Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple myeloma (MM) remains essentially incurable by conventional anti-tumour therapy. This has led to increased interest in the possibility that forms of immune therapy might be effective. The successful use of donor lymphocyte infusions (DLI) in a few cases of MM relapse following allogeneic bone marrow transplantation have added weight to this view. MM is characterized by several defects in the host's immune system. The influence of the malignant clone on the function of the immune effector cells results from both passive and active suppression. Despite an array of functional adhesion molecules and HLA class I and II molecules on their surface and the secretion of a tumour-specific peptide, they fail to express adequate levels of co-stimulatory molecules thus inducing anergy in potentially tumour-specific T cells. In addition to this passive evasion of immune regulation, MM tumour cells are capable of producing a number of immunologically active agents which can induce immunosuppression such as transforming growth factor-beta, Fas ligand (FasL), vascular endothelial growth factor and Muc-1. It is postulated that these agents may be produced by the tumour cell to influence the microenvironment to support growth and differentiation of the clone but may have the additional benefit of altering the function of the host immune effector cells and thus preventing tumour rejection. This duality of function is important if clinicians are to design immunotherapy strategies which will achieve the true potential and result in improved survival in MM.
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PMID:Immune regulation in multiple myeloma: the host-tumour conflict. 1052 67

We recently found that sperm protein 17 (Sp17), a spermatozoa-restricted protein, is aberrantly expressed on the tumor cells in patients with multiple myeloma (MM). It may therefore be possible to generate donor-derived Sp17-specific CTL for administration following allogeneic stem cell transplant to augment graft-versus-myeloma (GVM) effect without inducing a global GVHD. To assess this approach, we have produced recombinant Sp17 protein and used Sp17 protein-pulsed dendritic cells to generate HLA class I-restricted Sp17-specific CTL from a previously unimmunized healthy donor. These CTL were able to lyse autologous Epstein-Barr virus-transformed lymphoblastoid cells in a Sp17-dependent manner. Target lysis was HLA-A1 and HLA-B27 restricted. Cytotoxicity could be blocked by antibodies against monomorphic HLA class I, HLA-A1 and HLA-B27 molecules but not HLA class II molecules. Most importantly, the CTL lysed HLA class I-matched Sp17-positive tumor cells, suggesting that Sp17 is processed and presented in association with the HLA class I molecules in Sp17-positive tumor cells in a concentration and configuration that could be recognized by recombinant protein-primed CTL. Analysis by flow cytometry of the CTL indicated that they were predominantly CD8 in phenotype and they produced IFN-gamma and very little IL-4. Our results suggest the potential for the generation and administration of donor-derived Sp17-specific CTL to augment GVM without inducing GVHD following allogeneic stem cell transplant for MM.
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PMID:Sperm protein 17 (Sp17) in multiple myeloma: opportunity for myeloma-specific donor T cell infusion to enhance graft-versus-myeloma effect without increasing graft-versus-host disease risk. 1147 39

Sperm protein 17 (Sp17) is a protein recently identified as a novel cancer-testis (CT) antigen in multiple myeloma (MM). Because this tumor antigen demonstrates a very restricted normal tissue expression, Sp17 may be an excellent target for tumor vaccine of MM. In this study, we determined the ability to generate Sp17-specific HLA class I-restricted cytotoxic T lymphocytes (CTLs) from the peripheral blood of 4 patients with MM, 3 consecutive Sp17(+) patients, and 1 Sp17(-) patient. Dendritic cells were generated from monocytes of 4 patients with MM and used to present a recombinant Sp17 protein to autologous T cells. Following 4 rounds of antigen stimulation, the CTLs were tested for their ability to kill autologous targets in an Sp17-dependent and HLA-class I- restricted manner in standard cytotoxicity assays. Despite previous chemotherapy and the immunosuppression so often associated with MM, CTL generation was successful in all 4 patients, irrespective of the Sp17 status of their tumors. Most importantly, the CTLs were able to lyse autologous tumor cells that expressed Sp17. Tumor cell lysis in all cases appeared to be mainly mediated by perforin and could be blocked by concanamycin A. We conclude that Sp17 is a suitable target for immunotherapy of MM. Our findings provide the basis for a clinical study aimed at inducing a cellular immune response directed at Sp17(+) MM.
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PMID:Sperm protein 17 (Sp17) is a suitable target for immunotherapy of multiple myeloma. 1213 May 9

