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)

Accumulating evidence indicates that a graft-vs.-myeloma effect (GVM) and its associated clinical remission of the disease can be induced by donor lymphocyte infusion in myeloma patients who have relapsed after allogeneic bone marrow transplantation. Although it is believed that GVM is induced by allospecific T cells, T-cell subsets and the mechanisms involved in the killing of myeloma cells by donor T cells have not been studied. In this study, we generated allospecific cytotoxic T lymphocyte (CTL) lines against three different myeloma cell lines, ARK, ARP-1 and U266, from unmatched healthy donors and examined their cytotoxicity against the target cells. Our results demonstrate that the allospecific CTLs efficiently lysed myeloma cells. The observed cytotoxicity was mediated mainly by CD8+ T cells and inhibited by MHC class I-blocking antibody. Furthermore, the CTLs lysed the target cells via the perforin-mediated pathway, as concanamycin A, but not brefeldin A (the selective inhibitors for perforin- or Fas-mediated pathways respectively) or tumour necrosis factor-alpha (TNF-alpha)-blocking antibody, abrogated the cytolytic activity of the cells. These CTLs expressed and produced predominantly TNF-alpha and interferon-gamma (IFN-gamma), indicating that they belong to the type 1 T-cell subsets. Taken together, these results indicate that CD8+ allospecific T cells may be responsible for mediating GVM and that the granule-mediated lysis of target cells is the major pathway in the CD8+ T-cell response against myeloma cells.
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PMID:Myeloma-reactive allospecific cytotoxic T lymphocytes lyse target cells via the granule exocytosis pathway. 1116 40

Multiple myeloma (MM) is a B-cell malignancy. The monoclonal immunoglobulin, secreted by myeloma plasma cells, carries unique antigenic determinants (idiotype [Id]) that can be regarded as a tumor-specific antigen. Id-based immunotherapy has been explored in myeloma patients for the purpose of enhancing or inducing Id-specific immune responses that might lead to tumor destruction. However, despite some evidence obtained from mouse plasmacytoma models, it is still unclear whether Id-specific immunity may play a role in the regulation of tumor cells in MM. In the current study, using dendritic cells (DCs) as antigen-presenting cells, autologous Id-specific cytotoxic T lymphocyte (CTL) lines containing both CD4+ and CD8+ T cells were generated from myeloma patients. The results show that Id-specific CTLs not only recognized and lysed autologous Id-pulsed DCs but also significantly killed the autologous primary myeloma cells. The cytotoxicity against the primary tumor cells was major histocompatibility complex (MHC) class I- and, to a lesser extent, class II-restricted, indicating that myeloma cells could process Id protein and present Id peptides in the context of their surface MHC molecules. Furthermore, the CTLs lysed the target cells mainly through the perforin-mediated pathway because Concanamycin A, but not Brefeldin A-the selective inhibitors for perforin- or Fas-mediated pathways-abrogated the cytolytic activity of the cells. These CTLs secreted predominantly interferon-gamma and tumor necrosis factor-alpha on antigen stimulation, indicating that they belong to the type-1 T-cell subsets. Taken together, these findings represent the first demonstration that Id-specific CTLs are able to lyse autologous tumor cells in MM and, thus, provide a rationale for Id-based immunotherapy in the disease.
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PMID:Idiotype-specific cytotoxic T lymphocytes in multiple myeloma: evidence for their capacity to lyse autologous primary tumor cells. 1123 17

Eight multiple myeloma patients participated in a phase I trial evaluating the feasibility and safety of subcutaneous vaccination with adenovirus engineered, autologous plasma cells after high-dose therapy. Plasma cells were concentrated from bone marrow harvests by negative selection and high gradient magnetic separation. The mean plasma cell yield was 2.61 x 10(8). Transgene expression measured 48 h after plasma cell infection with an IL-2 expressing adenovirus averaged 2.95 ng/ml/10(6) cells. Vaccine production was successful for 88% of patients. Two months after high-dose therapy, six patients received from one to five injections of 3.5-9.0 x 10(7) cells/vaccine. Vaccines were well tolerated with only minor systemic symptoms reported. Injection with tumor cells induced a local inflammatory response consisting predominantly of CD8+ and/or TIA-1+ T-lymphocytes. Myeloma specific anti-tumor responses, assessed by interferon-gamma (IFN-gamma) release and cytotoxic T cell killing of autologous tumor cells, were not enhanced after vaccination in one evaluable patient. Clinical response, manifested as a decrease in serum paraprotein, was not observed in the one patient who had measurable disease at the time of vaccination. These results demonstrate that the generation of adenovector modified plasma cell vaccines is technically feasible and can be safely administered post-transplant. Further studies of immunlogic and clinical efficacy are required.
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PMID:Adenovector engineered interleukin-2 expressing autologous plasma cell vaccination after high-dose chemotherapy for multiple myeloma--a phase 1 study. 1136 48

