Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dendritic antigen-presenting cells are considered to be the most effective stimulators of T cell immunity. The use of dendritic cells has been proposed to generate therapeutic T cell responses to tumor antigens in cancer patients. One limitation is that the number of dendritic cells in peripheral blood is exceedingly low. Dendritic cells originate from CD34+ hematopoietic progenitor cells (HPC) which are present in the bone marrow and in small numbers in peripheral blood. CD34+ HPC can be mobilized into the peripheral blood by in vivo administration of granulocyte-colony-stimulating factor. The aim of the current study was to determine whether functional dendritic cells could be elicited and grown in vitro from CD34+ HPC derived from bone marrow or granulocyte-colony-stimulating factor-mobilized peripheral blood. Culture of CD34+ HPC with granulocyte-macrophage-colony-stimulating factor and tumor necrosis factor alpha yielded a heterogeneous cell population containing cells with typical dendritic morphology. Phenotypic studies demonstrated a loss of the CD34 molecule over 1 week and an increase in cells expressing surface markers associated with dendritic cells, CD1a, CD80 (B7/BB1), CD4, CD14, HLA-DR, and CD64 (Fc gamma RI). Function was validated in experiments showing that cultured cells could stimulate proliferation of allogeneic CD4+ and CD8+ T lymphocytes. Antigen-presenting capacity was further confirmed in experiments showing that cultured cells could effectively stimulate tetanus toxoid-specific responses and HER-2/neu peptide-specific responses. The derivation and expansion of dendritic cells from cultured bone marrow or granulocyte-colony-stimulating factor-mobilized CD34+ HPC may provide adequate numbers for testing of dendritic cells in clinical studies, such as vaccine and T cell therapy trials.
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PMID:Generation of immunostimulatory dendritic cells from human CD34+ hematopoietic progenitor cells of the bone marrow and peripheral blood. 753 43

Because regional spread to lymph nodes without systemic spread is a relatively common event in squamous cell cancer of the head and neck (SCCHN), it is possible that lymphoid-related receptors or cytokines might directly impact the growth of these tumors. In the present study, we have shown by flow cytometry and Western blotting that the central lymphoid regulatory molecule, CD40, is expressed on the surface of all seven SCCHN tumor cell lines studied. Tumor cell lines also expressed epidermal growth factor (EGF) receptor, MHC class I, and CD95 (Fas) but did not uniformly express other important lymphoid regulatory molecules such as CD80, CD86, or interleukin (IL) 2 receptor components. CD40 ligation by trimeric CD40 ligand (CD40L) resulted in a 20-45% inhibition of tumor cell growth in three of seven cell lines tested. The cytokines IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-11, and IL-15 neither inhibited nor stimulated growth in any of the cell lines tested. EGF had pleiotropic effects on cell growth; it inhibited growth in two cell lines, stimulated growth in one cell line, and had no effect in four cell lines. When coligation by EGF and CD40L was studied, additive or supra-additive growth inhibition was seen in four cell lines. Three cell lines were unaffected by EGF, CD40, or coligation with both reagents. Examination of tumor tissues from 12 previously untreated patients representing a broad spectrum of patients presenting with SCCHN demonstrated CD40 expression in all 12 tumor specimens. This study supports the notion that CD40 is a regulatory molecule for the growth of SCCHN. The important role of CD40-CD40L interactions in the regulation of immune cells in the lymph node and the unique high-level expression of CD40L by these immune cells lend support to the hypothesis that this ligand/receptor pair is an important mediator of cell growth in SCCHN.
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PMID:Surface membrane-expressed CD40 is present on tumor cells from squamous cell cancer of the head and neck in vitro and in vivo and regulates cell growth in tumor cell lines. 1047 14

