15 results on '"Holladay, M."'
Search Results
2. Effects of activating NK cell receptor expression and NK cell reconstitution on the outcomes of unrelated donor hematopoietic cell transplantation for hematologic malignancies
- Author
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Triplett, B M, Horwitz, E M, Iyengar, R, Turner, V, Holladay, M S, Gan, K, Behm, F G, and Leung, W
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- 2009
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3. 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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4. 7. farmaco-resistenza e sinergia tra farmaci
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Silverman, R., Holladay, M., and DI GIACOMO, Barbara
- Published
- 2015
5. Inhibitory KIR–HLA receptor–ligand mismatch in autologous haematopoietic stem cell transplantation for solid tumour and lymphoma
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Leung, W, primary, Handgretinger, R, additional, Iyengar, R, additional, Turner, V, additional, Holladay, M S, additional, and Hale, G A, additional
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- 2007
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6. Design of Cholecystokinin Analogs with High Affinity and Selectivity for Brain CCK Receptors
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ABBOTT LABS NORTH CHICAGO IL, Nadzan, A. M., Garvey, D. S., Holladay, M. W., Shiosaki, K., Tufano, M. D., ABBOTT LABS NORTH CHICAGO IL, Nadzan, A. M., Garvey, D. S., Holladay, M. W., Shiosaki, K., and Tufano, M. D.
- Abstract
This article is from 'Peptides. Chemistry and Biology: Proceedings of the American Peptide Symposium (12th) Held in Cambridge, Massachusetts on 16-21 June 1991', AD-A256 113, p100-102.
- Published
- 1992
7. Purification of human natural killer cells using a clinical-scale immunomagnetic method.
- Author
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Iyengar, R., Handgretinger, R., Babarin-Dorner, A., Leimig, T., Otto, M., Geiger, T. L., Holladay, M. S., Houston, J., and Wing Leung
- Subjects
TRANSPLANTATION immunology ,KILLER cells ,T cells ,LEUCOCYTES ,GRAFT versus host disease ,DISEASE relapse ,LEUKAPHERESIS ,B cells - Abstract
Background Infection, graft failure, disease relapse, and GvHD are significant adverse events associated with allogeneic BMT. Although donor leukocyte infusion has been used to prevent or to treat infection, graft failure, and relapse, the potential clinical benefits are often outweighed by the risk of T cell-mediated GvHD. Results from animal studies suggest that donor natural killer (NK) cells may be an ideal cell type for prevention or treatment of these adverse events. We have therefore sought to develop an automated, efficient, and clinical-scale human NK cell-purification method. Methods Twelve leukopheresis products were purified for NK cells using a two-step immunomagnetic method. CD3 + cells were first depleted from the apheresis products. CD56 + cells were then enriched from the CD3 + cell-depleted products. Results The median percentage of CD3 - CD56 + NK cells in the final products was 91.0%, and the median recovery was 48.7%. The median depletion for CD3 + CD56 - T cells was 5.3 log. Natural cytotoxicity of the purified cells was approximately five-fold higher than that of unpurified mononuclear cells, and it could be further increased by stimulation of the purified cell with IL2. Discussion We described a large-scale purification method for automated, efficient, and rapid isolation of human NK cells that yielded minimal contamination with T cells or B cells. These purified NK cells may be expedient for preclinical and clinical uses. [ABSTRACT FROM AUTHOR]
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- 2003
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8. TOX2 regulates human natural killer cell development by controlling T-BET expression.