The antiangiogenic activity of thalidomide (Thal), coupled with an increase in bone marrow angiogenesis in multiple myeloma (MM), provided the rationale for the use of Thal in MM. Previously, the direct anti-MM activity of Thal and its analogues (immunomodulatory drugs, IMiDs) on MM cells was demonstrated, suggesting multiple mechanisms of action. In this study, the potential immunomodulatory effects of Thal/IMiDs in MM were examined. It was demonstrated that Thal/IMiDs do not induce T-cell proliferation alone but act as costimulators to trigger proliferation of anti-CD3-stimulated T cells from patients with MM, accompanied by an increase in interferon-gamma and IL-2 secretion. However, an increase in autologous T-cell killing of patient MM cells could not be demonstrated. A role for natural killer (NK)- and LAK-cell-mediated killing is suggested because IL-2-primed peripheral blood mononuclear cells (PBMCs) treated with Thal/IMiDs demonstrated significantly increased lysis of MM cell lines. Cold target inhibition assays suggested NK- rather than LAK-cell-mediated killing. Furthermore, this killing was not major histocompatibility complex-class restricted, and the depletion of CD56(+) cells blocked the drug-induced MM cell lysis. It was significant that increased killing of patient MM cells by autologous PBMCs treated with Thal/IMiDs was also observed. Although the in vivo relevance of NK-cell-mediated MM cell killing is unknown, phenotypic analysis performed in MM patients receiving Thal therapy demonstrated an increase in CD3(-)CD56(+) cells in patients responding to therapy. Thus in vitro and in vivo data support the hypothesis that Thal may mediate its anti-MM effect, at least in part, by modulating NK cell number and function.
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PMID:Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. 1173 5

The revival of thalidomide began shortly after the drug was withdrawn from the market because of its teratogenic properties. Therapeutic effects of thalidomide were found accidentally in leprosy patients with erythema nodosum leprosum (ENL). Subsequent research widened the understanding of the activity of thalidomide, and with improved methodology and the augmented background knowledge of immunology it was possible to interpret the properties of thalidomide more coherently. Effects on tumour necrosis factor-alpha (TNFalpha) release play an important role in the ability of thalidomide to affect the immune system. Alteration of synthesis and release of cytokines such as interleukin (IL)-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12 and interferon-gamma is involved in the complex mechanisms of thalidomide. Thalidomide targets leucocytes, endothelial cells and keratinocytes, affecting them in a different manner and at different cellular levels. Changes in the density of adhesion molecules alter leucocyte extravasation and the inflammatory response in the tissue involved. Several mechanisms for the teratogenic action of thalidomide are currently under review, but this mode of action of the drug still remains unclear and we review evidence-based hypotheses for the teratogenicity of thalidomide. Thalidomide shows significant clinical impact in several diseases such as ENL in lepromatous leprosy, chronic graft-versus-host disease, systemic lupus erythematosus, sarcoidosis, aphthous lesions in HIV infection, wasting syndrome in chronic illness, inflammatory bowel disease, multiple myeloma and some solid tumours. In 1998 the US Food and Drug Administration approved thalidomide exclusively for the treatment of ENL, and strict conditions were stipulated for its use in order to prevent teratogenic adverse effects. However, despite the promising findings of thalidomide at the molecular level, namely its anti-TNFalpha properties and its intercalation with DNA, and activity in clinical trials, there is still a great need for more intensive research.
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PMID:Theoretical basis for the activity of thalidomide. 1160 49

Human interferon-gamma (IFN-gamma) purified to electrophoretic homogeneity by a cation exchange h.p.l.c., was used for the development of monoclonal antibodies. Following immunization, spleen lymphocytes of two mice showing the highest binding and neutralizing titers were isolated, fused with NSO mouse myeloma cells and cloned. The screening of hybridomas was based on precipitation of the immune complexes with a second antibody and recovery of the biological activity of IFN-gamma from the precipitate. Twenty nine independent hybridomas secreting antibodies specific to IFN-gamma were obtained. Twelve out of these 29 hybridomas produced antibodies that neutralized the antiviral activity of pure as well as crude IFN-gamma. Moreover, IFN-gamma obtained by various induction procedures was neutralized as well, indicating that these various IFN-gamma subtypes are immunologically cross-reactive. Immune precipitation of partially purified 125I-labelled IFN-gamma by several monoclonal antibodies revealed two protein bands of 26,000 and 21,000 daltons. Immunoaffinity chromatography of IFN-gamma gave a 50-fold purification to a specific activity > or = 4 x 10(7) units/mg. Two of the monoclonal antibodies were found suitable for a sensitive and rapid double antibody solid-phase radioimmunoassay, allowing the detection of IFN-gamma at concentrations of at least 4 ng/ml (150 units/ml) within 8 h.
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PMID:Monoclonal antibodies to human interferon-gamma: production, affinity purification and radioimmunoassay. 1189 6