Thirty HLA-A2 women with metastatic breast cancer received up to 14 vaccinations with MDA-MB-231-CD80, an HLA-A2 allogeneic breast cancer cell line, which had been lipofected with the cDNA for the CD80 costimulatory molecule. Tumor cells were administered with BCG or GM-CSF as an adjuvant. Sera obtained before and after vaccination were analyzed for antibodies to tumor cell lysate, MUC1, HER2/neu and p53. Since the cell line was grown in fetal bovine serum (FBS), sera were also analyzed for antibodies to FBS. Eighteen of 24 patients for whom sera were available exhibited anti-FBS activity at baseline. Eleven of these 18 patients and all six patients without baseline anti-FBS activity showed an increased titer after vaccination. The anti-FBS activity required that serum samples be absorbed in excess FBS to detect specific antibodies to tumor cell lysate. A two-fold increase in the titer of IgG specific to tumor cell lysate was observed in 6 patients. Eight of 24 patients made an antibody response to HER-2/neu, four of 24 to MUC1 and one of 24 to p53. Although antibody production to a variety of tumor cell-associated antigens was detected our results suggest that a whole cell vaccine comprising a CD80-transfected allogeneic breast cancer cell line with adjuvant BCG or GM-CSF was not a reliable method to induce significant antibody responses in women with advanced breast cancer.
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PMID:Identification of tumor-specific antibodies in patients with breast cancer vaccinated with gene-modified allogeneic tumor cells. 1261 8

DNA vaccines are ideally suited for immunizing against tumor antigens because constructs can be formulated that not only encode the tumor antigen but also encode molecules chosen to improve the ability to elicit an antitumor response. Ligands expressed on antigen-presenting cells associated with stimulating a robust T-cell response are excellent candidates for inclusion in a DNA vaccine. Mice transgenic for the HER-2/neu homologue, rat neu, were immunized with full-length rat neu cDNA given alone or in combination with plasmids encoding costimulatory molecules CD80 or CD86 and the ligand for CD137 (CD137L). Intradermal injection of the plasmid constructs resulted in both plasmid transcript and antigen protein expression being detected in lymph nodes draining the injection site. Immunization with plasmids encoding the neu antigen along with plasmids encoding CD137L and either CD80 or CD86 resulted in the generation of neu-specific antibodies that induced phopshorylation of the neu tyrosine kinase and inhibited the growth of cultured tumor cells overexpressing neu. Survival of animals was significantly prolonged after immunization with vaccines encoding neu together with the costimulatory molecules. Although tumors eventually occurred in the vaccinated animals, they were markedly infiltrated with CD4+ T cells. DNA vaccines encoding neu, when given in combination with both CD137L and either CD80 or CD86, can induce cellular and humoral immunity and result in an antitumor effect.
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PMID:Plasmid-based vaccines encoding rat neu and immune stimulatory molecules can elicit rat neu-specific immunity. 1457 64

Adjuvant treatment is still only working in a small percentage of breast cancer patients. Therefore, new strategies need to be developed. Immunotherapies are a very promising approach because they could successfully attack tumor cells in the stage of dormancy. To assess the feasibility of using an allogeneic approach for vaccination of breast cancer patients, we selected a CD80-transfected breast cancer cell line based on its immunogenic properties. Using CD80+ KS breast cancer cells and human leukocyte antigen (HLA)-A*02-matched peripheral blood mononuclear cells (PBMCs) of breast cancer patients in allogeneic mixed lymphocyte-tumor cell cultures (MLTCs), it was possible to isolate HLA-A*02-restricted cytotoxic T cells (CTLs). Furthermore, a genetically modified KS variant expressing influenza A matrix protein serving as a surrogate tumor-associated antigen (TAA) was able to stimulate flu peptide-specific T cells alongside the induction of alloresponses in MLTCs. KS breast cancer cells were demonstrated to express already known TAAs such as CEA, MUC-1, MAGE-1, MAGE-2, and MAGE-3. To further improve antigenicity, HER-2/neu was added to this panel as a marker antigen known to elicit HLA-A*02-restricted CTLs in patients with breast cancer. Thus, the antigen-processing and antigen-presentation capacity of KS cells was further demonstrated by the stimulation of HER-2/neu-specific CD8+ T cells in PBMCs of breast cancer patients in vitro. These results gave a good rationale for a phase I/II trial, where the CD80+ HER-2/neu-overexpressing KS variant is actually used as a cellular vaccine in patients with metastatic breast cancer. As a proof of principle, we present data from two patients where a significant increase of interferon-gamma (IFN-gamma) release was detected when postvaccination PBMCs were stimulated by allogeneic vaccine cells as well as by HLA-A*02-restricted HER-2/neu epitopes. In whole cell vaccine trials, monitoring is particularly challenging because of strong alloresponses and limited knowledge of TAAs. In this study, a panel of HER-2/neu epitopes, together with the quantitative real time (qRT)-PCR method to analyze vaccine-induced cytokines secreted by T cells, proved to be highly sensitive and feasible to perform an "immunological staging" following vaccination.
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PMID:A CD80-transfected human breast cancer cell variant induces HER-2/neu-specific T cells in HLA-A*02-matched situations in vitro as well as in vivo. 1536 76

