Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha) are potent immunostimulatory cytokines with demonstrated tumoricidal effects in a variety of cancers. With the aim of investigating their ability to generate antitumor immune responses in malignant brain tumors, we describe the use of in situ adenoviral-mediated IFNgamma and TNFalpha gene transfer in glioma-bearing rodents. Survival was prolonged in mice treated with AdmIFNgamma or AdTNFalpha compared to AdLacZ- and saline-inoculated controls, and AdmIFNgamma- or AdTNFalpha-treated animals revealed significantly smaller tumors. These effects were accompanied by significant up-regulation of tumor MHC-I expression in AdmIFNgamma-inoculated animals, and of MHC-II in AdTNFalpha-treated tumors. Significantly enhanced intratumoral infiltration with CD4(+) and CD8(+) T cells was visible in animals treated with AdmIFNgamma, AdTNFalpha, or a combination of AdmIFNgamma and AdTNFalpha. In addition, AdTNFalpha therapy down-regulated the expression of endothelial Fas ligand, a cell membrane protein implicated as a contributor to immune privilege in cancer. These findings demonstrate the effectiveness of local IFNgamma and TNFalpha gene transfer as a treatment strategy for glioma and illustrate possible physiological pathways responsible for the therapeutic benefit observed.
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PMID:Treatment of intracranial glioma with in situ interferon-gamma and tumor necrosis factor-alpha gene transfer. 1238 31

CD4(+) Th cells that are restricted by MHC class II molecules play an important role in the induction of antitumor immune responses. We have established a stable CD4(+) Th cell clone (Th35-1A) from the PBMCs of a patient with primary cutaneous melanoma. The Th cell clone is noncytolytic and proliferates specifically in the presence of irradiated autologous melanoma cells or autologous EBV-transformed B cells pulsed with melanoma tumor cell lysates. Th35-1A produces IFN-gamma (a Th1-type cytokine) after autologous tumor cell stimulation, and its proliferative reactivity is HLA class II-restricted. Th cells showed helper activity for PWM responses of PBMCs. Using a panel of HLA class II-matched and unmatched EBV-B cells as APCs and allogeneic melanoma tumor cell lysate as stimulant, DR7 was delineated as the HLA class II restriction element used by the Th cell clone. In agreement with these results, transfection of an allogeneic melanoma cell line with HLA-DR7 isolated from autologous EBV-B cells rendered the cell line stimulatory for Th35-1A cells. Specificity studies using autologous EBV-B cells (EBV-B35) pulsed with a panel of allogeneic tumor cell lysates of various tissue origins indicated that the Th cell clone recognizes an antigen shared by melanoma and glioma cells. The availability of the Th cell clone may lead to the development of new therapies against melanoma, using adoptive Th cell transfer and/or active immunization with a shared Th cell antigen.
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PMID:A CD4+, HLA-DR7-restricted T-helper lymphocyte clone recognizes an antigen shared by human malignant melanoma and glioma. 1256 60

Central and peripheral tolerance mechanisms are expected to hamper the generation of effective immunity against tumors. To break self tolerance against malignant gliomas, we assessed the therapeutic potential of self/foreign antigen cross-reactivity in an immunocompetent rat glioma model. Immunotherapy of tumors using xenogeneic human glioma membrane proteins (HGP) as a vaccine inhibited tumor growth, whereas no significant effect was obtained with rat glioma membrane proteins (RGP). In contrast to RGP, HGP elicited a specific IgG immune response that cross-reacted with RGP. This immune response was found to be mainly a Th1 type response. On tumor sections stained with hematoxylin and eosin, glioma cells are sparse and apoptotic in HGP-immunized rats, whereas control tumors showed condensed and viable cells. Tumor-specific CTL were induced in HGP-immunized rats. Immunohistochemical analysis revealed that a significant number of CD8(+) and CD4(+) cells infiltrated into tumors from HGP-vaccinated rats, whereas RGP vaccination led to only few tumor-infiltrating T cells. Taken together, the data establish the in vivo applicability of the cross-stimulation between self and foreign antigens as an alternative way to break tolerance against the poorly immunogenic gliomas.
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PMID:Generation of an effective anti-tumor immunity after immunization with xenogeneic antigens. 1259 30