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Vong QP, Leung WH, Houston J, Li Y, Rooney B, Holladay M, Oostendorp RA, and Leung W
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- Animals, Antigens, CD34 metabolism, Cell Differentiation, Fetal Blood cytology, Gene Silencing, HEK293 Cells, Humans, Lentivirus metabolism, Liver embryology, Lymphocytes cytology, Mice, Mice, Inbred NOD, Oligonucleotide Array Sequence Analysis, Protein Binding, Protein Structure, Tertiary, Transcription, Genetic, Gene Expression Regulation, Developmental, HMGB Proteins metabolism, Killer Cells, Natural cytology, T-Box Domain Proteins metabolism
- Abstract
Thymocyte selection-associated high mobility group box protein family member 2 (TOX2) is a transcription factor belonging to the TOX family that shares a highly conserved high mobility group DNA-binding domain with the other TOX members. Although TOX1 has been shown to be an essential regulator of T-cell and natural killer (NK) cell differentiation in mice, little is known about the roles of the other TOX family members in lymphocyte development, particularly in humans. In this study, we found that TOX2 was preferentially expressed in mature human NK cells (mNK) and was upregulated during in vitro differentiation of NK cells from human umbilical cord blood (UCB)-derived CD34(+) cells. Gene silencing of TOX2 intrinsically hindered the transition between early developmental stages of NK cells, whereas overexpression of TOX2 enhanced the development of mNK cells from UCB CD34(+) cells. We subsequently found that TOX2 was independent of ETS-1 but could directly upregulate the transcription of TBX21 (encoding T-BET). Overexpression of T-BET rescued the TOX2 knockdown phenotypes. Given the essential function of T-BET in NK cell differentiation, TOX2 therefore plays a crucial role in controlling normal NK cell development by acting upstream of TBX21 transcriptional regulation., (© 2014 by The American Society of Hematology.)
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- 2014
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9. NK cell genotype and phenotype at diagnosis of acute lymphoblastic leukemia correlate with postinduction residual disease.
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Sullivan EM, Jeha S, Kang G, Cheng C, Rooney B, Holladay M, Bari R, Schell S, Tuggle M, Pui CH, and Leung W
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- Adolescent, Biomarkers, Child, Child, Preschool, Female, Humans, Immunophenotyping, Infant, Male, Neoplasm, Residual immunology, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, RNA, Messenger genetics, RNA, Messenger metabolism, ROC Curve, Receptors, KIR genetics, Receptors, KIR metabolism, Receptors, Natural Killer Cell genetics, Receptors, Natural Killer Cell metabolism, Remission Induction, Treatment Outcome, Genotype, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Neoplasm, Residual genetics, Phenotype, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma immunology
- Abstract
Purpose: Not all natural killer (NK) cells are equally cytotoxic against leukemia because of differences in receptor gene content and surface expression. We correlated NK cell genotype and phenotype at diagnosis of childhood acute lymphoblastic leukemia (ALL) with minimal residual disease (MRD) after induction chemotherapy., Experimental Design: The NK cells and leukemia blasts of 244 patients were analyzed at diagnosis by killer-cell immunoglobulin-like receptor (KIR) typing and immunophenotyping. The results were correlated statistically with postinduction MRD status., Results: The odds of being MRD positive in patients with KIR telomeric (Tel)-A/B genotype were 2.85 times the odds in those with Tel-A/A genotype (P = 0.035). MRD-positive patients were more likely to have KIR2DL5A (P = 0.006) and expressed less activating receptor NKp46 and FASL on their NK cells (P = 0.0074 and P = 0.029, respectively). The odds of being MRD positive increased by 2.01-fold for every percentage increase in NK cells expressing KIR2DL1 in the presence of HLA-C2 ligand (P = 0.034). The quantity of granzyme B inhibitor PI-9 in the leukemia blasts was greater in patients who were MRD positive (P = 0.038). Collectively, five NK cell-related factors (Tel-B-associated KIR2DL5A, NKp46, FASL, granzyme B, and PI-9) are strongly associated with MRD positivity at the end of induction with 100% sensitivity and 80% specificity., Conclusions: Our data support the hypothesis that NK cells with a strong effector phenotype in the setting of decreased leukemia resistance are associated with better leukemia control., (©2014 American Association for Cancer Research.)
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- 2014
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10. Ex vivo activation of CD56(+) immune cells that eradicate neuroblastoma.
