Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Natural killer (NK) cells are implicated in the surveillance of hematological malignancies. They participate in the immune response against residual acute myeloid leukemia (AML) after hematopoietic stem cell transplantation with partial HLA class I disparity. However, the role of NK cells in autologous leukemia-specific immunity remains poorly understood. We studied the function of NK cells in AML patients at diagnosis. Following isolation, CD56+CD3- cells exhibited a high proliferative potential in vitro in response to interleukin (IL)-2. The polyclonal population of activated AML-NK cells expressed normal levels of the activating receptor NKG2D and the major natural cytotoxicity receptor NKp46. AML-NK cells were highly effective with respect to interferon-gamma production, cytotoxicity against HLA class I-deficient K562 erythroleukemia cells in vitro and retardation of tumor growth in vivo in K562-bearing NOD/SCID mice. Importantly, when AML blasts were injected into NOD/SCID mice, a single dose of adoptively transferred autologous AML-NK cells significantly reduced the AML load by 8-77%. Recognition of AML blasts may be related to the observed upregulation of ligands for NKG2D and natural cytotoxicity receptors in vivo. We conclude that AML patient-derived NK cells are fully functional, in support of exploring the benefit of AML immunotherapy with IL-2-stimulated autologous NK cells.
Leukemia 2005 Dec
PMID:Activated natural killer cells from patients with acute myeloid leukemia are cytotoxic against autologous leukemic blasts in NOD/SCID mice. 1622 86

Flt3 internal tandem duplications (Flt3-ITD) can be detected in 25 - 30% of acute myeloid leukaemia (AML) and differ in length and sequence. We sequenced patient specific Flt3-ITD mutations in 2 Flt3-ITD positive AML cell lines and 13 Flt3-ITD harbouring AML patients. We addressed the question whether Flt3-ITD mutations can harbour HLA class I specific neoepitopes potentially able to induce a leukaemia and Flt3-ITD specific immune response. Here, we demonstrate that all but 1 Flt3-ITD mutations were unique. Interestingly, the peptide sequence of several Flt3-ITD fusion regions harbour 9 mer neoepitopes that potentially bind to HLA class I molecules in a HLA restricted manner (e.g. A1, A2, B27). The specific binding of Flt3-ITD derived neoepitopes to HLA-A2 is demonstrated. Peptide affinity of HLA-A2-restricted putative neoepitopes can be significantly improved by construction of mimotope candidates. We suggest that Flt3-ITD mutations can form new immunogenic and HLA class I-restricted peptide epitopes.
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PMID:Flt3-ITD mutations can generate leukaemia specific neoepitopes: potential role for immunotherapeutic approaches. 1632 62

Minor histocompatibility antigens (mHags) HA-1 and HA-2 are encoded by biallelic loci, with immunogenic variants, HA-1H and HA-2V, which induce strong HLA-A2-restricted alloreactive T-cell responses, and nonimmunogenic counterparts, HA-1R and HA-2M, which represent functional null alleles that are poorly presented by HLA class I molecules. HA-1 and HA-2 are potential targets of selective graft-versus-leukemia and graft-versus-tumor reactivity after allogeneic hematopoietic stem cell transplantation (HSCT); however, these applications are restricted to a limited number of patients. Here, we show that a far more frequent application of HA-1 and HA-2 disparity relies on their use as markers for the state of host chimerism after allogeneic HSCT. We have determined allelic frequencies of 29.3% and 70.7% for HA-1H and HA-1R, respectively, and of 83.7% and 16.3% for HA-2V and HA-2M, respectively, in >200 healthy individuals from northern Italy. Similar frequencies were observed in nearly 100 patients affected by hematologic malignancies or solid tumors, thus showing that HA-1 and HA-2 variability are not associated with the presence of cancer. On the basis of these data, we predict that HA-1 and HA-2 can be used in 32.8% and 23.5% of Italian transplant patients, respectively, as markers for the state of host chimerism, whereas exploitation of disparity for these mHags for targeted immunotherapy will be possible in 10.7% and 1.1% of Italian patients, respectively. Retrospective HA-2 typing of bone marrow aspirates obtained from a patient during complete remission or recurrence of acute myeloid leukemia after haploidentical HSCT showed the feasibility of using HA-2 as a surrogate marker for disease monitoring. Because of an apparent north-south gradient for HA-1 allelic frequencies, with higher frequencies for the HA-1H variant reported in white populations from Southern Europe as compared with Northern Europe and North America, the diagnostic applicability of HA-1 disparity will be slightly more frequent in transplant patients from the north. Taken together, our data show that determination of HA-1 and HA-2 variability can be an important parameter for the selection of allogeneic stem cell donors, in particular for patients affected by hematologic malignancies without a tumor-specific molecular marker.
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PMID:Therapeutic and diagnostic applications of minor histocompatibility antigen HA-1 and HA-2 disparities in allogeneic hematopoietic stem cell transplantation: a survey of different populations. 1639 73