Dendritic cells (DC) are attractive candidates for innovative cancer immunotherapy by virtue of their ability to function as powerful antigen presenting cells and elicit potent antitumor cytotoxic immune responses. With the aim of generating antitumor immunity, the authors sought to enhance in vivo tumor antigen presentation by using an intratumoral DC vaccination strategy in the setting of partially irradiated intracranial brain tumors. Fisher rats, implanted with 9L gliomas in the right corpus striatum, were treated with freshly cultured, unpulsed syngeneic DC inoculated directly into the tumor bed. Intracranially inoculated DCs were found to drain to ipsilateral deep cervical lymph nodes. This was associated with increased local and systemic antitumor cytoxicity, as evidenced by robust infiltration of treated tumors with CD4 and CD8 T cells as well as by increased IFN-gamma protein and message levels in in vitro restimulated splenic lymphocytes. DC therapy resulted in prolonged survival and immunity to subsequent intracranial tumor re-challenge. These results demonstrate the viability of intratumoral DC vaccination as an effective therapeutic strategy for intracranial glioma.
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PMID:Intratumoral dendritic cell vaccination elicits potent tumoricidal immunity against malignant glioma in rats. 1261 2

The aim of our study was to develop and characterize solid brain tumors in Wistar rats, which could be used in investigations concerning the molecular mechanisms that lay beneath the genesis of the gliomas as well as in the testing of curative potentials of various therapeutics. The tumors were induced by intracerebral inoculation of 9L glioma cells and characterized by morphometrical, histological and immunohistochemical analysis after 7, 14 and 21 postimplantation days. Immunohistochemical characterization included detection of the nuclear antigene Ki-67 as the proliferative cell marker, GFAP as a tracer of reactive gliosis surrounding the tumor mass, and CD4/CD8 and ED1 antigens, as markers of the immunological response. Our results showed that after 7 days all experimental animals developed solid, well-circumcised tumors, which were clearly separated from the surrounding brain tissue. Tumors showed progressive growth from the 7th to the 21st day despite the observed immunological response starting after 14 days. Histologically tumors were hypercellular with neovascularization and necrosis. These results indicate that reproducible morphometric evaluation can be performed on 9L tumors growing in immunocompetent Wistar rats, enabling its use as an animal tumor model for the evaluation of various therapeutic approaches.
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PMID:Characterization of 9L glioma model of the Wistar rat. 1281 48

Rat T9.F glioma cells were transduced with the interleukin (IL)-2 gene. Clone T9.F/IL2/#12 secreted a high level of IL-2 (15 ng/10(6) cells/48 h). Enhanced tumor progression and reduced survival was observed when T9.F/IL2/#12 cells were implanted intracranially. Subcutaneous injection of T9.F/IL2/#12 cells induced a palpable nodule, which regressed in approximately 15 days, resulting in tumor-specific protection. Lymphocytes from T9.F/IL2/#12 primed rats specifically respond to T9.F antigens but lacked cytotoxicity towards T9.F cells. Intracranial T9.F/IL2/#12 tumors were markedly infiltrated by CD4(+) and CD8(+) T cells, natural killer (NK)-T cells and myeloid progenitor cells, whereas subcutaneous T9.F/IL2/#12 tumors contained an elevated level of NK cells.
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PMID:Contrasting effects of interleukin-2 secretion by rat glioma cells contingent upon anatomical location: accelerated tumorigenesis in the central nervous system and complete rejection in the periphery. 1286 71

We designed a phase I clinical trial of vaccinations with autologous glioma cells expressing transgene-derived interleukin-4 (IL-4), and treated one patient with a right temporal lobe recurrent glioblastoma. This 62-year-old man underwent craniotomy and partial tumor removal, at which time autologous tumor cells were obtained for vaccine preparation. After confirming the patient's cellular immune function by skin test, two cycles of vaccination with irradiated autologous glioma cells admixed with gene transfected fibroblasts were given intradermally. The patient demonstrated no evidence of allergic encephalitis throughout this course. Immunohistochemistry with biopsy samples taken from the vaccine sites demonstrated that the infiltration level of CD4, CD8 and CD1a positive cells increased proportionally to the amount of IL-4 produced at the each site, suggesting that there was local immune response induced at the vaccine site. While it is premature to assess effectiveness of the vaccine, this initial patient's course suggested a transient response to the vaccine, and he survived 10 months after treatment.
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PMID:Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibroblasts in the treatment of recurrent glioblastoma: preliminary observations in a patient with a favorable response to therapy. 1295 82

