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

Idiotypic structures expressed on the myeloma Ig protein might be regarded as a tumor-specific antigen. Five patients with IgG myeloma were immunized with the purified serum M-component by repeated intradermal injections together with soluble granulocyte-macrophage colony-stimulating factor (GM-CSF). All patients developed an idiotype (Id)-specific T-cell immunity, defined as blood T cells predominantly secreting interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) (type I cells). Id-specific DNA synthesis was induced in one patient. Delayed-type hypersensitivity against the Id was not evoked. The specific IFN-gamma/IL-2 T-cell response was inhibited (46% to 100%) by a major histocompatibility complex (MHC) class I monoclonal antibody (MoAb) in all five patients. A 5% to 37% inhibition by an MHC class II MoAb was seen in four patients. CD4+ as well as CD8+ T cells enriched by magnetic microbeads contained Id-specific cells. The T cells recognized peptides corresponding to the complementarity-determining regions 1, 2, and 3 of the heavy chain of the Id. There was a transient rise of B cells producing IgM anti-idiotypic antibodies in all patients. The results indicate that immunization of myeloma patients using the autologous M-component and soluble GM-CSF may evoke an Id-specific predominantly MHC class I-restricted type I T-cell response.
 ...
PMID:Idiotype immunization combined with granulocyte-macrophage colony-stimulating factor in myeloma patients induced type I, major histocompatibility complex-restricted, CD8- and CD4-specific T-cell responses. 951 46

The combination of a cyclophosphamide (CTX)-based chemotherapy regimen and interleukin-2 (IL-2) has been shown to provide synergistic effects against malignancy in animal models. We therefore conducted a phase I-II trial combining CTX-based combination chemotherapy or CTX alone with high-dose IL-2 in patients with advanced and refractory malignant disease. Fifteen patients with hemato-oncological malignancies (malignant lymphoma 8, multiple myeloma 3, solid tumor 2, leukemia 2) were enrolled in the study. Continuous high-dose IL-2 infusion was shown to be safely administered, starting as soon as recovery of white blood cell count. All patients developed rebound lymphocytosis 24-48 h after termination of IL-2 infusion. Although grade IV toxicity was observed in 5 patients (7 episodes), all side effects completely subsided. Triple chemotherapy (CTX, etoposide and Ara-C) seemed rather toxic (in this group of heavily treated patients) while CTX alone was well tolerated. Four out of 13 (31%) evaluable patients had partial response and another patient (7%) had stabilization of disease progression lasting 2-8 months. Our conclusion is that the combination of CTX and continuous infusion of IL-2 is feasible and should be investigated in patients with various malignant neoplasms.
 ...
PMID:Continuous interleukin-2 infusion combined with cyclophosphamide- based combination chemotherapy in the treatment of hemato-oncological malignancies. Results of a phase I-II study. 979 34

Dendritic cells, with their extraordinary capacity for initiating primary and secondary T-lymphocyte responses, may be pivotal in the development of immunotherapeutic strategies for multiple myeloma. Although host lymphocytes are able to recognize tumor-associated antigens (TAAs), many tumors are able to avoid dendritic cell-mediated immune surveillance. One reason may be that the tumor environment inhibits the maturation and activation of dendritic cells. A recently developed strategy to use dendritic cells in immunotherapy involves removing them from the tumor, pulsing them in vitro with antigen, and reinfusing them into the patient to generate responding T cells in vivo. Methods for reliably obtaining dendritic cells for therapeutic use are currently being investigated. Among other efforts to induce T-cell-mediated immunity against cancer, the presentation of tumor antigens by the tumor cells themselves is being investigated. Issues to be resolved include defects of antigen presentation by tumor cells and whether all cells present the same set of peptides. Moreover, as long as all the tumor antigens have not been identified, the tumor cell itself remains the primary source of unknown antigens and, therefore, is a worthwhile subject for study. Phase I trials of immunotherapy using adenovirus-infected autologous plasma cells have recently been undertaken. The adenoviral vectors carry genes with therapeutic potential, including interleukin-2 (IL-2), interleukin-12, and B7-1. Initial results showed that the vector can be readily detected in tumor cells at 13 days postinjection, and IL-2 expression was evident at 7 days. The chief side effect reported was inflammation.
 ...
PMID:Presentation of tumor antigens. 998 85

