Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Haematopoietic stem cell transplantation (HSCT) is now an established treatment fora number of non-malignant and malignant conditions. Bone marrow- or peripheral blood-derived allogeneic SCT from an HLA-identical sibling or matched unrelated donor cures more than half the patients with severe aplastic anaemia, thalassaemia major, congenital immunodeficiency diseases and genetic metabolic disorders. Among the malignant conditions, acute and chronic leukaemia, multiple myeloma, Hodgkin and non-Hodgkin lymphoma, and high risk neuroblastoma are important conditions that can be treated by HSCT. The major morbidities associated with HSCT are regimen-related toxicities, development of acute or chronic graft-versus-host disease (GVHD), failure of engraftment of the bone marrow and complications related to the immunodeficiency that occurs in the post-transplant period. Peripheral blood stem cells are now being used as an alternative to bone marrow stem cells for allogeneic HSCT and exclusively for autologous HSCT. Reduced intensity conditioning for allogeneic HSCT has resulted in a lower frequency and severity of GVHD and risk of infections. This has resulted in allogeneic HSCT being done in older patients and for those with co-morbid conditions. Patients with low grade Hodgkin and non-Hodgkin lymphoma, chronic lymphocytic leukaemia and multiple myeloma appear to benefit more with this approach. Prevention of acute GVHD while maintainingthe graft-versus-tumour effect and close monitoring of the kinetics of chimerism hold promise for improving the outcome of those receiving reduced intensity allogeneic HSCT. In recipients ofautologous HSCT, identification of patients at increased risk for relapse and use of agents (interferon, interleukin-2) post-transplant to augment the graft-versus-tumour effect are possible areas of further research.
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PMID:Haematopoietic stem cell transplantation: current status. 1786 17

The results of blood or marrow transplantation in patients with chemorefractory aggressive lymphoma, that is, those not responding to conventional-dose chemotherapy at the time of transplant, have been poor. The relapse rate has been high after autologous bone marrow transplant, whereas allogeneic transplantation has been associated with excessive transplant-related toxicity. Administration of cyclosporine after autologous transplantation can induce an autoreactive syndrome that resembles graft-versus-host disease (GVHD). This syndrome, named autologous graft-versus-host disease, has clear antitumor activity in animal models that can be enhanced by the addition of cytokines such as gamma-interferon and interleukin-2. A randomized, prospective study was conducted to evaluate the antitumor effect of autologous graft-versus-host disease induced with cyclosporine, and augmented by the administration of gamma-interferon and interleukin-2 in patients with chemorefractory Hodgkin and aggressive non-Hodgkin lymphomas. Fifty-one patients were randomized, 24 to the autologous GVHD induction arm, and 27 to the noninduction arm after autologous transplant using mobilized peripheral blood stem cell (PBSC) grafts. There were no differences in treatment-related mortality, overall and event-free survival (OS, EFS) between both groups; however, in the induction arm, GVHD developed only in 4 patients. The administration of oral cyclosporine followed by interleukin-2 and gamma-interferon is generally not well tolerated, and does not appear to be an effective method to induce autologous GVHD in patients receiving autologous PBSC grafts.
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PMID:Induction of autologous graft-versus-host disease: results of a randomized prospective clinical trial in patients with poor risk lymphoma. 1788 55

Non-Hodgkin's lymphomas (NHL) represent a heterogenous group of diseases including low, intermediate and high grade histological subtypes. Most entities are sensitive to chemotherapy and radiotherapy. However, most relapsed patients are incurable with conventional treatment. The major reason for unsatisfactory long-term results in NHL is tumour cells that persist after standard treatment. New sensitive techniques have been developed to detect occult lymphoma cells. These cells might be eradicated by new immunotherapeutic agents with different modes of action, such as cytokines or antibody-based agents. In NHL, most experience has been accumulated with interferon-alpha, which seems to be effective against minimal residual disease (MRD). The experience with interleukin-2 and interleukin-3 is less convincing. Monoclonal antibodies have been used in their native form, or conjugated with radioisotopes or toxins to selectively destroy lymphoma cells. Such immunotoxins and radioisotope-coupled antibodies have shown promising results in early clinical trials, and are now being evaluated in patients with smaller tumour burdens.
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PMID:Non-Hodgkin's Lymphoma: A Review of Immunotherapeutic Approaches to Treatment. 1802 May 12