Gliomas are the most common primary neoplasm of the central nervous system. The failure of conventional treatment modalities to improve outcome over the last two decades has led to interest in alternative treatment modalities. Dendritic cell (DC)-based immunotherapy has utilized DC pulsed with tumor lysate or peptide to induce an antitumor immune response mediated largely by CD8 T cells. While this has been effective in preclinical studies, clinical efficacy remains unproven. Recently, hybrid cells produced by fusions of tumor and autologous DC have demonstrated remarkable efficacy for stimulating an anti-tumor immune response in both preclinical and clinical studies of extra-cranial neoplasms. The advantage of generating such hybrid cells is that the entire cellular material of the tumor is processed and presented in both endogenous and exogenous pathways. This leads to activation of both MHC class I restricted CD8 cells as well as MHC class II restricted CD4 T cells. Here, we examined in vitro T cell stimulatory capacity of autologous human DC-glioma fusion in comparison to DC loaded with apoptotic glioma. DC fused with autologous tumor or loaded with apoptotic tumor cells (DC/apo) were first used to stimulate autologous non-adherent peripheral blood mononuclear cells (PBMC), in vitro. The PBMC were then examined for phenotype (CD3, CD4, CD8) and intracellular IFN-gamma using flow cytometry. Lymphocyte proliferation and cytolytic responses were also assessed. Lymphocytes stimulated in vitro with fusion or DC/apo cells showed significantly enhanced cytotoxicity and proliferation against autologous tumor cells compared with PBMC stimulated with tumor cells or DC alone. Both strategies had similar efficacy. Tumor-cytolytic responses were enhanced by the addition of CD40 ligand (CD40L), and partially blocked by anti-MHC class I antibody. Flow cytometric analysis detected CD3+ CD8+ T cells, which also stained positive for intracellular IFN-gamma. The study suggests that DC/glioma fusion and DC/apo have comparable efficacy for stimulation of CTL with cytolytic and proliferative activity against human malignant gliomas. These findings may have implications for future studies of DC-based immunotherapy in malignant gliomas.
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PMID:Human autologous dendritic cell-glioma fusions: feasibility and capacity to stimulate T cells with proliferative and cytolytic activity. 1295 98

Human glioblastoma is a highly lethal tumor known for its capability of interfering with effective antitumor immune responses. Costimulatory signals are of critical relevance in both the inductive and effector phases of immune responses. Inducible costimulator-ligand (ICOSL), a member of the B7 family of costimulatory molecules related to CD80/CD86, regulates CD4 as well as CD8 T-cell responses via interaction with its receptor, ICOS, on activated T cells. We report the expression of ICOSL by glioma cells in vitro and in vivo. In contrast to CD80 (B7.1) and CD86 (B7.2), ICOSL protein and mRNA was expressed in 7 of 12 glioma cell lines. ICOSL expression is upregulated by the inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), whereas interferon-gamma (IFN-gamma) has no such effect. Further, immunohistochemical analysis of human brain tumors demonstrates the expression of ICOSL in three of four tissue samples. ICOSL expression is functional in that a neutralizing ICOSL antibody (HIL-131) reduces Th1 and Th2 cytokine levels in cocultures of peripheral blood lymphocytes or T-cell subsets (CD4 and CD8) with glioma cells. However, ICOSL gene transfer into glioma cells does not alter their immunogenicity under primary or secondary alloreactive coculture assays.
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PMID:Expression of the B7-related molecule ICOSL by human glioma cells in vitro and in vivo. 1460 70

PGE(2), synthesized by cyclooxygenase-2 (COX-2)-overexpressing tumor, is known to contribute to cellular immune suppression in cancer patients, but the mechanism remains unclear. We report the mechanism of a CD4(+) T regulatory type 1 (Tr1) induction by CD11c(+) mature dendritic cells (DCs) that phagocytose allogeneic and autologous COX-2-overexpressing glioma. A human glioma cell line, U-87MG, and primary cultured glioblastoma cells (MG-377) overexpressed COX-2. We did not detect IL-10Ralpha expression in these gliomas, and rIL-10 did not suppress their COX-2 expression. Exposure to COX-2-overexpressing glioma induced mature DCs to overexpress IL-10 and decreased IL-12p70 production. These DCs induced a Tr1 response, which is characterized by robust secretion of IL-10 and TGF-beta with negligible IL-4 secretion by CD4(+) T cells, and an inhibitory effect on admixed lymphocytes. Peripheral CD4(+) T cell populations isolated from an MG-377 patient also predominantly demonstrated a Tr1 response against MG-377 cells. Selective COX-2 inhibition in COX-2-overexpressing gliomas at the time of phagocytic uptake by DCs abrogated this regulatory response and instead elicited Th1 activity. COX-2 stable transfectants in LN-18 (LN-18-COX2) also induced a Tr1 response. The effect of a COX-2 inhibition in LN-18-COX2 is reversible after administration of PGE(2). Taken together, robust levels of PGE(2) from COX-2-overexpressing glioma, which is unresponsive to IL-10 within the local microenvironment, may cause DCs to secrete high levels of IL-10. These results indicate that COX-2-overexpressing tumors induce a Tr1 response, which is mediated by tumor-exposed, IL-10-enhanced DCs.
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PMID:Induction of a CD4+ T regulatory type 1 response by cyclooxygenase-2-overexpressing glioma. 1538 64


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