Interferon (IFN)-alpha has a therapeutic effect in several B cell malignancies, including low-grade non-Hodgkin's lymphoma (NHL), multiple myeloma, and hairy cell leukemia, whereas its efficacy in the treatment of B cell chronic lymphocytic leukemia (B-CLL) is rather limited. In the present study, we investigated the effect of IFN-alpha on the biologic functions of B-CLL cells, which were stimulated by cross-linking of the CD40 antigen. In cell samples from 16 B-CLL patients, the addition of IFN-alpha to CD40-stimulated purified B-CLL cells caused a significant increase in [3H]thymidine uptake (p < 0.003). In B-CLL cells maximally activated by CD40 cross-linking and interleukin-2 (IL-2)/IL-10, proliferation was not further enhanced or inhibited by IFN-alpha. In contrast, proliferation of normal tonsillar B cells stimulated by the combination CD40/IL-2/IL-10 was significantly inhibited by IFN-alpha. Because B-CLL activation might be enhanced by induction of the autocrine growth factor tumor necrosis factor-alpha (TNF-alpha), we investigated the effect of IFN-alpha on the secretion of B cell tropic cytokines. In fact, IFN-alpha significantly stimulated the secretion of IL-6 and TNF-alpha in CD40-activated B-CLL cells (p < 0.01). Although exogenous addition of TNF-alpha did not influence activation of CD40-stimulated B-CLL cells, neutralization of TNF-alpha by polyclonal antibodies led to a complete inhibition of CD40-mediated proliferation of B-CLL cells, suggesting that enhanced proliferation and increased cytokine production by CD40-activated B-CLL cells are independent IFN-alpha-mediated events. The studies presented here provide evidence that IFN-alpha mediates costimulatory signals in the context of T cell-mediated B-CLL cell activation.
 ...
PMID:IFN-alpha stimulates proliferation and cytokine secretion of CD40-stimulated B cell chronic lymphocytic leukemia cells in vitro. 1033 84

To develop a new immunotherapy for multiple myeloma, we have generated a monoclonal antibody (MoAb) that detects a human plasma cell-specific antigen, HM1.24. Our previous study has shown that mouse anti-HM1.24 MoAb inhibits the proliferation of human myeloma cells implanted into severe combined immunodeficiency mice. In this report, we evaluated the antitumor activity of the humanized anti-HM1.24 MoAb (IgG1kappa), which was constructed by grafting the complementarity-determining regions. In contrast to the parent mouse MoAb, humanized anti-HM1.24 MoAb mediated antibody-dependent cellular cytotoxicity (ADCC) against both myeloma cell lines and myeloma cells from patients in the presence of human peripheral blood mononuclear cells (PBMCs). The PBMCs from untreated myeloma patients exhibited ADCC activity as efficiently as those of healthy donors. Although decreased ADCC activity of PBMCs was observed in patients who responded poorly to conventional chemotherapy, it could be significantly augmented by the stimulation with interleukin-2 (IL-2), IL-12, or IL-15. There was a strong correlation between the percentage of CD16(+) cells and ADCC activity in the PBMCs of myeloma patients. Moreover, peripheral blood stem cell collections from myeloma patients contained higher numbers of CD16(+) cells than PBMCs and exhibited ADCC activity that was enhanced by IL-2. These results indicate that humanized anti-HM1.24 MoAb has potential as a new therapeutic strategy in multiple myeloma and that treatment of effector cells with immunomodulating cytokines can restore the effect of humanized anti-HM1.24 MoAb in patients with diminished ADCC activity.
 ...
PMID:Humanized anti-HM1.24 antibody mediates myeloma cell cytotoxicity that is enhanced by cytokine stimulation of effector cells. 1033 1

