UMLS:C0023473 - FACTA Search

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Query: UMLS:C0023473 (chronic myeloid leukemia)
18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously showed (E. Clave et al., J. Immunother., 22: 1-6, 1999; J. Molldrem et al., Blood, 88: 2450-2457, 1996) that PR1, a human-lymphocyte-antigen (HLA)-A2.1-restricted peptide from proteinase 3, could be used to elicit CTLs from normal individuals. These CTLs showed HLA-restricted cytotoxicity and colony inhibition of myeloid leukemia cells that overexpress proteinase 3. In this study, we constructed a phycoerythrin-labeled PR1-HLA-A2 tetramer to identify PR1-specific CTLs by flow cytometry. No peripheral blood lymphocytes from three HLA-2.1+ donors stained with the tetramer, but, after 20 days in culture with weekly PR1 stimulation, 2-8% became tetramer+. Tetramer staining identified up to 40-fold more PR1-specific CTLs than were identified by limiting dilution analysis and correlated better with lysis of PR1-coated T2 cells (R2 = 0.95 versus R2 = 0.76). Tetramer+ CTLs were memory phenotype (91% CD45RO+), and most (58% CD95+) were activated. Tetramer-sorted allogeneic CTLs produced 83% lysis of HLA-A2.1+ chronic myelogenous leukemia (CML) blasts at an E:T ratio of 2.5:1, compared with 23% lysis by nonsorted CTLs, with no background lysis of HLA-A2.1+ normal cells. Cytoplasmic proteinase-3 expression was one log greater in CML blasts than in normal granulocytes. These results show that a PR1-HLA-A2 tetramer can be used to identify and select CTLs from normal donors that preferentially lyse CML cells, which could be used for leukemia-specific adoptive immunotherapy.
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PMID:A PR1-human leukocyte antigen-A2 tetramer can be used to isolate low-frequency cytotoxic T lymphocytes from healthy donors that selectively lyse chronic myelogenous leukemia. 1036 91

The product of the Wilms' tumor gene WT1 is a transcription factor overexpressed not only in leukemic blast cells of almost all patients with acute myeloid leukemia, acute lymphoid leukemia, and chronic myeloid leukemia, but also in various types of solid tumor cells. Thus, it is suggested that the WT1 gene plays an important role in both leukemogenesis and tumorigenesis. Here we tested the potential of WT1 to serve as a target for immunotherapy against leukemia and solid tumors. Four 9-mer WT1 peptides that contain HLA-A2.1-binding anchor motifs were synthesized. Two of them, Db126 and WH187, were determined to bind to HLA-A2.1 molecules in a binding assay using transporter associated with antigen processing-deficient T2 cells. Peripheral blood mononuclear cells from an HLA-A2.1-positive healthy donor were repeatedly sensitized in vitro with T2 cells pulsed with each of these two WT1 peptides, and CD8(+) cytotoxic T lymphocytes (CTLs) that specifically lyse WT1 peptide-pulsed T2 cells in an HLA-A2.1-restricted fashion were induced. The CTLs also exerted specific lysis against WT1-expressing, HLA-A2.1-positive leukemia cells, but not against WT1-expressing, HLA-A2.1-negative leukemia cells, or WT1-nonexpressing, HLA-A2. 1-positive B-lymphoblastoid cells. These data provide the first evidence of human CTL responses specific for the WT1 peptides, and provide a rationale for developing WT1 peptide-based adoptive T-cell therapy and vaccination against leukemia and solid tumors.
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PMID:Human cytotoxic T-lymphocyte responses specific for peptides of the wild-type Wilms' tumor gene (WT1 ) product. 1066 72

