Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adoptive transfer of antigen-specific T lymphocytes is an attractive form of immunotherapy for haematological malignancies and cancer. The difficulty of isolating antigen-specific T lymphocytes for individual patients limits the more widespread use of adoptive T cell therapy. The demonstration that cloned T cell receptor (TCR) genes can be used to produce T lymphocyte populations of desired specificity offers new opportunities for antigen-specific T cell therapy. The first trial in humans demonstrated that TCR gene-modified T cells persisted for an extended time period and reduced tumor burden in some patients. The WT1 protein is an attractive target for immunotherapy of leukemia and solid cancer since elevated expression has been demonstrated in AML, CML, MDS and in breast, colon and ovarian cancer. In the past, we have isolated high avidity CTL specific for a WT1-derived peptide presented by HLA-A2 and cloned the TCR alpha and beta genes of a WT1-specific CTL line. The genes were inserted into retroviral vectors for transduction of human peripheral blood T lymphocytes of leukemia patients and normal donors. The treatment of leukemia-bearing NOD/SCID mice with T cells transduced with the WT1-specific TCR eliminated leukemia cells in the bone marrow of most mice, while treatment with T cells transduced with a TCR of irrelevant specificity did not diminish the leukemia burden. In order to improve the safety and efficacy of TCR gene therapy, we have developed lentiviral TCR gene transfer. In addition, we employed strategies to enhance TCR expression while avoiding TCR mis-pairing. It may be possible to generate dominant TCR constructs that can suppress the expression of the endogenous TCR on the surface of transduced T cells. The development of new TCR gene constructs holds great promise for the safe and effective delivery of TCR gene therapy for the treatment of malignancies.
 ...
PMID:WT1-specific T cell receptor gene therapy: improving TCR function in transduced T cells. 1785 29

The paediatric population of 19 eastern European countries amounts to approximately 80 million children. Between 1985 and 2004, the number of centres performing haematopoietic stem cell transplantation (HSCT) in children increased from 1 in 1985 to 24 in 2004 and the yearly number of paediatric HSCTs rose from 1 in 1985 to 291 in 2004. Altogether, 2342 transplants were reported to the EBMT Registry during this time (Poland 953, Czech Republic 501, Hungary 269, Russia 217, Croatia 129, Slovakia 71, Bulgaria 45, Serbia and Montenegro 36, Slovenia 35, Belarus 33, Estonia 26, Lithuania 19 and Romania 8). Out of the 2342 transplants, 1487 (63.5%) transplants were performed in paediatric centres, 453 (19.3%) in centres for adults and 402 (17.2%) in combined centres. The number of children who underwent autologous HSCT (auto-HSCT) was 1053 (45%), whereas 1289 (55%) underwent allogeneic HSCT (allo-HSCT). Peripheral blood (PB) was the source of HSC in 751 (71.3%) out of 1053 auto-transplants, BM in 246 (23.4%) and PB+BM in 52 (4.9%) (missing data in 4, that is, 0.4%). Among the 1289 allo-transplants, BM was the source of HSC in 827 (64.3%), PB in 416 (32.3%), CB in 23 (1.8%) and BM+PB in 14 (1.1%) (missing data in 9, that is, 0.7%). Among them, 728 (57.4%) obtained HSC from MSD, 322 (25.4%) from UD, 195 (15.4%) from MMFD, 14 (1.1%) from CB family donor and 9 (0.7%) from CB unrelated donor (missing data in 21, that is, 1.6%). The number of children who underwent allo-HSCT for malignant diseases was 945 (73.4%), including ALL 376 (29.2%), AML 234 (18.2%), CML 177 (13.8%), MDS 97 (7.5%), NHL 35 (2.7%) and other malignancy 31 (2.4%), while 339 (26.9%) for non-malignant disorders, including SAA 202 (15.7%), immunodeficiencies 61 (4.7%), inborn errors of metabolism 40 (3.1%), Fanconi anaemia 19 (1.5%) and others 17 (1.3%). Out of 1053 recipients of auto-HSCT, 168 (16%) were transplanted for neuroblastoma, 129 (12.2%) for NHL, 124 (11.7%) for AML, 114 (10.8%) for ALL, 109 (10.4%) for Hodgkin's disease, 62 (5.9%) for Ewing's sarcoma, 16 (1.5%) for CNS tumour, 15 (1.4%) for Wilms tumour and 316 (30%) for other tumours. In 2001, the EBMT in collaboration with the European School of Haematology (ESH) developed the Outreach Programme, that is a programme supporting emerging HSCT projects and transplant centres in countries with limited resources and/or experience.
 ...
PMID:Haematopoietic stem cell transplantation in children in eastern European countries 1985-2004: development, recent activity and role of the EBMT/ESH Outreach Programme. 1854 32