Igs contain unique portions, collectively termed idiotypes (Id), that can be recognized by the immune system. Id expressed by tumor cells in B-cell malignancies can be regarded as tumor-specific antigens and a target for vaccine immunotherapy. We have started a vaccination trial in multiple myeloma (MM) using Id-specific proteins conjugated to keyhole limpet hemocyanin (KLH) as immunogens and low doses of subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2 (IL-2) as immunoadjuvants. Twelve patients who had previously been treated with high-dose chemotherapy followed by peripheral blood progenitor cell (PBPC) transplantation entered this study from August 1995 to January 1998. All patients were in first remission at the time of vaccination. They received subcutaneous injections of Id vaccines and immunoadjuvants in an outpatient setting. The generation of Id-specific T-cell proliferative responses was documented in 2 patients, whereas a positive Id-specific delayed-type hypersensitivity (DTH) reaction was observed in 8 of the 10 patients studied. DTH specificity was confirmed in 1 patient by investigating the reactivity to synthetic peptides derived from the VDJ sequence of the tumor-specific Ig heavy chain. None of the patients generated soluble immune responses to Id, whereas the generation of soluble and cellular immune responses to KLH was observed in 100% and 80%, respectively. Eleven patients completed the treatment, whereas 1 patient failed to finish owing to progression of disease. Freedom from disease progression (FFDP), measured from the date of first Id/KLH injection to the date of first treatment after vaccination or last follow-up, ranged from 9 to 36 months. These data indicate that the immune competence status of MM patients is still susceptible to specific immunization after high-dose chemotherapy and PBPC transplantation. It remains to be determined whether generation of Id-specific immune responses can reduce the relapse rate of patients with minimal residual disease.
 ...
PMID:Idiotype vaccination in human myeloma: generation of tumor-specific immune responses after high-dose chemotherapy. 1039 34

Multiple myeloma (MM) is a cancer of plasma cells, characterized by profound suppression of host immune responses. Here we show that MM cell lines significantly suppress the proliferation, blasting, response to interleukin-2 (IL-2), and expression of CD25 by concanavalin A (Con A)-activated or allostimulated peripheral blood T lymphocytes. T cells arrest in the G1 stage of the cell cycle, and do not enter the IL-2 autocrine growth pathway. T cell inhibition was mediated by a soluble factor. MM cell lines did not produce IL-10 but did produce large amounts of transforming growth factor beta1 (TGF-beta1). T cells were assessed for their ability to respond to IL-2 when co-cultured with MM cells in the presence or absence of the TGF-beta inhibitor, TGF-beta latency-associated peptide (LAP). MM cells suppressed IL-2 responses but this inhibition was completely reversed by TGF-beta LAP. A CD25-, IL-2-dependent blast cell line was not inhibited by MM cells or rhTGF-beta, confirming the specificity of the inhibition mechanism for the IL-2 autocrine growth pathway. We conclude that MM cells suppress T cells in their entry into the autocrine IL-2/CD25 pathway and in response to IL-2, and that TGF-beta has a significant role to play.
 ...
PMID:Transforming growth factor beta from multiple myeloma cells inhibits proliferation and IL-2 responsiveness in T lymphocytes. 1061 81

Impaired hematopoiesis and dysregulated cytokine expression have important implications for cancer in the elderly. In aged people, hematopoiesis is dysregulated and becomes paradoxically down-modulated under periods of increased hematopoietic demand. This down-modulation may explain, at least in part, the increased incidence of anemia in the elderly, although the cause of anemia can usually be identified in these patients and frequently reversed with targeted therapy. An age-associated decrease in the expression of interleukin-2 may contribute to impaired cellular immunity. Additionally, the increased interleukin-6 production frequently found in the elderly may participate in promoting the survival and proliferation of malignant myeloma and in inducing resistance by myeloma cells to therapies that act through apoptosis. Dysregulation of the expression of these and other cytokines may be a mechanism contributing to age-related impairment of the hematopoietic response, the genesis and therapeutic resistance of specific malignancies, and cancer cachexia.
 ...
PMID:Hematopoiesis and cytokines. Relevance to cancer and aging. 1068 71