Although donor lymphocyte infusion (DLI) induces complete remissions in 70% of patients with relapsed chronic myeloid leukemia (CML) after allogeneic stem-cell transplantation (SCT), some patients are refractory to DLI by showing disease persistence. In a patient who received DLI for relapsed CML, we observed persisting molecular disease despite a hematological and cytogenetic remission in the absence of graft-versus-host disease (GVHD). To determine the nature of this immune response, we isolated leukemia-reactive donor T-cell clones from the bone marrow (BM) of the patient at the time of clinical response. Four different types of CD8+ HLA class I restricted T-cell clones were obtained that were cytotoxic against Ebstein-Barr virus-transformed B-cell lines (EBV-LCL) of the patient, but not the donor, indicating recognition of minor histocompatibility antigens (mHags). By using survival studies with CFSE labelled BM cells populations, a hematopoietic progenitor cell inhibition assay and direct morphological examination we showed that the T-cell clones recognized mature monocytic and myeloid cells, whereas immature BM progenitor cells were insufficiently lysed. This patient's refractoriness for DLI appears to be caused by inadequate lysis of progenitor cells by these cytotoxic T cells. These findings support the hypothesis that for eradication of CML a cytotoxic T-cell response against leukemic progenitor cells is essential.
Leukemia 2006 Jun
PMID:Molecular persistence of chronic myeloid leukemia caused by donor T cells specific for lineage-restricted maturation antigens not recognizing immature progenitor-cells. 1652 95

Matching for HLA class I alleles, including HLA-C, is an important criterion for outcome of unrelated donor transplantation. However, haplotype-mismatched transplantations for myeloid malignancies, mismatched for killer immunoglobulin-like receptor (KIR) ligands in the graft-versus-host (GVH) direction, is associated with lower rates of graft-versus-host disease (GVHD), relapse, and mortality. This study investigated the effect of KIR ligand mismatching on the outcome of unrelated donor transplantation. The outcomes after 1571 unrelated donor transplantations for myeloid malignancies where donor-recipient pairs were HLA-A, -B, -C, and -DRB1 matched (n = 1004), GVH KIR ligand-mismatched (n = 137), host-versus-graft (HVG) KIR ligand-mismatched (n = 170), and HLA-B and/or -C-mismatched but KIR ligand-matched (n = 260) were compared using Cox regression models. Treatment-related mortality (TRM), treatment failure, and overall mortality were lowest after matched transplantations. Patients who received grafts from donors mismatched at the KIR ligand in the GVH or HVG direction and mismatched at HLA-B and/or C but matched at the KIR ligand had similar rates of TRM, treatment failure, and overall mortality. There were no differences in leukemia recurrence between the 4 groups. These results do not support the choice of an unrelated donor on the basis of KIR ligand mismatch determined from HLA typing.
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PMID:The effect of KIR ligand incompatibility on the outcome of unrelated donor transplantation: a report from the center for international blood and marrow transplant research, the European blood and marrow transplant registry, and the Dutch registry. 1686 58

Human NK cell function is regulated by clonally distributed inhibitory receptors termed "Killer cell Immunoglobulin-like Receptors" (KIRs) that recognize epitopes ("KIR ligands") shared by HLA-C and HLA-B class I allele groups and every functional NK cell in the repertoire expresses at least one receptor for self HLA-class I molecules. Consequently, when NK cells are confronted with allogeneic targets which do not express the inhibiting class I ligand(s) NK cell alloreactions may occur. Donor versus recipient NK alloreactions occur in full HLA haplotype-mismatched ("haploidentical") hematopoietic transplants that are KIR ligand mismatched in the Graft-versus-Host (GvH) direction. Variable frequencies of functional NK cells in the donor repertoire expressing a KIR for the HLA class I group which is absent in the recipient as their sole inhibitory receptor for self, sense the missing expression of the self class I ligand on allogeneic targets and mediate alloreactions ("missing self" recognition). In clinical trials, donor versus recipient NK alloreactions are highly beneficial as they reduce the risk of leukemia relapse, do not cause GvHD and markedly improve event-free survival.
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PMID:Natural killer cell recognition of missing self and haploidentical hematopoietic transplantation. 1691 11

