Franco
- Subjects
ZOLEDRONIC acid ,STEM cell transplantation ,ACUTE leukemia ,CELL analysis ,HEMATOPOIETIC stem cell transplantation ,IMMUNOREGULATION - Abstract
TcRαβ/CD19-cell depleted HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) represents a promising new platform for children affected by acute leukemia in need of an allograft and lacking a matched donor, disease recurrence being the main cause of treatment failure. The use of zoledronic acid to enhance TcRγδ+ lymphocyte function after TcRαβ/CD19-cell depleted haplo-HSCT was tested in an open-label, feasibility, proof-of-principle study. Forty-six children affected by high-risk acute leukemia underwent haplo-HSCT after removal of TcRαβ+ and CD19+ B lymphocytes. No post-transplant pharmacological graft-versus-host disease (GvHD) prophylaxis was given. Zoledronic acid was administered monthly at a dose of 0.05 mg/kg/dose (maximum dose 4 mg), starting from day +20 after transplantation. A total of 139 infusions were administered, with a mean of 3 infusions per patient. No severe adverse event was observed. Common side effects were represented by asymptomatic hypocalcemia and acute phase reactions (including fever, chills, malaise, and/or arthralgia) within 24–48 h from zoledronic acid infusion. The cumulative incidence of acute and chronic GvHD was 17.3% (all grade I-II) and 4.8% (all limited), respectively. Patients given 3 or more infusions of zoledronic acid had a lower incidence of both acute GvHD (8.8 vs. 41.6%, p = 0.015) and chronic GvHD (0 vs. 22.2%, p = 0.006). Transplant-related mortality (TRM) and relapse incidence at 3 years were 4.3 and 30.4%, respectively. Patients receiving repeated infusions of zoledronic acid had a lower TRM as compared to those receiving 1 or 2 administration of the drug (0 vs. 16.7%, p = 0.01). Five-year overall survival (OS) and disease-free survival (DFS) for the whole cohort were 67.2 and 65.2%, respectively, with a trend toward a better OS for patients receiving 3 or more infusions (73.1 vs. 50.0%, p = 0.05). The probability of GvHD/relapse-free survival was significantly worse in patients receiving 1–2 infusions of zoledonic acid than in those given ≥3 infusions (33.3 vs. 70.6%, respectively, p = 0.006). Multivariable analysis showed an independent positive effect on outcome given by repeated infusions of zoledronic acid (HR 0.27, p = 0.03). These data indicate that the use of zoledronic acid after TcRαβ/CD19-cell depleted haploHSCT is safe and may result in a lower incidence of acute GvHD, chronic GvHD, and TRM. [ABSTRACT FROM AUTHOR]
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- 2020
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48. Targeting T cell malignancies using CAR-based immunotherapy: challenges and potential solutions.
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Fleischer, Lauren C., Spencer, H. Trent, and Raikar, Sunil S.
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T cells ,T cell receptors ,CHIMERIC antigen receptors ,IMMUNOTHERAPY ,CELLULAR therapy - Abstract
Chimeric antigen receptor (CAR) T cell therapy has been successful in treating B cell malignancies in clinical trials; however, fewer studies have evaluated CAR T cell therapy for the treatment of T cell malignancies. There are many challenges in translating this therapy for T cell disease, including fratricide, T cell aplasia, and product contamination. To the best of our knowledge, no tumor-specific antigen has been identified with universal expression on cancerous T cells, hindering CAR T cell therapy for these malignancies. Numerous approaches have been assessed to address each of these challenges, such as (i) disrupting target antigen expression on CAR-modified T cells, (ii) targeting antigens with limited expression on T cells, and (iii) using third party donor cells that are either non-alloreactive or have been genome edited at the T cell receptor α constant (TRAC) locus. In this review, we discuss CAR approaches that have been explored both in preclinical and clinical studies targeting T cell antigens, as well as examine other potential strategies that can be used to successfully translate this therapy for T cell disease. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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49. The Evolution of T Cell Depleted Haploidentical Transplantation.
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Aversa, Franco, Pierini, Antonio, Ruggeri, Loredana, Martelli, Massimo Fabrizio, and Velardi, Andrea
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BONE marrow transplantation ,CELLULAR evolution ,T cells ,TRANSPLANTATION of organs, tissues, etc. ,GRAFT rejection - Abstract
Work on bone marrow transplantation from haploidentical donor has been proceeding for over 20 years all over the world and new transplant procedures have been developed. To control both graft rejection and graft vs. host disease, some centers have preferred to enhance the intensity of the conditioning regimens and the post-transplant immune suppression in the absence of graft manipulation; others have concentrated on manipulating the graft in the absence of any additional post-transplant immune suppressive agent. Due to the current high engraftment rates, the low incidence of graft-vs.-host disease and regimen related mortality, transplantation from haploidentical donors have been progressively offered even to elderly patients. Overall, survivals compare favorably with reports on transplants from unrelated donors. Further improvements will come with successful implementation of strategies to enhance post-transplant immune reconstitution and to prevent leukemia relapse. [ABSTRACT FROM AUTHOR]
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- 2019
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50. A Prospective, Open, Non-randomized Phase I/II Study of Therapeutic Angiogenesis in Diabetic Patients With Critic Ischemia of Lower Limbs While Administering Positive CD133 Mobilized With G-CSF
- Author
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PETHEMA Foundation
- Published
- 2014
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