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1.
Wien Klin Wochenschr ; 132(15-16): 415-422, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32533444

ABSTRACT

BACKGROUND: Several clinical trials in chronic phase (CP) chronic myeloid leukemia (CML) showed that early response to tyrosine kinase inhibitor (TKI) treatment results in an improved long-term survival and progression-free survival. This study assessed whether patients achieving early treatment response (ETR; partial cytogenetic response or BCR-ABL1 mRNA ≤10% at 3 months) in daily practice also have a long-term survival benefit. METHODS: The Retrospective Evaluation of Early response in CML for long-term Treatment outcome (R-EFECT), a multicenter, retrospective chart review, documented patients with newly diagnosed CML-CP starting first-line TKI therapy in routine clinical practice. The primary aim was to assess the 5­year overall survival rate. RESULTS: Of the 211 patients from 12 centers across Austria (January 2004-May 2010), 176 (median age, 56 years) were included in the analysis. All patients received first-line therapy with imatinib. Overall, 136 patients (77.3%) achieved ETR (ETR+ group), whereas 40 (22.7%) did not reach ETR (ETR- group). The ETR+ group had higher 5­year overall survival (92.5% vs. 77.5%, P = 0.018) and progression-free survival (95.6% vs. 87.5%, P = 0.06) rates compared with the ETR- group. As expected, more patients in the ETR- group were switched to another TKI. At the last contact, 120 patients were still on imatinib and 44 had switched to another TKI (25 to nilotinib, 15 to dasatinib, and 4 to bosutinib). CONCLUSION: The data are in line with randomized trials demonstrating that ETR is associated with improved survival and thus confirmed these results in patients treated in daily clinical routine.


Subject(s)
Antineoplastic Agents , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Leukemia, Myeloid, Chronic-Phase , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Austria , Dasatinib/therapeutic use , Female , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myeloid, Chronic-Phase/drug therapy , Male , Middle Aged , Retrospective Studies , Treatment Outcome , Young Adult
2.
Proc Natl Acad Sci U S A ; 113(16): E2316-25, 2016 Apr 19.
Article in English | MEDLINE | ID: mdl-27044095

ABSTRACT

To study the development and function of "natural-arising" T regulatory (nTreg) cells, we developed a novel nTreg model on pure nonobese diabetic background using epigenetic reprogramming via somatic cell nuclear transfer. On RAG1-deficient background, we found that monoclonal FoxP3(+)CD4(+)Treg cells developed in the thymus in the absence of other T cells. Adoptive transfer experiments revealed that the thymic niche is not a limiting factor in nTreg development. In addition, we showed that the T-cell receptor (TCR) ß-chain of our nTreg model was not only sufficient to bias T-cell development toward the CD4 lineage, but we also demonstrated that this TCR ß-chain was able to provide stronger TCR signals. This TCR-ß-driven mechanism would thus unify former per se contradicting hypotheses of TCR-dependent and -independent nTreg development. Strikingly, peripheral FoxP3(-)CD4(+)T cells expressing the same TCR as this somatic cell nuclear transfer nTreg model had a reduced capability to differentiate into Th1 cells but were poised to differentiate better into induced nTreg cells, both in vitro and in vivo, representing a novel peripheral precursor subset of nTreg cells to which we refer to as pre-nTreg cells.


Subject(s)
Cell Differentiation/immunology , Models, Immunological , Nuclear Transfer Techniques , Receptors, Antigen, T-Cell, alpha-beta/immunology , T-Lymphocytes, Regulatory/immunology , Adoptive Transfer , Animals , Mice , Mice, Knockout , T-Lymphocytes, Regulatory/cytology
3.
PLoS One ; 8(8): e72749, 2013.
Article in English | MEDLINE | ID: mdl-24023642

ABSTRACT

BACKGROUND: Cellular therapy is a promising therapeutic strategy for malignant diseases. The efficacy of this therapy can be limited by poor infiltration of the tumor by immune effector cells. In particular, NK cell infiltration is often reduced relative to T cells. A novel class of fusion proteins was designed to enhance the recruitment of specific leukocyte subsets based on their expression of a given chemokine receptor. The proteins are composed of an N-terminal chemokine head, the mucin domain taken from the membrane-anchored chemokine CX3CL1, and a C-terminal glycosylphosphatidylinositol (GPI) membrane anchor replacing the normal transmembrane domain allowing integration of the proteins into cell membranes when injected into a solid tumor. The mucin domain in conjunction with the chemokine head acts to specifically recruit leukocytes expressing the corresponding chemokine receptor. METHODOLOGY/PRINCIPAL FINDINGS: A fusion protein comprising a CXCL10 chemokine head (CXCL10-mucin-GPI) was used for proof of concept for this approach and expressed constitutively in Chinese Hamster Ovary cells. FPLC was used to purify proteins. The recombinant proteins efficiently integrated into cell membranes in a process dependent upon the GPI anchor and were able to activate the CXCR3 receptor on lymphocytes. Endothelial cells incubated with CXCL10-mucin-GPI efficiently recruited NK cells in vitro under conditions of physiologic flow, which was shown to be dependent on the presence of the mucin domain. Experiments conducted in vivo using established tumors in mice suggested a positive effect of CXCL10-mucin-GPI on the recruitment of NK cells. CONCLUSIONS: The results suggest enhanced recruitment of NK cells by CXCL10-mucin-GPI. This class of fusion proteins represents a novel adjuvant in cellular immunotherapy. The underlying concept of a chemokine head fused to the mucin domain and a GPI anchor signal sequence may be expanded into a broader family of reagents that will allow targeted recruitment of cells in various settings.