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Rujkijyanont P, Chan WK, Eldridge PW, Lockey T, Holladay M, Rooney B, Davidoff AM, Leung W, and Vong Q
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- Animals, Antigens, Differentiation, T-Lymphocyte immunology, Antigens, Differentiation, T-Lymphocyte metabolism, Cell Culture Techniques standards, Cell Degranulation immunology, Cell Line, Tumor, Coculture Techniques, Cytotoxicity, Immunologic, Disease Models, Animal, Graft vs Host Reaction immunology, Humans, Killer Cells, Natural cytology, Leukocytes, Mononuclear cytology, Leukocytes, Mononuclear immunology, Leukocytes, Mononuclear metabolism, Mice, Natural Killer T-Cells cytology, Natural Killer T-Cells immunology, Natural Killer T-Cells metabolism, Neuroblastoma therapy, Receptors, Natural Killer Cell immunology, Receptors, Natural Killer Cell metabolism, CD56 Antigen metabolism, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Lymphocyte Activation immunology, Neuroblastoma immunology, Neuroblastoma metabolism
- Abstract
Despite the use of intensive contemporary multimodal therapy, the overall survival of patients with high-risk neuroblastoma is still less than 50%. Therefore, immunotherapy without cross-resistance and overlapping toxicity has been proposed. In this study, we report the development of a novel strategy to specifically activate and expand human CD56(+) (NCAM1) natural killer (NK) immune cells from normal donors and patients with neuroblastoma. Enriched CD56(+) cells from peripheral blood were mixed with CD56(-) fraction at 1:1 ratio and cultured in the presence of OKT3, interleukin (IL)-2, and -15 for five days and then without OKT3 for 16 more days. The final products contained more than 90% CD56(+) cells and could kill neuroblastoma cells effectively that were originally highly resistant to nonprocessed NK cells. Mechanistically, cytolysis of neuroblastoma was mediated through natural cytotoxicity receptor (NCR), DNAX accessory molecule-1 (DNAM-1; CD226), perforin, and granzyme B. Successful clinical scale-up in a good manufacturing practices (GMP)-compliant bioreactor yielded effector cells that in a neuroblastoma xenograft model slowed tumor growth and extended survival without GVHD. Investigation of CD56(+) cells from patients with neuroblastoma revealed a similar postactivation phenotype and lytic activity. Our findings establish a novel and clinically expedient strategy to generate allogeneic or autologous CD56(+) cells that are highly cytotoxic against neuroblastoma with minimal risk of GVHD., (©2013 AACR.)
- Published
- 2013
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11. Blood dendritic cells suppress NK cell function and increase the risk of leukemia relapse after hematopoietic cell transplantation.
- Author
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Perez-Martinez A, Iyengar R, Gan K, Chotsampancharoen T, Rooney B, Holladay M, Ramírez M, and Leung W
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- Animals, Antigens, CD1, Antigens, Surface analysis, Antineoplastic Agents administration & dosage, Biomarkers analysis, Cell Culture Techniques, Coculture Techniques, Dendritic Cells immunology, Glycoproteins, Hematopoietic Stem Cell Transplantation, Humans, K562 Cells, Killer Cells, Natural immunology, Leukemia mortality, Leukemia pathology, Leukemia therapy, Lymphocyte Activation, Mice, Neoplasm Transplantation, Neuroblastoma immunology, Neuroblastoma pathology, Recurrence, Survival Analysis, T-Lymphocytes immunology, Transplantation, Homologous, Whole-Body Irradiation, Cell Communication immunology, Dendritic Cells metabolism, Interleukin-10 biosynthesis, Interleukin-6 biosynthesis, Killer Cells, Natural metabolism, Leukemia immunology, Signal Transduction immunology
- Abstract
NK cells play an important role in hematopoietic stem cell transplantation (HCT) and in cross talk with dendritic cells (DCs) to induce primary T cell response against infection. Therefore, we hypothesized that blood DCs should augment NK cell function and reduce the risk of leukemia relapse after HCT. To test this hypothesis, we conducted laboratory and clinical studies in parallel. We found that although, phenotypically, NK cells could induce DC maturation and DCs could in turn increase activating marker expression on NK cells, paradoxically, both BDCA1(+) myeloid DCs and BDCA4(+) plasmacytoid DCs suppressed the function of NK cells. Patients who received an HLA-haploidentical graft containing a larger number of BDCA1(+) DCs or BDCA4(+) DCs had a higher risk of leukemia relapse and poorer survival. Further experiments indicated that the potent inhibition on NK cell cytokine production and cytotoxicity was mediated in part through the secretion of IL-10 by BDCA1(+) DCs and IL-6 by BDCA4(+) DCs. These results have significant implications for future HCT strategies., (Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
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12. Significant functional heterogeneity among KIR2DL1 alleles and a pivotal role of arginine 245.