CML is characterized by the chromosomal translocation t(9;22) (q34;q11) resulting in the chimeric bcr-abl oncogene that encodes P210 fusion proteins with novel amino acid sequences in the breakpoint region. If these peptides derived from P210 are presented by HLA molecules on the cell membrane of leukemic cells an immunological response may occur. Recent studies using synthetic peptides identical to the bcr-abl fusion region revealed that some peptides are capable of binding to the class I molecules HLA-A2,-A3,-A11 and -B8 and the class II molecules HLA-DR1, -DR2, -DR3, -DR4 and -DR11. Moreover T cell responses have been induced against bcr-abl-derived synthetic peptides bound to some of these HLA molecules. For HLA class I, we have previously shown that individuals expressing HLA-A3 and -B8 have a diminished risk of development of CML. To assess a similar protective effect of class II molecules we performed a large multi-center study. This study compared the frequencies of HLA-DR1, -DR2, -DR3, -DR4 and -DR11 of patients with CML from the database of the EBMT (n = 1462) with unaffected individuals from the registry of Bone Marrow Donors Worldwide (n = 500 596). Patients and controls were matched per country. This analysis yielded significantly lower odds ratios (ORs) of 0.86 (95% CI 0.75-0.98) for HLA-DR3 and of 0.80 (95% CI 0.71-0.89) for HLA-DR4. The OR was 0.91 (95% CI 0.80-1.04) for HLA-DR1, 1.05 (95% CI 0.94-1.18) for HLA-DR2 and 0.87 (95% CI 0.74-1.01) for HLA-DR11. To assess a possible effect of the linkage disequilibrium between HLA-B8 and HLA-DR3 we found that coexpression of HLA-B8 and HLA-DR3 gave an OR of 0.84 (95% CI 0.72-0.98), whereas HLA-DR3 positive/HLA-B8 negative individuals showed an OR of 1.02 (95% CI 0.84-1.24). This means that the protective effect of HLA-DR3 of the development of CML was probably caused by its linkage disequilibrium with HLA-B8. In contrast, as there is no linkage disequilibrium of HLA-DR4 with HLA-A3 or HLA-B8, the results indicate that HLA-DR4 expression itself is associated with a diminished incidence of CML possibly by the presentation of bcr-abl breakpoint peptides in these HLA molecules on the membrane of the leukemic cells.
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PMID:HLA-DR4 is associated with a diminished risk of the development of chronic myeloid leukemia (CML). Chronic Leukemia Working Party of the European Blood and Marrow Transplant Registry. 1124 94

The objective of this study was to analyse human leukocyte antigen (HLA) and disease association in common blood diseases [chronic myelogenous leukemia (CML), acute nonlymphocytic leukemia (ANLL), thalassemia and severe aplastic anemia] in Thais. The subjects were patients from the Hematological Clinic, Departments of Medicine and Pediatrics, Ramathibodi Hospital who were referred for HLA typing for bone marrow transplantation (BMT) at the Histocompatibility Laboratory from March 1988 to September 1997. A total of 129 patients had complete HLA-ABC typing. The patients included 45 CML, 40 ANLL, 26 thalassemia (Thal) and 18 severe aplastic anemia (SAA). Of these, 88 patients were typed for HLA class II. The HLA class I (ABC) and II (DR, DQ) typings were performed by microlymphocytotoxicity test. It was found that HLA class I was associated with CML, ANLL and Thal, whereas, HLA class II was associated with SAA. HLA-B8 and HLA-B18 were increased in CML with R.R. values of 12.2 and 3.9, respectively, whereas, HLA-B18 was increased in ANLL with R.R. value of 4.5. In addition, HLA-DR2 and DR3 were increased in SAA with R.R. values of 3.8 and 4.8, respectively. For Thal, HLA-A2 and B46 were increased in Thal in Central Thais with R.R. values of 3.3 and 6.1, respectively, whereas, HLA-B13 was increased in Thal in Northern Thais with R.R. value of 8.5. On the other hand, HLA-B7 was absent in CML. HLA-Cw7 was decreased in CML and SAA, whereas, HLA-DR6 was decreased in ANLL and SAA. Furthermore, HLA-Cw6 was also decreased in CML, whereas, HLA-A33 and Bw4 were decreased in SAA. Although the sample size of each disease was small, the increase of HLA-DR2 was observed in SAA in Thais which was similar to other studies in different ethnic groups. These preliminary data may be useful for further study in HLA and blood disease association.
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PMID:Preliminary study of HLA-ABCDR antigens in CML, ANLL, thalassemia and severe aplastic anemia in Thais. 1086 19