Myeloma tumor cells, both freshly excised and cultured, are extremely resistant to cell-mediated cytolysis. As evidence suggests that B-cell susceptibility to lysis is dependent upon its state of differentiation and activation, we tested the ability of a variety of B-cell proliferation and differentiation agents, including pokeweed mitogen (PWM), to enhance the sensitivity of myeloma cells to cell-mediated lysis. PWM was found to significantly enhance the susceptibility of myeloma cell lines and freshly isolated myeloma cells to interleukin-2 (IL-2)-activated cell-mediated cytolysis. This effect was seen with the use of both IL-2-stimulated natural killer (NK) cells and T cells as effectors. The enhanced sensitivity of myeloma cells to cytolysis correlated with an increase in their cell surface expression of CD9, a pre-B cell marker and member of the transmembrane 4 superfamily. Incubation of PWM-stimulated myeloma cells with either monoclonal antibodies or antisense oligonucleotides directed against CD9 abrogated the effect of PWM. In order to determine whether there was a direct relationship between the expression of CD9 and enhanced sensitivity to cytolysis, myeloma cell lines that lacked CD9 expression were transfected with the CD9 gene. The level of cell surface CD9 expression correlates with enhanced susceptibility to lysis. Therefore, CD9 appears to be an important component in enhancing the sensitivity of myeloma cells to lysis mediated by IL-2-activated T cells and NK cells.
 ...
PMID:CD9 expression enhances the susceptibility of myeloma cell lines to cell-mediated cytolysis. 1089 55

Interleukin-2 (IL-2) has proven to be able to generate an effective anticancer immunity against both solid and hematologic malignancies. Moreover, recent advances in the knowledge of psychoneuroimmunology have demonstrated that anticancer immunity is under neuroendocrine control and that the pineal hormone melatonin (MLT) may stimulate the IL-2-dependent anticancer reaction. Finally, preliminary clinical studies have already shown that the concommitant administration of MLT may amplify the efficacy of IL-2 in the treatment of advanced solid neoplasms, whereas there are no data about MLT influence on IL-2 activity in hematologic malignancies. The aim of the present study was to evaluate the efficacy and tolerability of a neuroimmunotherapeutic combination of low-dose IL-2 plus MLT in advanced hematologic malignancies which did not respond to previous standard therapies. The study included 12 evaluable patients. Tumor histotypes were as follows: non-Hodgkin's lymphoma (NHL) 6; Hodgkin's disease (HD), 2; multiple myeloma, 2; acute myelogenous leukemia (ALM), 1 and chronic myelomonocytic leukemia (CMML), 1. IL-2 was injected subcutaneously at a dose of 3 million IU/day for 6 days per week for 4 weeks, corresponding to one cycle. MLT was given orally at 20 mg/day in the evening, without interruption. In non-progressing patients, a second IL-2 cycle was planned after a 3 week-rest period. A partial response was achieved in one patient with multiple myeloma. Stable disease occurred in 7 other patients (NHL, 3; HD, 1; AML, 1; CLLM, 1; multiple myeloma, 1), whereas the other 4 patients progressed. Therefore, lack of progression was obtained in 8 out of 12 (67%) patients, with a median duration of 21+ months (14-30+ months). The treatment was well tolerated in all patients. These preliminary results would suggest that the concomitant administration of low-dose IL-2 plus the pineal hormone MLT may prolong the survival time in untreatable advanced hematologic malignancies, with results comparable to those previously reported using a more toxic immunotherapy, consisting of high-dose IL-2 alone.
 ...
PMID:A phase II study of neuroimmunotherapy with subcutaneous low-dose IL-2 plus the pineal hormone melatonin in untreatable advanced hematologic malignancies. 1092 60


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