Clonotypic B cells circulating in patients with multiple myeloma (MM) express CD20, and it has been suggested that these cells may be clonogenic. Furthermore, 20% of patients with MM express CD20 on their bone marrow plasma cells (BMPCs). Therefore, the authors began a phase II clinical study to determine the activity of the anti-CD20 monoclonal antibody rituximab in MM patients. Nineteen previously treated MM patients received 375 mg/m2 rituximab per week for 4 weeks. Three months after initiation of treatment, patients were assessed for response and received a second course of therapy if their disease was stable (SD) or they achieved a partial response (PR). Six of 19 (32%) patients had either a PR (n = 1) or SD (n = 5), with a median time to treatment failure of 5.5 months (mean, 10.3 months; range, 3-27+ months). All six patients who had a PR or SD had CD20+ BMPC. Overall, rituximab therapy was well tolerated. Because most patients with MM poorly express CD20 on their BMPCs, the authors evaluated agents for their ability to induce CD20 expression and thereby facilitate rituximab binding on MM cells. These studies show that interferon-gamma (IFN-y) induced CD20 expression on MM BMPCs, MM B cells, and healthy donor BMPCs. In contrast, CD20 expression on chronic lymphocytic leukemia, follicular non-Hodgkin's lymphoma, healthy donor B cells, and progenitor cells was unaffected by IFN-y. Rituximab binding to the BMPCs of MM patients was also increased after culture with pharmacologically attainable levels of IFN-gamma (1-100 U/mL). In conclusion, these studies suggest that MM patients with CD20+ BMPCs may benefit from rituximab therapy. Furthermore, IFN-gamma induces CD20 expression on MM BMPCs and B cells and facilitates rituximab binding to MM BMPCs, providing the rationale for clinical trials to examine its use with CD20-directed serotherapies in MM.
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PMID:CD20-directed serotherapy in patients with multiple myeloma: biologic considerations and therapeutic applications. 1192 12

The idiotype protein, secreted by myeloma plasma cells, is a tumor-specific but weak antigen. Idiotype-based immunotherapy has been explored in myeloma patients with disappointing results. It is conceivable that myeloma cells contain a multitude of tumor antigens that can more effectively stimulate antitumor T cells. To explore the possibility of using whole myeloma cells as a source of tumor antigens for immunotherapy, the current study was undertaken to generate and examine the function of myeloma-specific cytotoxic T lymphocytes (CTLs) by using dendritic cells (DCs) pulsed with myeloma cell lysates as stimulating cells. After repeated stimulation, specific CTL lines, containing CD4(+) and CD8(+) T cells, were generated from myeloma patients. Our results show that these T cells not only recognized and lysed autologous myeloma protein-pulsed DCs, they also killed autologous primary myeloma cells. Occasionally, CTLs responded to autologous idiotype-pulsed DCs and to allogeneic primary myeloma cells. No cytolytic activity, however, was detected against autologous lymphocytes including B cells, suggesting that the T cells acted specifically against myeloma cells. Cytotoxicity against target cells was major histocompatibility complex class 1 and, to a lesser extent, class 2 restricted and was dependent mainly on the perforin-mediated pathway. CTLs secreted predominantly interferon-gamma and tumor necrosis factor-alpha on antigenic stimulation, indicating a type 1 T-cell subset. These findings represent the first demonstration that tumor cell lysate-primed CTLs kill only myeloma cells, not autologous lymphocytes. This provides a rationale for myeloma cell-based immunotherapy in multiple myeloma.
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PMID:Tumor lysate-specific cytotoxic T lymphocytes in multiple myeloma: promising effector cells for immunotherapy. 1196 94

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

We studied the function of antitumor T and natural killer T (NKT) cells from the blood and tumor bed in 23 patients with premalignant gammopathy, nonprogressive myeloma, or progressive multiple myeloma. We show that antitumor killer T cells can be detected in patients with both progressive or nonprogressive myeloma. V alpha 24+V beta 11+ invariant NKT cells are detectable in the blood and tumor bed of all cohorts. However, freshly isolated NKT cells from both the blood and tumor bed of patients with progressive disease, but not nonprogressive myeloma or premalignant gammopathy, have a marked deficiency of ligand-dependent interferon-gamma production. This functional defect can be overcome in vitro using dendritic cells pulsed with the NKT ligand, alpha-galactosylceramide (alpha-GalCer). Fresh myeloma cells express CD1d, and can be efficiently killed by autologous NKT cells. We hypothesize that presentation of tumor derived glycolipids by myeloma cells leads to NKT dysfunction in vivo. These data demonstrate that clinical progression in patients with monoclonal gammopathies is associated with an acquired but potentially reversible defect in NKT cell function and support the possibility that these innate lymphocytes play a role in controlling the malignant growth of this incurable B cell tumor in patients.
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PMID:A reversible defect in natural killer T cell function characterizes the progression of premalignant to malignant multiple myeloma. 1279 69


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