The Wilms' tumor (WT1) gene encodes a zinc finger transcription factor, which is preferentially expressed in acute leukemia cells and chronic myelogenous leukemia cells in blast crisis, but not in most normal cells. These findings strongly suggest that WT1 is a potential target of immunotherapy for human leukemia. We have established a CD8+ cytotoxic T lymphocyte (CTL) clone, designated TAK-1, which is specific for a WT1-derived 9-mer peptide consisting of HLA-A24-binding anchor motifs. TAK-1 lysed both HLA-A24-positive allogeneic cells and autologous cells that were loaded with a WT1-derived peptide. TAK-1 was cytotoxic to HLA-A24-positive leukemia cells, but not to HLA-A24-positive lymphoma cells that did not express WT1, to HLA-A24-negative leukemia cells, or to HLA-A24-positive normal cells. Treating leukemia cells with an antisense oligonucleotide complementary to WT1 reduced TAK-1-mediated cytotoxicity. TAK-1 did not inhibit colony formation of HLA-A24-positive normal bone marrow cells. Recently, other groups have also reported the establishment of HLA-A2-restricted anti-leukemic CTLs specific for WT1-derived peptide. In addition, a murine model of immunotherapy against WT1-expressing tumors has been reported. Recent studies have demonstrated that WT1 is also aberrantly expressed in various kinds of cancer cells. Taken together, these results suggest that immunotherapy targeting WT1 should be effective against both solid tumors and leukemia.
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PMID:Immunotherapy for leukemia targeting the Wilms' tumor gene. 1169 91

Wild-type Wilms' tumor gene WT1 is expressed at high levels not only in most of acute myelocytic, acute lymphocytic, and chronic myelocytic leukemia, but also in various types of solid tumors including lung cancer. We tested the ability of the gene product (WT1) to serve as a target antigen for tumor specific immunotherapy both in human in vitro system and mouse in vivo system. In the latter, we can evaluate the efficacy and the side effects of WT1 vaccination in vivo. In the human in vitro system, two WT1 peptides that contain HLA-A2.1 binding anchor motifs were determined to bind to HLA-A2.1 molecules. Peripheral blood mononuclear cells (PBMC) from an HLA-A2.1-psitive donor were repeatedly stimulated in vitro with TAP-deficient T2 cells pulsed with each of these two peptides, and CD8-positive cytotoxic T lymphocytes (CTLs) that specifically lyse WT1-expressing, HLA-A2.1-positive tumor cells were induced. Other groups also have succeeded in generating CTLs which specifically lyse WT1-expressing leukemia cells, and which do not inhibit colony-formation of normal hematopoietic cells that express WT1 at physiological levels. In the mouse in vivo system, immunization of C57BL/6 mice with one WT1 peptide with relatively high binding affinity for H-2D(b) molecules, which contain H-2D(b) binding anchor motifs, induced CTLs, which specifically lysed WT1-expressing tumor cells in an H-2D(b)-restricted manner. Furthermore, mice immunized with the WT1 peptide (peptide vaccination) or WT1 cDNA (DNA vaccination) rejected challenges by WT1-expressing tumor cells and survived with no signs of auto-aggression to WT1-expressing normal organs by the induced CTLs. The WT1 protein has been identified as a novel tumor antigen and recent investigations provide a rationale for developing WT1-based adoptive T cell therapy and vaccination against various kinds of malignant neoplasms.
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PMID:WT1 as a novel target antigen for cancer immunotherapy. 1218 20

Recent advances have made haploidentical transplantation for leukemia feasible, but the rigorous T-cell depletion used contributes to the high relapse rates observed. We have attempted to improve the graft-versus-leukemia (GVL) effect by generating allorestricted cytotoxic T lymphocytes (CTLs) directed against human CD45. Such CTLs should recognize patient hematopoietic cells including leukemia, enhancing donor cell engraftment and improving the GVL effect, but they should not recognize host nonhematopoietic tissues or donor cells from the graft. Using the T2 binding assay, 4 CD45-derived peptides were found to bind HLA-A2 molecules. These peptides were used to generate cytotoxic T-cell lines from HLA-A2(-) donors by sequential stimulation with peptide-pulsed HLA-A2(+) stimulators, and the lines obtained were screened for peptide-specific cytotoxicity. Using one of these peptides (P1218), it was possible to generate peptide-specific, allorestricted CTLs in 3 of 7 responders. P1218-specific CTL lines show potent cytotoxicity against hematopoietic cell lines coexpressing HLA-A2 and CD45 but not CD45 loss variants. Studies with stable transfectants of 293 cells demonstrated recognition by P1218-specific CTLs of endogenously expressed CD45. Likewise P1218-specific CTLs recognized peripheral blood mononuclear cells (PBMCs) from HLA-A2(+) patients with chronic myeloid leukemia (CML) and leukemic blasts in HLA-A2(+) patients with acute myeloid leukemia (AML), but they were unable to lyse HLA-A2(+) fibroblasts or HLA-A2(-) normal PBMCs. Coculture of CD34(+) PBMCs and bone marrow mononuclear cells (BMMCs) with P1218-specific CTL significantly inhibited colony-forming unit-granulocyte macrophage (CFU-GM) formation in HLA-A2(+) healthy controls and CML patients but resulted in no significant inhibition in HLA-A2(-) healthy controls. These studies demonstrate that P1218-specific cytotoxic T lymphocytes (CTLs) have potent activity against leukemic progenitors and suggest that adoptive immunotherapy with allorestricted CTLs directed against CD45 epitopes may be useful in restoring the GVL effect after HLA-A2-mismatched haploidentical transplantation. Further, because P1218-specific CTLs also recognize healthy HLA-A2(+) progenitors, such CTLs could also contribute to host myeloablation and enhance donor cell engraftment.
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PMID:Allorestricted cytotoxic T cells specific for human CD45 show potent antileukemic activity. 1239 6