Subject(s)
Adjuvants, Immunologic/therapeutic use , Chemokine CXCL10/therapeutic use , Glycosylphosphatidylinositols/therapeutic use , Immunotherapy , Killer Cells, Natural/immunology , Neoplasms/therapy , Recombinant Fusion Proteins/therapeutic use , Animals , CHO Cells , Cell Adhesion , Cell Line , Cell Membrane/metabolism , Cricetinae , Cricetulus , Endocytosis , Endothelial Cells/cytology , Endothelial Cells/metabolism , Female , Glycosylphosphatidylinositols/isolation & purification , Humans , Mice , Mice, Inbred C57BL , Mucins/metabolism , Neoplasm Transplantation , Neoplasms/immunology , Neoplasms/pathology , Protein Engineering , Recombinant Fusion Proteins/isolation & purification , Rheology
4.
Stem Cells ; 31(9): 1795-805, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23744498

ABSTRACT

The facilitated recruitment of vascular progenitor cells (VPCs) to ischemic areas might be a therapeutic target for neovascularization and repair. However, efficient and directed attraction of VPCs remains a major challenge in clinical application. To enhance VPC homing, we developed a fusion protein (S1FG), based on the biology of stroma-derived factor-1/CXCL12 and the mucin backbone taken from fractalkine/CXCL12. A GPI-anchor was included to link the fusion-protein to the cell surface. HUVECs transfected with S1FG were capable of increasing firm adhesion of CXCR4+-mononuclear cells (THP-1) under shear stress conditions in vitro. In an in vivo rabbit model of chronic hind limb ischemia, local S1FG application enhanced the recruitment of adoptively transferred embryonic EPCs (eEPCs) to the ischemic muscles 2.5-fold. S1FG combined with eEPC(low) (2 × 10(6)) yielded similar capillary growth as eEPC(high) (5 × 10(6)) alone. Compared to controls, collateral formation was increased in the S1FG eEPC(low) group, but not the eEPC(high) group without S1FG, whereas perfusion was found enhanced in both groups. In addition, S1FG also increased collateral formation and flow when combined with AMD3100 treatment, to increase circulating levels of endogenous VPC. These data demonstrate that the fusion protein S1FG is capable of enhancing the recruitment of exogenously applied or endogenously mobilized progenitor cells to sites of injury. Recombinant versions of S1FG applied via catheters in combination with progenitor cell mobilization may be useful in the treatment of chronic ischemic syndromes requiring improved perfusion.


Subject(s)
Chemokine CX3CL1/metabolism , Chemokine CXCL12/metabolism , Glycosylphosphatidylinositols/metabolism , Neovascularization, Physiologic/drug effects , Recombinant Fusion Proteins/pharmacology , Animals , Cell Adhesion/drug effects , Endocytosis/drug effects , Human Umbilical Vein Endothelial Cells/cytology , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Mice , Rabbits , Receptors, CXCR4/metabolism , Stem Cells/cytology , Stem Cells/drug effects , Stem Cells/metabolism
5.
Oncoimmunology ; 2(11): e26619, 2013 Nov 01.
Article in English | MEDLINE | ID: mdl-24427544

ABSTRACT

Adoptive or active cancer immunotherapy can fail owing to the inefficient recruitment of effector leukocytes to malignant lesions. The intratumoral injection of recombinant proteins comprising a chemokine-derived domain linked to the mucin stalk of chemokine (C-X3-C motif) ligand 1 (CX3CL1) and a glycosylphosphatidylinositol anchor can specifically enhance the recruitment of effector cell subsets to solid tumors.

6.
Am J Pathol ; 179(1): 436-51, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21703422

ABSTRACT

Tissue dendritic cells (DCs) may influence the progression of renal cell carcinoma (RCC) by regulating the functional capacity of antitumor effector cells. DCs and their interaction with T cells were analyzed in human RCC and control kidney tissues. The frequency of CD209(+) DCs in RCCs was found to be associated with an unfavorable T(H)1 cell balance in the tissue and advanced tumor stages. The CD209(+) DCs in RCC were unusual because most of them co-expressed macrophage markers (CD14, CD163). The phenotype of these enriched-in-renal-carcinoma DCs (ercDCs) could be reiterated in vitro by carcinoma-secreted factors (CXCL8/IL-8, IL-6, and vascular endothelial growth factor). ErcDCs resembled conventional DCs in costimulatory molecule expression and antigen cross-presentation. They did not suppress cognate cytotoxic T-lymphocyte function and did not cause CD3ζ down-regulation, FOXP3 induction, or T-cell apoptosis in situ or in vitro; thus, they are different from classic myeloid-derived suppressor cells. ErcDCs secreted high levels of metalloproteinase 9 and used T-cell crosstalk to increase tumor-promoting tumor necrosis factor α and reduce chemokines relevant for T(H)1-polarized lymphocyte recruitment. This modulation of the tumor environment exerted by ercDCs suggests an immunologic mechanism by which tumor control can fail without involving cytotoxic T-lymphocyte inhibition. Pharmacologic targeting of the deviated DC differentiation could improve the efficacy of immunotherapy against RCC.