Increased angiogenesis has been shown to be a feature of non-Hodgkin lymphomas (NHL). In the current study, the pretreatment levels of circulating molecules related to angiogenesis were determined in 49 B-cell NHL patients and correlated with histological grade, disease stage and prognostic score. In 25 patients, the same molecules were defined after standard treatment. Vascular endothelial growth factor (VEGF), angiogenin, interleukin-2 (IL-2), IL-6, IL-8 and IL-16 were measured. Increased levels of VEGF, IL-6 and IL-8 were found in the whole group of untreated patients in comparison with normal controls (P < 0.05), whereas, IL-2 was higher in the subgroup of indolent NHL. Overall, there was no significant decrease in the levels of these molecules after treatment. However, by stratification into group of responders vs. non-responders pretreatment IL-8 was significantly increased whereas IL-16 was decreased in the subgroup of complete responders. According to the REAL classification IL-2 was higher in the low risk compared with intermediate plus high-risk group. There was no association with disease stage or the International Prognostic Score. Both indolent and aggressive B cell lymphomas have increased production of angiogenic mediators and cytokines with IL-8 and IL-16 potentially reflecting the response to treatment.
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PMID:Angiogenesis-related growth factors and cytokines in the serum of patients with B non-Hodgkin lymphoma; relation to clinical features and response to treatment. 1819 Apr 63

The latent membrane protein-2 (LMP2) of Epstein-Barr virus is a potential target for T-cell receptor (TCR) gene therapy of Hodgkin lymphoma and nasopharyngeal carcinoma. Here, we modified a human leukocyte antigen-A2-restricted, LMP2-specific TCR to achieve efficient expression following retroviral TCR gene transfer. The unmodified TCR was poorly expressed in primary human T cells, suggesting that it competed inefficiently with endogenous TCR chains for cell surface expression. In order to improve this TCR, we replaced the human constant region with murine sequences, linked the two TCR genes using a self-cleaving 2A sequence and finally, codon optimized the TCR-alpha-2A-beta cassette for efficient translation in human cells. Retroviral transfer of the modified TCR resulted in efficient surface expression and HLA-A2/LMP2 pentamer binding. The transduced cells showed peptide-specific interferon-gamma and interleukin-2 production and killed target cells displaying the LMP2 peptide. Importantly, the introduced LMP2-TCR suppressed the cell surface expression of a large proportion of endogenous TCR combinations present in primary human T cells. The design of dominant TCR is likely to improve TCR gene therapy by reducing the risk of potential autoreactivity of endogenous and mispaired TCR combinations.
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PMID:Retroviral transfer of a dominant TCR prevents surface expression of a large proportion of the endogenous TCR repertoire in human T cells. 1830 79

Peripheral T-cell lymphoma (PTCL) is an aggressive form of non-Hodgkin's lymphoma (NHL), associated with poor prognosis and without standard approach to treatment. Denileukin diftitox (Ontak) is a synthetic fusion protein combining the receptor-binding domain of interleukin-2 to the enzymatically active portion of diphtheria toxin. While approved for the treatment of cutaneous T-cell lymphoma, it has demonstrated activity in non-Hodgkin's lymphomas of both T-cell and B-cell origin. This report documents the first case of de novo maintenance therapy with denileukin diftitox sustaining an ongoing complete response at the molecular level for 2 years in a patient with PTCL.
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PMID:De novo maintenance therapy with denileukin diftitox (Ontak) in a patient with peripheral T-cell lymphoma is associated with prolonged remission. 1838 17

The antibody-mediated delivery of therapeutic agents to sites of angiogenesis is an attractive strategy for anticancer therapy, but is largely unexplored in hematologic malignancies. In the present study, we show that the extra domain B (EDB) of fibronectin, a marker of angiogenesis, is expressed in B-cell non-Hodgkin lymphoma (NHL) and that the human monoclonal anti-EDB antibody L19 can selectively localize to the lymphoma-associated subendothelial extracellular matrix. In vivo, the preferential accumulation of the antibody at the tumor site was confirmed by quantitative biodistribution analyses with radioiodinated antibody preparations. The fusion protein L19-IL2, which mediates the delivery of interleukin-2 (IL-2) to the neovasculature, displayed a superior antilymphoma activity compared with unconjugated IL-2 in localized and systemic xenograft models of NHL. When coadministered with rituximab, L19-IL2 induced complete remissions of established localized lymphomas and provided long-lasting protection from disseminated lymphoma. The combined use of rituximab and L19-IL2, which dramatically increases the infiltration of immune effector cells in lymphomas, may deserve clinical investigations, facilitated by the fact that L19-IL2 is currently being studied in phase II clinical trials in patients with solid tumors.
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PMID:Complete eradication of human B-cell lymphoma xenografts using rituximab in combination with the immunocytokine L19-IL2. 1926 22