The cure of chronic myeloid leukemia (CML) patients following allogeneic stem cell transplantation (SCT) is attributed to graft-versus-leukemia (GVL) effects targeting alloantigens and/or leukemia-associated antigens (LAA) on leukemia cells. To assess the potential of LAA-peptide vaccines in eliminating leukemia in CML patients, we measured WT1, PR3, ELA2 and PRAME expression in CD34+ progenitor subpopulations in CML patients and compared them with minor histocompatibility antigens (mHAgs) HA1 and SMCY. All CD34+ subpopulations expressed similar levels of mHAgs irrespective of disease phase, suggesting that in the SCT setting, mHAgs are the best target for GVL. Furthermore, WT1 was consistently overexpressed in advanced phase (AdP) CML in all CD34+ subpopulations, and mature progenitors of chronic phase (CP) CML compared to healthy individuals. PRAME overexpression was limited to more mature AdP-CML progenitors only. Conversely, only CP-CML progenitors had PR3 overexpression, suggesting that PR1-peptide vaccines are only appropriate in CP-CML. Surface expression of WT1 protein in the most primitive hematopoietic stem cells in AdP-CML suggest that they could be targets for WT1 peptide-based vaccines, which in combination with PRAME, could additionally improve targeting differentiated progeny, and benefit patients responding suboptimally to tyrosine kinase inhibitors, or enhance GVL effects in SCT patients.
 ...
PMID:Hematopoietic stem cells and progenitors of chronic myeloid leukemia express leukemia-associated antigens: implications for the graft-versus-leukemia effect and peptide vaccine-based immunotherapy. 1854 92

From March 1991 through 31st December 2007, 2042 patients underwent stem cell transplantation at the Hematology-Oncology and Stem Cell Transplantation Research Center, affiliated to Tehran University of Medical Sciences. These transplantations included 1405 allogeneic stem cell transplantation, 624 autologous stem cell transplantation, and 13 syngeneic stem cell transplantation. Stem cell transplantation was performed for various diseases including acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic lymphoblastic leukemia, thalassemia major, sickle cell thalassemia, sickle cell disease, multiple myeloma, myelodysplasia, mucopolysaccharidosis, paroxysmal nocturnal hemoglobinuria, non-Hodgkin's lymphoma, Hodgkin's disease, severe aplastic anemia, plasma cell leukemia, Niemann-Pick disease, Fanconi anemia, severe combine immunodeficiency, congenital neutropenia, leukocyte adhesion deficiencies, Chediak-Higashi syndrome, osteopetrosis, histiocytosis X, Hurler syndrome, amyloidosis, systemic sclerosis, breast cancer, Ewing's sarcoma, testicular cancer, germ cell tumors, neuroblastoma, medulloblastoma, renal cell carcinoma, nasopharyngeal carcinoma, ovarian cancer, Wilms' tumor, rhabdomyosarcoma, pancreatoblastoma, and multiple sclerosis. We had 105 cellular therapies for postmyocardial infarction, multiple sclerosis, cirrhosis, head of femur necrosis, and renal cell carcinoma. About 30 patients were retransplanted in this center. About 74.9% of the patients (1530 of 2042) remained alive between one to 168 months after stem cell transplantation. Nearly 25.1% (512 of 2042) of our patients died after stem cell transplantation. The causes of deaths were relapse, infections, hemorrhagic cystitis, graft versus host disease, and others.
 ...
PMID:Stem cell transplantation; Iranian experience. 1911 Oct 33