While the exact aetiology of myeloma is unknown, genetic factors feature among the potential risk factors. The HLA phenotypes in African blacks with myeloma (the commonest haematopoietic malignancy in this group) have not been characterized. The purpose of this study was to determine the HLA class I and class II phenotypes of patients with multiple myeloma and to compare the findings to an ethnically matched control group of 100 individuals. Analysis of the HLA class I and class II phenotypes in 62 myeloma patients revealed: (i) a corresponding statistically significant association with HLA B18 [odds ratio (OR) 6.3; 95% confidence interval (CI) 1.013-39.727; P < 0.005]; (ii) no statistically significant association with HLA B13, Cw2, Cw6 or the DR and DQ antigens; and (iii) a statistically significant negative (protective) association with HLA Cw7 (OR 0.4; 95% CI 0.21-0.87; P < 0.005). This study suggests that although genetic factors may play a role in the multifactorial aetiology of multiple myeloma, with the exception of HLA B18, there is no specific association between HLA types and multiple myeloma in South African blacks.
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PMID:HLA class I and class II antigens associated with multiple myeloma in southern Africa. 1218 Oct 24

Sperm protein 17 (Sp17) is a highly immunogenic cancer-testis antigen expressed by tumour cells from up to 30% of patients with multiple myeloma (MM). We recently successfully generated Sp17-specific human leucocyte antigen (HLA)-A1 and B27-restricted cytotoxic T lymphocytes (CTLs) from the peripheral blood of a healthy donor. Because CTLs were able to kill HLA-matched fresh myeloma cells, it may be possible to generate and administer myeloma-specific donor T cells to MM patients following allogeneic stem cell transplantation to enhance graft-versus-myeloma (GVM) without inducing graft-versus-host disease (GVHD). To determine how widely applicable this approach is, we have determined the ability to generate Sp17-specific CTLs from four consecutive healthy donors with other HLA class I phenotypes. We found that Sp17-specific HLA class I-restricted CTLs could be easily generated from all four donors. Sp17-specific CTLs were primarily CD8 in phenotype and produced interferon-gamma and very little interleukin-4. These T cells killed target cells primarily via the perforin-mediated route. These results therefore suggest that myeloma-specific donor T-cell infusion that targets Sp17 to selectively enhance GVM could be applicable to patients with Sp17+ MM.
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PMID:Successful generation of sperm protein 17 (Sp17)-specific cytotoxic T lymphocytes from normal donors: implication for tumour-specific adoptive immunotherapy following allogeneic stem cell transplantation for Sp17-positive multiple myeloma. 1223 64

Donor lymphocyte infusions (DLI) provide effective therapy for patients with multiple myeloma who have relapsed after allogeneic bone marrow transplantation. However, the immunological mechanisms of the graft-versus-myeloma (GVM) effect have not been defined, and the target antigens of this response have not been identified. Molecular analysis of CDR3 Vbeta repertoire after CD4+ DLI demonstrated previously that the development of GVM and graft-versus-host-disease (GVHD) were associated with the clonal expansion of distinct T-cell populations in patient peripheral blood. In the current study, we undertook a molecular and functional characterization of GVM- and GVHD-associated T-cell clones. T-cell clones associated with GVM were detectable by clone-specific PCR at a low level in peripheral blood before DLI and expanded approximately 10-fold after DLI. In contrast, T-cell clones associated with GVHD were not detectable before DLI or before the development of clinical GVHD. Two T-cell clones associated with GVM were isolated and expanded in vitro, allowing their phenotypic and functional characterization. Both GVM clones were derived from donor cells and had a CD3+CD8+CD4- phenotype. One GVM clone specifically recognized patient myeloma cells in an HLA class I-restricted manner, but was not reactive with patient normal bone marrow cells or patient EBV transformed B cells. Taken together, these findings suggest that the GVM response is mediated by donor-derived CD8+ T-cell clones with antimyeloma specificity that may be present before DLI. In contrast, T-cell clones associated with GVHD are expanded de novo after DLI.
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PMID:Expansion of tumor-specific CD8+ T cell clones in patients with relapsed myeloma after donor lymphocyte infusion. 1275 Feb 80