Chronic myeloid leukemia (CML) appears an ideal and exciting immunological target. Novel and rational immunotherapy may therefore play an important adjuvant role in the treatment of CML patients. Peptides derived from the BCR-ABL fusion region have been shown to be immunogenic and are able to stimulate the production of BCR-ABL-specific T cell lines and clones. In this study, A 280 bp multiple epitope region of BCR-ABL fusion antigen was designed and synthesized. This region contains three BCR-ABL antigen epitopes which can bind to HLA-A2, HLA-A3 and HLA-DR11 molecules, respectively, and epitopes of cholera toxin B (CTB) and tetanus toxoid (TT) which are able to elicit vigorous T cell responses. The fusion antigen gene has highly been expressed in E. coli and the purified fusion protein reserved satisfied activity and antigenicity. The results of this investigation provided a basis for further research on the developing specific T cell immunotherapy of CML.
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PMID:[Synthesis, Cloning and Expression of a Multiple Epitope Antigen of BCR-ABL Fusion Gene] 1257 95

Chronic myelogenous leukemia (CML) is characterized by a reciprocal translocation leading to the Philadelphia chromosome. Two fusion genes are created by this translocation: bcr/abl and abl/bcr. The fusion regions of both translocation products are unique and strictly limited to leukemia cells, giving rise to potential tumor-specific antigens. Although several studies on the immunogenicity of peptides spanning the bcr/abl fusion region have been reported, little is known about the corresponding reciprocal translocation product abl/bcr. Here we report that synthetic peptides representing the fusion region of the abl/bcr forms a1bb3 and a1bb4 can be specifically recognized by HLA-A2-restricted cytotoxic T lymphocytes from healthy donors. Furthermore, HLA-matched a1bb3-expressing CML cells can be recognized by a1bb3-specific HLA-A2-restricted T cells, indicating natural processing and presentation of abl/bcr protein by leukemia cells. Moreover, a 19-mer peptide encompassing this class I-binding sequence also elicited a1bb3-specific class II-restricted T-cell responses. Thus, both class I- and class II-restricted T-cell responses can be stimulated in healthy donors by abl/bcr peptides in vitro. Because abl/bcr is expressed in the majority of CML patients, it may represent a highly leukemia-specific antigen with potential use in immunotherapy.
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PMID:The abl/bcr gene product as a novel leukemia-specific antigen: peptides spanning the fusion region of abl/bcr can be recognized by both CD4+ and CD8+ T lymphocytes. 1259 72

We have shown that cytotoxic T lymphocytes specific for PR1, an HLA-A2-restricted nonopeptide derived from proteinase 3, kill leukemia cells and may contribute to the elimination of chronic myelogenous leukemia (CML) after treatment with IFN or allogeneic bone marrow transplant. Some patients with persistent disease also have circulating PR1-specific T cells, however, suggesting the likelihood of immune tolerance. Here we show that both high- and low-avidity PR1-specific T cells from the peripheral blood of healthy donors can be identified and selectively expanded in vitro. Although high-avidity PR1-specific T cells killed CML more effectively than low-avidity T cells, only high-avidity T cells underwent apoptosis when stimulated with high PR1 peptide concentration or when exposed to leukemia that overexpressed proteinase 3. No high-avidity PR1-specific T cells could be identified or expanded from newly diagnosed leukemia patients, whereas low-avidity T cells were readily expanded. Circulating high-avidity PR1-specific T cells were identified in IFN-sensitive patients in cytogenetic remission, however. These results provide evidence that CML shapes the host immune response and that leukemia outgrowth may result in part from leukemia-induced selective deletion of high-avidity PR1-specific T cells.
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PMID:Chronic myelogenous leukemia shapes host immunity by selective deletion of high-avidity leukemia-specific T cells. 1261 11

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