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Bari R, Bell T, Leung WH, Vong QP, Chan WK, Das Gupta N, Holladay M, Rooney B, and Leung W
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- Arginine metabolism, Arginine physiology, Arrestins genetics, Arrestins metabolism, Cell Line, Tumor, Cytotoxicity Tests, Immunologic, Cytotoxicity, Immunologic immunology, Flow Cytometry, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, HLA-C Antigens genetics, HLA-C Antigens metabolism, Humans, Interferon-gamma metabolism, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Lysosomal-Associated Membrane Protein 1 metabolism, Microscopy, Fluorescence, Mutation, Polymorphism, Genetic, Receptors, KIR2DL1 metabolism, Receptors, KIR2DL1 physiology, Signal Transduction immunology, Transfection, beta-Arrestin 2, beta-Arrestins, Alleles, Arginine genetics, Receptors, KIR2DL1 genetics
- Abstract
Killer immunoglobulin-like receptors (KIRs) play an essential role in the regulation of natural killer cell functions. KIR genes are highly polymorphic in nature, showing both haplotypic and allelic variations among people. We demonstrated in both in vitro and in vivo models a significant heterogeneity in function among different KIR2DL1 alleles, including their ability to inhibit YT-Indy cells from degranulation, interferon gamma production, and cytotoxicity against target cells expressing the HLA-Cw6 ligand. Subsequent experiments showed that the molecular determinant was an arginine residue at position 245 (R245) in its transmembrane domain that mechanistically affects both the efficiency of inhibitory signaling and durability of surface expression. Specifically, in comparison with R245-negative alleles, KIR2DL1 that included R245 recruited more Src-homology-2 domain-containing protein tyrosine phosphatase 2 and beta-arrestin 2, showed higher inhibition of lipid raft polarization at immune synapse, and had less down-regulation of cell-surface expression upon interaction with its ligand. Thus, our findings provide novel insights into the molecular determinant of KIR2DL1 and conceivably a fundamental understanding of KIR2DL1 allelic polymorphism in human disease susceptibility, transplant outcome, and donor selection.
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- 2009
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13. Selection of stem cells by using antibodies that target different CD34 epitopes yields different patterns of T-cell differentiation.
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Otto M, Chen X, Martin WJ, Leung W, Knowles J, Holladay M, Houston J, Handgretinger R, and Barfield RC
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- Animals, Bone Marrow, Child, Child, Preschool, Flow Cytometry, Hematopoietic Stem Cell Transplantation, Humans, Infant, Leukocyte Common Antigens immunology, Mice, Mice, SCID, Receptors, Antigen, T-Cell biosynthesis, T-Lymphocytes immunology, Thymus Gland cytology, Antibodies immunology, Antigens, CD34 immunology, Cell Differentiation, Epitopes immunology, Stem Cells cytology, Stem Cells immunology, T-Lymphocytes cytology
- Abstract
The objective of this study was to compare the patterns of T-cell differentiation from CD34(+) human stem cells selected with different classes of antibody targeting the CD34 molecule. We compared signal-joint T-cell receptor excision circle (sjTREC) production in thymocytes selected with different classes of anti-CD34 antibody. Based on these results, we studied immune reconstitution in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice using human stem cells selected with the same antibodies that yielded variation in the thymocytes. Human CD34(+) stem cells were immunomagnetically selected using the class II QBEnd antibody (prevalent in clinical graft engineering) and the class III 8G12 antibody (common in diagnostic tests). Engraftment and T-cell reconstitution were examined after transplantation. Thymocytes selected with the 8G12 class III antibody have a higher TREC production than those selected with the QBEnd class II antibody. Of mice transplanted with cells selected using the 8G12 antibody, 50% had sjTREC production, compared with 14% of mice transplanted with cells selected using the clinically common antibody QBEnd. 8G12 thymic progenitors are characterized by higher quality in thymic distribution and higher activity in T-cell differentiation. Using class III antibody targeting the CD34 molecule resulted in increased T-cell reconstitution in the NOD/SCID mouse. Use of a single antibody epitope targeting the CD34 molecule may lead to loss of cells that might provide richer T-cell reconstitution. Use of different or multiple epitopes, targeting of alternate stem cell markers, or use of cell-depletion strategies might prevent this loss.
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- 2007
- Full Text
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14. CD40 ligand induces an antileukemia immune response in vivo.