Wild-type Wilms' tumor gene WT1 is highly expressed not only in hematopoietic malignancies, including leukemia and myelodysplastic syndromes (MDS), but also in various kinds of solid tumors. Human cytotoxic T lymphocytes (CTLs) which could specifically lyse WT1-expressing tumor cells with HLA class I restriction were generated in vitro. We have also demonstrated that mice immunized with the WT1 peptide or WT1 cDNA rejected challenges by WT1-expressing tumor cells and survived with no signs of auto-aggression to normal organs which physiologically expressed WT1 in prophylactic and therapeutic models. Furthermore, we and others detected IgM and IgG WT1 antibodies in the patients with hematopoietic malignancies, indicating that WT1 protein was highly immunogenic, and that immunoglobulin class-switch-inducing WT1-specific cellular immune responses were elicited in the patients. CD8+ WT1-specific CTLs were also detected in peripheral blood or tumor-draining lymph nodes of cancer patients. These results provided us with the rationale for elicitation of CTL responses targeting the WT1 product for cancer immunotherapy. On the basis of the findings mentioned above, we performed a phase I clinical trial of WT1 peptide cancer vaccine for the patients with malignant neoplasms. These results strongly suggested that WT1 peptide cancer vaccine had efficacy in the clinical setting, because clinical responses, including reduction of leukemic blast cells or regression of tumor masses, were observed after the WT1 vaccination in patients with hematopoietic malignancies or solid cancers. The power of TAA-derived cancer vaccine may be enhanced by combination with stronger adjuvants, helper peptide, or conventional treatments such as molecular-target-based drugs.
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PMID:Development of WT1 peptide cancer vaccine against hematopoietic malignancies and solid cancers. 1691 59

For immunotherapy of residual disease in patients with Philadelphia-positive leukemias, the BCR-ABL fusion regions are attractive disease-specific T-cell targets. We analyzed these regions for the prevalence of cytotoxic T lymphocyte (CTL) epitopes by an advanced reverse immunology procedure. Seventeen novel BCR-ABL fusion peptides were identified to bind efficiently to the human lymphocyte antigen (HLA)-A68, HLA-B51, HLA-B61 or HLA-Cw4 HLA class I molecules. Comprehensive enzymatic digestion analysis showed that 10 out of the 28 HLA class I binding fusion peptides were efficiently excised after their C-terminus by the proteasome, which is an essential requirement for efficient cell surface expression. Therefore, these peptides are prime vaccine candidates. The other peptides either completely lacked C-terminal liberation or were only inefficiently excised by the proteasome, rendering them inappropriate or less suitable for inclusion in a vaccine. CTL raised against the properly processed HLA-B61 epitope AEALQRPVA from the BCR-ABL e1a2 fusion region, expressed in acute lymphoblastic leukemia (ALL), specifically recognized ALL tumor cells, proving cell surface presentation of this epitope, its applicability for immunotherapy and underlining the accuracy of our epitope identification strategy. Our study provides a reliable basis for the selection of optimal peptides to be included in immunotherapeutic BCR-ABL vaccines against leukemia.
Leukemia 2006 Oct
PMID:BCR-ABL fusion regions as a source of multiple leukemia-specific CD8+ T-cell epitopes. 1693 47

Target cell resistance against natural killer (NK) cell-mediated cytotoxicity obstructs NK cell-based immunotherapy of leukaemia. Several mechanisms of resistance have been described. Because of lack of simple assays for analysing these mechanisms, their relative impact on a given effector-target pair is mostly unknown. We here analysed the combination of the Granzyme B (GrB) enzyme-linked immunospot assay (ELISPOT) for the assessment of NK cell reactivity and cytotoxicity assays to estimate target cell escape mechanisms. Target cell recognition failure leads to negative GrB ELISPOT results, whereas target cell resistance shows positive GrB ELISPOT results in the absence of cytotoxicity. We confronted NK cells with the sensitive target cell line K562, and with the resistant cell lines ML2, SupB15 and Raji. ML2 cells sufficiently activated GrB-release whilst being resistant against cytotoxic granules of NK cells. Partial resistance of Raji results from the interaction of HLA class I with inhibitory killer immunglobulin-like receptors (KIR) on the NK cells. Failure of target recognition by HLA class I-KIR interaction, lacking ligands to stimulatory NK cell receptors and partial resistance to cytotoxic granules all contributed to resistance of SupB15. In conclusion, revealing the mechanisms of resistance against NK cell-mediated cytotoxicity may allow improving the results of NK-based immunotherapy.
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PMID:Resistance against natural killer cell cytotoxicity: analysis of mechanisms. 1697 Jun 88

Adoptive immunotherapy using natural killer (NK) cells is currently under investigation, especially in situations where anti-neoplastic effect is needed but infusion of T cells is considered hazardous, such as in recipients of haematopoietic stem-cell transplantation (HSCT) from haploidentical donors. NK-cell therapy is mainly but not exclusively investigated in the setting of allogeneic stem-cell transplantation. NK cells may induce potent anti-leukaemic and possibly anti-rejection activity, and may even mitigate graft-versus-host disease (GvHD). It remains to be determined whether such effects are clinically important and whether or not they are mediated mainly or exclusively by KIR-HLA class I interactions. Recent advances in graft engineering has provided methods for isolating large numbers of purified NK cells. Several groups have shown that clinical-grade NK cells at doses up to 10(7)/kg may be collected and purified for the purpose of infusion to patients. Early results in a limited number of patients show that these cell doses may be administered without adverse events and possibly without inducing GvHD. Further study is required to determine whether such infusions will be useful in preventing graft rejection, exerting graft-versus-leukaemia effects, and/or hastening immune recovery.
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PMID:Natural-killer-cell-based treatment in haematopoietic stem-cell transplantation. 1699 85


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