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder, characterized by the presence of BCR/ABL fusion gene. It is unclear which cellular events drive BCR/ABL gene translocation or initiate leukemogenesis in CML. Bcl-2 promotes survival of hematopoietic stem cells. Accordingly, apoptosis-related pathway may involve in the leukemogenesis of CML. In the current study, we evaluated 80 single nucleotide polymorphism (SNP) markers involved in the pathways of apoptosis (n = 30), angiogenesis (n = 7), myeloid cell growth (n = 14), xenobiotic metabolism (n = 13), WT1 signaling (n = 7), interferon signaling (n = 4), and others (n = 5) in 170 CML patients and 182 healthy controls. In a single-marker analysis, the following SNPs were identified including VEGFA, BCL2, CASP7, JAK3, CSF3, and HOCT1. In the multivariate logistic model with these SNPs and covariates, only BCL2 (rs1801018) was significantly associated with the susceptibility to CML (P = .05; odds ratio [OR] 2.16 [1.00-4.68]). In haplotype analyses, haplotype block of BCL2 consistently showed significant association with the susceptibility to CML. Risk allele analysis showed that a greater number of risk alleles from BCL2 SNP correlated to increasing risk of CML (overall P = .1, OR 1.84 [1.06-3.22] for 3-4 risk alleles vs 0-1 risk alleles). The current study indicated that BCL2 SNP seemed to be associated with increasing susceptibility to CML.
 ...
PMID:Genetic variants in the candidate genes of the apoptosis pathway and susceptibility to chronic myeloid leukemia. 1914 60

In haematological cancers, malignant cells circulate in the blood and lymphatic system. This may make leukaemic cells easier to target by immunotherapy than in other types of cancer. Various immunotherapy strategies have been trialled in several leukaemias including chronic myeloid leukaemia (CML) and in general, these have been aimed at targeting tumour-associated antigens (TAA). There are numerous TAA expressed by CML patients including WT1, proteinase 3, BCR-ABL and HAGE amongst others. The immunogenicity of the CML-specific tumour antigen, BCR-ABL, has been the subject of much debate and its role in the development of the disease and its unique sequence spanning the breakpoint region make it an ideal target for immunotherapy. However, there are a limited number of immunogenic epitopes across the junctional region, which are restricted to only a few HLA types, namely A2, A3 and B7 (Clark et al. in Blood 98:2887-2893, 2001). The second CML-associated antigen is the helicase antigen HAGE, a cancer-testis antigen found to be over-expressed in more than 50% of myeloid leukaemias (Adams et al. in Leukaemia 16:2238-2242, 2002). Very little is known about the function of this antigen and its significance to CML. However, its membership of the DEAD-box family of ATP-dependent RNA helicases and the involvement of other members of this family in tumour cell proliferation (Eberle et al. in Br J Cancer 86:1957-1962, 2002; Yang et al. in Cell Signal 17:1495-504, 2005) suggest a crucial role in the RNA metabolism of tumour cells. For these reasons, HAGE also seems to be a good target for immunotherapy as it would be applicable for the majority of patients with CML. This review aims to discuss the potential of immunotherapy for the treatment of leukaemia, in particular CML, and the prospect of targeting three CML associated antigens: BCR, ABL and HAGE. During his career, Prof. Tony Dodi made a significant contribution in this area of leukaemia research, confirming the identity of immunogenic HLA-A3 and B7-restricted peptides as targets for CTL. Published, as a highlighted paper in Clark et al. (Blood 98:2887-2893, 2001), this study demonstrated the expression of MHC-peptide complexes on the surface of CML cells and the presence of tetramer-positive CTL activity in CML patients positive for these two HLA alleles. His drive and dedication for research excellence will be remembered by all who knew and worked with him.
 ...
PMID:Tumour antigen-targeted immunotherapy for chronic myeloid leukaemia: is it still viable? 1925 70

The determination of patient's resistance to a particular drug contributes to more efficient therapeutical approach. The aim of this study was to evaluate if the responsiveness of Chronic Myeloid Leukemia (CML) patients to Imatinib therapy was predictable from WT1 gene expression in peripheral blood leukocytes. To examine the resistance we implemented an in vitro cultivation of the primary cells of 48 CML patients with Imatinib. The effect of Imatinib was characterized not only by the expression of WT1 but also by BCR-ABL, and proliferative factor Ki-67. <br />Our results showed that leukocytes of CML patients, clinically responsive to Imatinib treatment, significantly decreased WT1 expression after in vitro incubation with Imatinib. It was accompanied by an inhibition of expression of Ki-67 but not BCR-ABL. In leukocytes of CML patients clinically resistant to Imatinib, the expression of WT1, Ki-67, and BCR-ABL remained unaffected. The presented results showed that in vitro testing using peripheral blood cells enabled clinicians to predict responsiveness of CML patients to Imatinib.
 ...
PMID:WT1 expression in peripheral leukocytes of patients with chronic myeloid leukemia serves for the prediction of Imatinib resistance. 1958 Mar 40