Peripheral blood CD14+ monocytes from multiple myeloma (MM) patients can be induced to differentiate into fully functional, mature, CD83+ dendritic cells (DCs) which are highly efficient in priming autologous T lymphocytes in response to the patient-specific tumor idiotype (Id). We have recently scaled up our manufacturing protocol for application in a phase I-II clinical trial of anti-Id vaccination with DCs in MM patients. Elegible patients received a series of by-monthly immunizations consisting of three subcutaneous and two intravenous injections of Id-keyhole limpet hemocyanin (KLH)-pulsed DCs (5 x -, 10 x -, 50 x 10(6) cells and 10 x -, 50 x 10(6) cells, respectively). To generate DCs, monocytes were labeled with clinical grade anti-CD14 conjugates and positively selected by immunomagnetic separation. Cells were then cultured, according to Good Manufacturing Practice guidelines, in FCS-free medium in cell culture bags, and differentiated to DCs with GM-CSF plus IL-4 followed by TNF-alpha or, more recently, by a cocktail of IL-1beta, IL-6, TNF-alpha and prostaglandin-E2. Before maturation, Mo-DCs were pulsed with the autologous Id as whole protein or Id (VDJ)-derived HLA class I restricted peptides. Ten MM patients, who had been treated with two courses of high-dose chemotherapy with peripheral blood stem cell support, entered into the clinical study. CD14+ monocytes were enriched from 16.1+/-5.7% to 95.5+/-3.2% (recovery 67.9+/-15%, viability > 97%). After cell culture, phenotypic analysis showed that 89.6+/-6.6% of the cells were mature DCs. We obtained 2.89+/-1 x 10(8) DCs/leukapheresis which represented 24.5+/-9% of the initial number of CD14+ cells. Notably, the cytokine cocktail induced a significantly higher percentage and yield (31+/-10.9 of initial CD14+ cells) of DCs than TNF-alpha alone, secretion of larger amounts of IL-12, potent stimulatory activity on allogeneic and autologous T cells. Storage in liquid nitrogen did not modify the phenotype or functional characteristics of pre-loaded DCs. The recovery of thawed, viable DCs, was 78+/-10%. Thus, positive selection of CD14+ monocytes allows the generation of a uniform population of mature pre-loaded DCs which can be cryopreserved with no effects on phenotype and function and are suitable for clinical trials. Based on these results, a DCs-based phase II trial of anti-Id vaccination with VDJ-derived HLA class I-restricted peptides and KLH is underway for lymphoma patients.
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PMID:Generation of dendritic cells from positively selected CD14+ monocytes for anti-tumor immunotherapy. 1535 43

The development of immunotherapy approaches designed to obtain tumor-specific T cells might help eradicate residual malignant cells in multiple myeloma (MM) patients. To this end, we used autologous primary MM cells as antigen-presenting cells (APC). Gene transfer of both CD80 and CD154 by lentiviral vectors was necessary to significantly improve the APC function of human MM cells. Simultaneous CD80/CD154 expression on MM cells allowed the generation of CD8+ T cells that recognized unmodified MM cells in 11 of 16 cases, specifically in six of six patients with low-stage disease, but only in five of ten patients with advanced disease. The activity of CD8+ T cells was MHC restricted and MM specific. In seven of seven cases, CD8+ T cell activity was inhibited by monoclonal antibodies against HLA class I, and in four of four cases, CD8+ T cells recognized autologous MM cells but not autologous normal B and T lymphocytes nor bone marrow stromal cells. In addition, the activity of CD8+ T cells was directed against allogeneic MM cells that shared at least one MHC allele with the autologous counterpart, but not against MHC mismatched MM cells. These data lay the ground for the isolation of new MM antigens and for the design of vaccination protocols with primary MM cells genetically engineered to express immunostimulatory molecules.
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PMID:Lentiviral transduction of primary myeloma cells with CD80 and CD154 generates antimyeloma effector T cells. 1587 76