Subject(s)
Carcinoma, Renal Cell/immunology , Dendritic Cells/immunology , Kidney Neoplasms/immunology , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes/immunology , Adult , Aged , Aged, 80 and over , Apoptosis , Blotting, Western , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Case-Control Studies , Cell Differentiation , Cell Movement , Cell Proliferation , Chemokines/metabolism , Cross-Priming , Cytokines/metabolism , Dendritic Cells/metabolism , Dendritic Cells/pathology , Endocytosis , Female , Flow Cytometry , Fluorescent Antibody Technique , Humans , Immunoenzyme Techniques , Interleukin-6/metabolism , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Male , Middle Aged , Phagocytosis , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , T-Lymphocytes/metabolism , T-Lymphocytes/pathology , T-Lymphocytes, Cytotoxic/metabolism , T-Lymphocytes, Cytotoxic/pathology , Th1 Cells/immunology , Th1 Cells/metabolism , Th1 Cells/pathology , Tumor Cells, Cultured
7.
Mol Immunol ; 47(5): 1047-57, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20004976

ABSTRACT

Acute renal allograft damage is caused by early leukocyte infiltration which is mediated in part by chemokines presented by glycosaminoglycan (GAG) structures on endothelial surfaces. CXCL8 can recruit neutrophils and induce the firm arrest of monocytes on activated endothelial cells. A human CXCL8-based antagonist (dnCXCL8) designed to generate a dominant-negative mutant protein with enhanced binding to GAG structures and reduced CXCR1/2 receptor binding ability was tested in models of early allograft injury. The agent displayed enhanced binding to GAG structures in vitro and could antagonize CXCL8-induced firm adhesion of monocytes as well as neutrophils to activated microvascular endothelium in physiologic flow assays. In a rat model of acute renal damage, dnCXCL8 treatment limited proximal tubular damage and reduced granulocyte infiltration. In a Fischer 344 (RT1(lvl)) to Lewis (RT1(l)) rat acute renal allograft model, dnCXCL8 was found to reduce monocyte and CD8+ T-cell infiltration into glomeruli and to limit tubular interstitial inflammation and tubulitis in vivo. Early treatment of allografts with agents like dnCXCL8 may help reduce acute allograft damage and preserve renal morphology and thereby help limit chronic dysfunction.


Subject(s)
Glycosaminoglycans/immunology , Graft Rejection/drug therapy , Interleukin-8/antagonists & inhibitors , Interleukin-8/pharmacology , Kidney Transplantation/immunology , Animals , CD8-Positive T-Lymphocytes/immunology , Disease Models, Animal , Glycosaminoglycans/genetics , Graft Rejection/immunology , Humans , Interleukin-8/genetics , Interleukin-8/immunology , Monocytes/immunology , Neutrophils/immunology , Rats , Rats, Inbred F344 , Rats, Inbred Lew , Receptors, Interleukin-8A/genetics , Receptors, Interleukin-8A/immunology , Receptors, Interleukin-8B/genetics , Receptors, Interleukin-8B/immunology , Transplantation, Homologous
8.
Biol Chem ; 390(9): 893-7, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19558322

ABSTRACT

Exogenous application of recombinant TIMP-1 protein modified by addition of a glycosylphosphatidylinositol (GPI) anchor allows efficient insertion of the fusion protein into cell membranes. This 'cell surface engineering' leads to changes in the proteolytic environment. TIMP-1-GPI shows enhanced as well as novel in vitro biological activities including suppression of proliferation, reduced migration, and inhibition of invasion of the colon carcinoma cell line SW480. Treatment of SW480 tumors implanted in Rag (-/-) common gamma chain (-/-) C57BL/6 mice with peritumorally applied TIMP-1-GPI, control rhTIMP-1 protein, or vehicle shows that TIMP-1-GPI leads to a significant reduction in tumor growth.


Subject(s)
Colonic Neoplasms/drug therapy , DNA-Binding Proteins/physiology , Glycosylphosphatidylinositols/therapeutic use , Tissue Inhibitor of Metalloproteinase-1/therapeutic use , Animals , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , DNA-Binding Proteins/genetics , Glycosylphosphatidylinositols/chemistry , Humans , Matrix Metalloproteinase 7/metabolism , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred C57BL , Tissue Inhibitor of Metalloproteinase-1/chemistry
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