A retrospective comparison of WT1 and BCR-ABL1 expression was performed in 40 imatinib-treated chronic myeloid leukaemia patients. The overall correlation of WT1 and BCR-ABL1 was low. In two patients WT1 expression was increasing despite very low BCR-ABL1 levels. As both revealed Ph-negative aberrant clones, a second independent cohort of 20 cases, all with Ph-negative clonal evolution, was analysed. High WT1 expression (5.0-177.0%) was detected in a case with +11 and in four of eight cases with +8, but not in cases with del(20q) or -Y. Thus, increasing WT1 levels in molecular responders may indicate Ph-negative clonal cytogenetic evolution during imatinib treatment.
 ...
PMID:RQ-PCR based WT1 expression in comparison to BCR-ABL quantification can predict Philadelphia negative clonal evolution in patients with imatinib-treated chronic myeloid leukaemia. 1962 38

Although antigen-specific immune responses including cytotoxic T cells (CTLs) against antigen peptide could be enhanced after tumor antigen peptide vaccinations, the immune responses do not necessarily result in a decrease or eradication of tumor cells in the vaccination trials. We focused on whether antigen-specific CTLs could be damaged by the repeated stimulation of antigenic peptide and whether regulatory T (Treg) cells would be increased by the administration of WT1 peptide. We administered WT1 peptide 22 times over 18 months in a CML patient who was being treated with imatinib. Although WT1 peptide administration every 2 weeks did not show any beneficial effects on the minimal residual disease (copies of bcr-abl transcripts), the transcripts remarkably decreased to the level of major molecular response after changing the administration interval of WT1 peptide from 2 to 4 weeks. An ex vivo study demonstrated that re-stimulation with WT1 peptide made WT1-specific T cells less reactive to WT1 tetramers and the impaired reactivity of CTLs lasted at least for 1 week. In addition, the cytotoxicity of the T cells was hampered by re-stimulation. Treg cells increased up to more than fivefold at the end of the WT1 administration period. The present findings suggested that the administration of the peptide every 4 weeks is superior to every 2 weeks. In addition, the findings that Treg cells increased gradually in accordance with the duration of WT1 peptide administration revealed the significance of manipulating Treg cells for establishing an efficient tumor antigen peptide vaccination.
 ...
PMID:WT1 peptide vaccination in a CML patient: induction of effective cytotoxic T lymphocytes and significance of peptide administration interval. 2010 36

Clinical studies have shown that NST has better therapeutic results with chronic myelogenous leukemia (CML) than acute leukemia (AL), but whether the generation of graft-versus-leukemia (GVL) effects is different between AL and CML patients early after NST has not yet been studied, so we used a pentamer-staining technique in combination with ICCS to detect WT1(+)CD8(+)CTL/WT1(+)Tc1 and WT1(+)Th1 cells in these two groups of patients. Results showed that the emergence time of WT1(+)CD(8) (+)CTL/WT1(+)Tc1 cells after NST in AL patients was similar to that in CML patients (P = 0.58), while the emergence time of WT1(+)Th1 cells after NST in AL patients was shorter than in CML patients (P = 0.047). Furthermore, the peak proportions of WT1(+)CD(8) (+)CTL/WT1(+)Tc1 (P > 0.05) and WT1(+)Th1 (P > 0.05) cells were similar between AL and CML patients, and the increased rates (P > 0.05) and elevated levels (P > 0.05) of WT1-specific T cells were not statistically different between the groups after G-CSF mobilized donor mononuclear cell infusion. In addition, the reconstruction of lymphocyte subsets (P > 0.05) and CD4/8 ratios (P > 0.05) in AL patients were not statistically different from those in CML patients within 180 days after NST. These results suggested that WT1 maybe induces similar GVL effects in both AL and CML patients early after NST.
 ...
PMID:Comparison of Wilms' tumor antigen 1-specific T lymphocyte generation soon after nonmyeloablative allergenic stem-cell transplantation in acute and chronic leukemia patients. 2037 82


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>