Serum beta2-microglobulin, the light chain of the HLA class I molecular complex, remains one of the best survival prognostic factors in multiple myeloma, but other HLA class I molecules might be of interest in monoclonal gammopathies. In this study, we evaluate total soluble HLA class I (HLA-Is) and soluble HLA-G (HLA-Gs) in 103 patients with newly diagnosed multiple myeloma, 30 patients with monoclonal gammopathy of undetermined significance (MGUS), and 30 healthy subjects, studying their prognostic value in multiple myeloma. In multiple myeloma patients, HLA-Is and HLA-Gs median values were 0.8 microg/mL and 28 ng/mL, respectively. Median HLA-Is concentration was higher in stage II and III multiple myeloma patients than in stage I multiple myeloma, MGUS, and control patients. Median HLA-Gs was significantly lower in healthy controls than in MGUS and multiple myeloma patients. A high level of HLA-Is (> or =2.1 microg/mL) was predictive of short survival (P = 0.017). For each given level of beta2-microglobulin, the relative risk of death was higher for patients with HLA-Is > or = 2.1 microg/mL than in patients with a lower level (P = 0.047). HLA-Gs, a marker of monoclonal gammopathy, was of no prognostic value, but the addition of HLA-Is to beta2-microglobulin produced an efficient prognostic score (P < 0.0001). HLA-Is is a new marker of multiple myeloma tumor load and provides additional survival prognostic information to beta2-microglobulin.
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PMID:Total soluble HLA class I and soluble HLA-G in multiple myeloma and monoclonal gammopathy of undetermined significance. 1624

Myeloma vaccines, based on dendritic cells pulsed with idiotype or tumor lysate, have been met with limited success, probably in part due to insufficient cross-priming of myeloma antigens. A powerful method to introduce myeloma-associated antigens into the cytosol of dendritic cells is protein transduction, a process by which proteins fused with a protein transduction domain (PTD) freely traverse membrane barriers. NY-ESO-1, an immunogenic antigen by itself highly expressed in 60% of high-risk myeloma patients, was purified to near homogeneity both alone and as a recombinant fusion protein with a PTD, derived from HIV-Tat. Efficient entry of PTD-NY-ESO-1 into dendritic cells, confirmed by microscopy, Western blotting, and intracellular flow cytometry, was achieved without affecting dendritic cell phenotype. Experiments with amiloride, which inhibits endocytosis, and N-acetyl-l-leucinyl-l-norleucinal, a proteasome inhibitor, confirmed that PTD-NY-ESO-1 entered dendritic cells by protein transduction and was degraded by the proteasome. Tetramer analysis indicated superior generation of HLA-A2.1, CD8+ T lymphocytes specific for NY-ESO-1(157-165) with PTD-NY-ESO-1 compared with NY-ESO-1 control protein (44% versus 2%, respectively). NY-ESO-1-specific T lymphocytes generated with PTD-NY-ESO-1 secreted IFN-gamma indicative of a Tc1-type cytokine response. Thus, PTD-NY-ESO-1 accesses the cytoplasm by protein transduction, is processed by the proteasome, and NY-ESO-1 peptides presented by HLA class I elicit NY-ESO-1-specific T lymphocytes.
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PMID:Protein transduction of dendritic cells for NY-ESO-1-based immunotherapy of myeloma. 1626 30


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