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Dilloo D, Brown M, Roskrow M, Zhong W, Holladay M, Holden W, and Brenner M
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- Animals, Antigens, Differentiation, T-Lymphocyte genetics, Antigens, Differentiation, T-Lymphocyte immunology, CD40 Ligand, Cytotoxicity, Immunologic immunology, Female, Gene Transfer Techniques, Leukemia, Experimental genetics, Mice, Mice, Inbred BALB C, CD8-Positive T-Lymphocytes immunology, Cytotoxicity, Immunologic genetics, Leukemia, Experimental immunology, Membrane Glycoproteins genetics
- Abstract
Leukemia cells may express tumor specific antigens in association with Class I and II major histocompatability complex (MHC) molecules. However, lack of expression of conventional costimulator molecules means that these cells tend to induce specific T-cell anergy rather than activation. CD40 ligand (CD40L) is a costimulator molecule that directly activates T cells and may promote antigen presentation by CD40-expressing cells, which include professional antigen presenting cells and B-acute lymphoblastic leukemia (ALL) cells from many patients. We determined whether transgenic expression of CD40L could enhance an antileukemia immune response using a CD40+ murine lymphoblastic (A20) leukemia and a CD40- myeloblastic (WEHI-3) leukemia in a tumor treatment model. Injection of otherwise nonimmunogenic A20 cells in the presence of CD40L induced an immune response active against preexisting A20 tumor at a distant site. Moreover, concomitant local secretion of transgenic interleukin-2 (IL-2) further amplified the antileukemic response induced and increased protection against preexisting tumor. In ex vivo studies, CD40 activation of A20 cells enhances the antigen presenting potential of A20 cells by upregulating expression of B7.1 (CD80), Class I and II MHC molecules, and increases expression of fas antigens. The importance of CD40 activation to the resulting antitumor response is further emphasized by the failure of transgenic CD40L to protect against the CD40- WEHI myeloblastic leukemia. Depletion studies showed the protective effects against A20 cells to be mediated by a combination of CD4+ and CD8+ T lymphocytes and by natural killer (NK) cells. These results suggest a means by which CD40+ leukemia cells may be rendered immunogenic in vivo.
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- 1997
15. A novel herpes vector for the high-efficiency transduction of normal and malignant human hematopoietic cells.
- Author
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Dilloo D, Rill D, Entwistle C, Boursnell M, Zhong W, Holden W, Holladay M, Inglis S, and Brenner M
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- Animals, Antigens, CD34 analysis, Female, Gene Expression, Granulocyte-Macrophage Colony-Stimulating Factor physiology, Humans, Leukemia, Experimental pathology, Mice, Mice, Inbred BALB C, Recombinant Fusion Proteins metabolism, Transfection, Tumor Cells, Cultured, Genetic Vectors genetics, Granulocyte-Macrophage Colony-Stimulating Factor genetics, Hematopoietic Stem Cells metabolism, Neoplastic Stem Cells metabolism, Simplexvirus genetics
- Abstract
Herpes simplex viruses (HSVs) would offer numerous advantages as vectors for gene transfer, but as yet they have not proved capable of transducing hematopoietic cells. Using a genetically inactivated form of HSV that is restricted to a single cycle of replication (disabled single-cycle virus, [DISC-HSV]), we have transduced normal human hematopoietic progenitor cells and primary leukemia blasts with efficiencies ranging from 80% to 100%, in the absence of growth factors or stromal support. Toxicity was low, with 70% to 100% of cells surviving the transduction process. Peak expression of transferred genes occurred at 24 to 48 hours after transduction with the DISC-HSV vector, declining to near background levels by 14 days. Despite this limitation, sufficient protein is produced by the inserted gene to permit consideration of the vector for applications in which transient expression is adequate. One example is the transfer of immunostimulatory genes, to generate leukemia immunogens. Thus, murine A20 leukemia cells transduced with a DISC-HSV vector encoding granulocyte-macrophage colony-stimulating factor were able to stimulate a potent antitumor response in mice, even against pre-existing leukemia. The exceptional transducing ability of the DISC-HSV vector should therefore facilitate genetic manipulation of normal and malignant human hematopoietic cells for biological and clinical investigation.
- Published
- 1997
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