Although therapy of CD30-positive lymphomas such as classical Hodgkin lymphoma and anaplastic large cell lymphoma has been improved considerably during the last decades, patients suffer from high toxicity of current therapeutic regimens. Since CD30 expression is very restricted, CD30-positive tumors are well suited for immunotherapeutic approaches. Several distinct immunotherapeutic approaches with chimeric, humanized, and bispecific antibodies as well as immunotoxins are already described. In this report, we give a short overview of CD30-targeting approaches in humans. Furthermore, we introduce two novel anti-CD30 fusion proteins consisting of the single chain variable fragment of the CD30 monoclonal antibody Ber-H2 and human interleukin-2, evaluate their biological activity in a human CD30-positive syngeneic murine model, and demonstrate the immunological mechanisms leading to tumor rejection by these reagents. The data indicate that there are several promising approaches in CD30-targeted immunotherapy. The findings of the anti-CD30 IL-2 constructs suggest that these fusion proteins are particularly useful to remove small, residual tumors.
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PMID:Anti-CD30 human IL-2 fusion proteins display strong and specific cytotoxicity in vivo. 1919 6

B-cell malignancies seem to be particularly amenable to immunotherapy and as such make particularly attractive targets for adoptive T-cell therapy. Murine T cells gene-modified to express a chimeric immune receptor specific for CD19+ (aCD19z) efficiently kill CD19 B-cell lymphoma cells in vitro. aCD19z T cells also secrete high levels of interleukin-2 during culture with target cells in a CD86 independent manner. aCD19z T cells proved effective at eradicating established B-cell lymphoma in a syngeneic model system when combined with a lymphodepleting preconditioning regimen. In mice deficient of T, B, and natural killer cells (severe combined immunodeficient/Beige), aCD19z T cells efficiently eradicated long-term (13 d) established tumors with 100% of treated animals remaining tumor free for greater than 77 days. Although gene-modified CD4+ and CD8+ were both active in this setting, poor engraftment by CD8+ T cells coupled with the rigorous expansion of CD4+ cells in the Balb/c background suggests that CD4+ T cells may be playing a predominant role in lymphoma rejection in this model. Taken together, the therapeutic effectiveness of aCD19z T cells in this model supports a recently opened phase 1 trial of this receptor in non-Hodgkin lymphoma.
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PMID:Eradication of established B-cell lymphoma by CD19-specific murine T cells is dependent on host lymphopenic environment and can be mediated by CD4+ and CD8+ T cells. 1924 79

Latent membrane antigen 1 and -2 (LMP-1/2)-specific CD8(+) T cells from newly diagnosed and relapsed Hodgkin's lymphoma (HL) patients display a selective functional impairment. In contrast, CD8(+) T cells specific for Epstein-Barr virus (EBV) nuclear proteins and lytic antigens retain normal T-cell function. Reversion to a dysfunctional phenotype of LMP-1/2-specific T cells is coincident with the regression of HL. To delineate the potential basis for this differential susceptibility for the loss of function, we have carried out a comprehensive functional analysis of EBV-specific T cells using ex vivo multiparametric flow cytometry in combination with assessment of antigen-driven proliferative potential. This analysis revealed that LMP-1/2-specific T cells from healthy virus carriers display a deficient polyfunctional profile compared to that of T cells specific for epitopes derived from EBV nuclear proteins and lytic antigens. Furthermore, LMP-specific T-cells are highly susceptible to galectin-1-mediated immunosuppression and are less likely to degranulate following exposure to cognate peptide epitopes and poorly recognized endogenously processed epitopes from virus-infected B cells. More importantly, ex vivo stimulation of these T cells with an adenoviral vector encoding multiple minimal CD8(+) T-cell epitopes as a polyepitope, in combination with a gammaC cytokine, interleukin-2, restored polyfunctionality and shielded these cells from the inhibitory effects of galectin-1.
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PMID:Acquisition of polyfunctionality by Epstein-Barr virus-specific CD8+ T cells correlates with increased resistance to galectin-1-mediated suppression. 1935 66


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