Ribonucleic acid (RNA) transfection of dendritic cells (DCs) was shown to be highly efficient in eliciting CD8+ and CD4+ T-cell responses. We analyzed whether electroporation of DCs with RNA coding for a tumor-associated antigen (TAA) would elicit antigen-specific effector cytotoxic T lymphocyte (CTL) responses and whether these responses could be modulated by cotransfection with a second specific synthetic RNA. Therefore in vitro generated human monocyte-derived DCs were electroporated with in vitro transcribed RNA (in vitro transcript, IVT) encoding the TAA HER-2/neu. Additionally, these cells were cotransfected with IVT coding for human 4-1BBL. Transfection of DCs with 4-1BBL-IVT did not alter their typical phenotype. However, it increased the expression of the costimulatory molecules CD80 and CD40. Coadministration of HER-2/neu- and 4-1BBL-IVT resulted in an increased specific lysis of target cells by the in vitro induced CTL lines, indicating that 4-1BBL enhances their ability to elicit primary CTL responses. Interestingly, transfection of DCs with 4-1BBL-IVT did not augment their capacity to stimulate allogeneic lymphocyte responses. The here established approach of cotransfection of DCs with tumor-RNA and a second specific IVT could improve and optimize the in vitro manipulation of DCs for the induction of antigen-specific CTL responses.
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PMID:Cotransfection of dendritic cells with RNA coding for HER-2/neu and 4-1BBL increases the induction of tumor antigen specific cytotoxic T lymphocytes. 1587 82

The specificity and potency of the immune system make immunotherapy a potential strategy for the treatment of cancer. To exploit this potential, we have developed cell-based cancer vaccines consisting of tumor cells expressing syngeneic MHC class II and costimulatory molecules. The vaccines mediate tumor regression in mice and activate human CD4+ T cells in vitro. Previous vaccines were generated by transducing MHC II negative tumor cells with a single HLA-DR allele. Because expression of multiple MHC II alleles would facilitate presentation of a broader repertoire of tumor antigens, we have now transduced tumor cells with the MHC class II transactivator (CIITA), a regulatory gene that coordinately increases expression of all MHC II alleles. Previous studies in mice indicated that coexpression of the MHC II accessory molecule invariant chain (Ii) inhibited presentation of endogenously synthesized tumor antigens and reduced vaccine efficacy. To determine if Ii expression affects presentation of MHC class II-restricted endogenously synthesized tumor antigens in human tumor cells, HLA-DR-MCF10 breast cancer cells were transduced with the CIITA, CD80 costimulatory molecule gene, and with or without small interfering RNAs (siRNA) specific for Ii. Ii expression is silenced >95% in CIITA/CD80/siRNA transductants; down-regulation of Ii does not affect HLA-DR expression or stability; and Ii(+) and Ii(-) transductants activate human CD4+ T cells to DRB1*0701-restricted HER-2/neu epitopes. Therefore, tumor cells transduced with the CIITA, CD80, and with or without Ii siRNA present endogenously synthesized tumor antigens and are potential vaccines for activating tumor-specific CD4+ T cells.
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PMID:Tumor cells transduced with the MHC class II Transactivator and CD80 activate tumor-specific CD4+ T cells whether or not they are silenced for invariant chain. 1642 52